sle depression case study

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A cross-sectional study on the association of anxiety and depression with the disease activity of systemic lupus erythematosus

• Jiafen Liao 1 ,
• Jin Kang 1 ,
• Jia Wang 1 ,
• Qi Tang 1 ,
• Shu Li 1 &
• Xi Xie   ORCID: orcid.org/0000-0002-9296-2324 1  

BMC Psychiatry volume  22 , Article number:  591 ( 2022 ) Cite this article

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Systemic Lupus Erythematosus (SLE) is an autoimmune disease that affects multiple systems and increases the risk of mental disorders such as depression and anxiety. We conducted an observational, single-center, cross-sectional study to investigate the relationship between depression, anxiety, and SLE disease activity.

The Patient Health Questionnaire 9 (PHQ-9) was used to assess depression, and the 7-item Generalized Anxiety Disorders Scale was used to assess anxiety (GAD-7). Using the chi-square/exact Fisher's tests, socio-demographic data, clinical and other characteristics of SLE patients were compared between depression or anxiety and non-depression/non-anxiety groups. To identify optimal levels of Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) for predicting depression or anxiety, receiver-operator curves (ROC) were drawn.

Among the 325 patients involved in this study, patients with depression or anxiety had significantly higher SLE activity ( p  < 0.001), and more frequent musculoskeletal ( p  < 0.05) and neuropsychiatric symptoms ( p  < 0.05). Depression and anxiety are more common in the moderate-severe active group than in the inactive-mild active group (depression: OR 3.350, 95%CI 2.015, 5.570, p  < 0.001; anxiety: OR 4.085, 95%CI 2.493, 6.692, p  < 0.001). The optimal SLEDAI cutoff value of 8.5 predicted depression with a sensitivity of 50.5% and a specificity of 78.4% (AUC 0.660, p  < 0.001) and anxiety with a sensitivity of 54.2% and a specificity of 78.4% (AUC 0.684, p  < 0.001).

SLE disease activity is positively associated with the severity of depression and anxiety. Those patients whose SLEDAI scores are greater than 8.5 are more likely to suffer from mental disorders which require additional attention to them.

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Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease that affects multiple organs and systems. However, apart from the somatic damage, there is an increased risk of mental disorders in SLE patients, including depression and anxiety. A number of studies have been carried out to evaluate the prevalence of depression and anxiety in SLE patients, and results show a wide range of prevalence rates ranging from 2.1–78.6% and 2.9–84.9%, respectively [ 1 ]. However, the diagnosis of depression and anxiety in SLE patients is usually delayed or missed in regular clinical practice.

What’s more, it is demonstrated by plenty of research that the interplay between depression, anxiety, and SLE can lead to an increased incidence of suicidal ideation, poor adherence to treatment, and increased functional disability [ 2 , 3 ] . These factors ultimately play an important role in decreasing patients’ quality of life [ 4 , 5 , 6 ] . With the high prevalence and risk of these mental disorders in SLE patients, it is crucial to early identify patients with anxiety and depression.

There have been numerous researches being intended to figure out the impact factor of depression and anxiety in SLE patients. And a number of factors have been reported to contribute to the higher prevalence. Among them, disease activity is the most frequently explored. However, whether the relationship between depression, anxiety, and disease activity is definite or not is still controversial. Some studies have reported that greater disease activity is linked to a greater risk of depression and anxiety, while others found no association between higher SLE activity and the occurrence of these symptoms.

In light of this, we conducted an observational, single-center, cross-sectional, and descriptive study in patients with SLE, in order to find out the relationship between depression, anxiety, and disease activity.

Study population

This cross-sectional study was conducted between 10 – 17 May 2021 in the outpatient clinic and inpatient department of the second Xiangya Hospital, Central South University, China. Participants in this study were previously diagnosed with SLE according to the 2012 SLICC criteria. The inclusion criteria were (a) age 18 or older; (b) volunteer to participate in this survey; (c) capable of reading and writing; (d) capable of finishing the questionnaire survey by smartphone independently. We excluded participants if they had any of the following items: (a) history of depression or anxiety before the diagnosis of SLE; (b) history of the treatment of mental disease; (c) history of substance abuse; (d) serious disorders of heart, liver, kidney, or other major organs; (e) diagnosed with any disease or impairment that might prevent them from completing the questionnaire independently. All of the participants gave written informed consent and the study was approved by the Second Xiangya Hospital local ethics committee.

Data collection

The questionnaire includes 3 sections. The opening section is socio-demographic data including age, gender, educational levels, annual household income, time of onset of SLE, and history of smoking and drinking. The second section is the SLE disease activity assessment, and the third section is the mental disease activity assessment. It took about 3–5 min for participants to complete the questionnaire.

SLE disease activity assessment

SLE disease activity was assessed by SLE Disease Activity Index 2000 (SLEDAI-2000) [ 7 ] . The SLEDAI-2000 tool is a cumulative and weighted index used to assess disease activity across 24 separate disease descriptors in patients with SLE. All SLE-related descriptors that are present at the time of the visit or within the previous 10 days should be checked off on the form. A total score can fall between 0 and 105, with a higher score representing a more significant degree of disease activity. The results were divided into 4 levels based on the scores: a score between 0–4 is considered disease inactive, a score between 5–9 is considered mildly active, a score between 10–14 is considered moderate activity, and a score of more than 15 is considered severe activity.

Assessment of anxiety/depression

Anxiety was measured by the 7-item Generalized Anxiety Disorders Scale (GAD-7). GAD-7 consists of seven items measuring anxiety symptoms. Each item is scored on a four-point Likert scale (0–3) with higher total scores reflecting greater anxiety severity. The following cut-offs correlate with the level of anxiety severity: a score between 0–4 is considered to be non-anxiety, a score between 5–9 is considered mild anxiety, a score between 10–14 is considered moderate anxiety, and a score more than 15 is considered severe anxiety. The GAD-7 has shown good reliability and construct validity [ 8 ] .

Depression was measured by the Patient Health Questionnaire 9 (PHQ-9). PHQ-9 consists of nine items measuring depressive symptoms corresponding to the diagnostic criteria for major depressive disorder. Each item is scored on a four-point Likert scale (0–3) with scores ranging from 0–27, with higher scores reflecting greater depression severity. PHQ-9 scores more than 0, 5, 10, and 15 represented non-depression, mild, moderate, and severe depression, respectively. PHQ-9 has shown good psychometric properties [ 9 ] .

Statistical analysis

Categorical data were summarized as counts and percentages, while continuous data were reported as the mean and standard deviation. Categorical variables were compared with the chi-square/Fisher’s exact tests, while continuous variables were compared with the Student’s t -test. Receiver-operator curves (ROC) were drawn to identify optimal levels of SLEDAI for predicting depression or anxiety. The statistical analysis was performed using SPSS software for Windows Version 19.0 (SPSS Inc., IL, USA). A p -value less than 0.05 was considered statistically significant.

Characteristics of study subjects

This study enrolled 325 patients. Among them, 61.5% of patients (200/325) had a score reflecting the level of depression with the use of cutoff points in PHQ-9, while 54.4% of patients (177/325) had a score reflecting the level of anxiety with the use of cutoff points in GAD-7. Table 1 summarized the demographic and clinical characteristics. Patients with depression or anxiety significantly more often had moderate-severe SLE activity ( p  < 0.001, p  < 0.001, respectively), musculoskeletal ( p  = 0.002, p  = 0.023, respectively) and neuropsychiatric symptoms ( p  = 0.002, p  < 0.001, respectively). Patients with depression also more often had lower than 50,000 RMB in annual household income compared with those without depression( p  = 0.005). Meanwhile, we found no difference in age, gender, educational levels, time of onset of SLE, history of smoking, and drinking between the depression or anxiety group and non-depression/non-anxiety group.

The relationship between SLE disease activity and depression or anxiety

Among the patients involved in this study, the higher the disease activity, the higher the proportion of depression(Table 2 , Fig.  1 A) or anxiety(Table 3 , Fig.  1 B) in SLE patients, and the difference was statistically significant ( p  < 0.001).

The relationship between SLEDAI and depression or anxiety. 1A. The relationship between SLEDAI and depression; 1B. The relationship between SLEDAI and anxiety

We further investigated the risk of depression or anxiety in SLE patients with different levels of disease activity (Table 4 ). Based on the SLEDAI score, we divided SLE patients into a moderate-severe active group and an inactive-mild active group. The risk of depression or anxiety in both groups is shown in Table 4 . Prevalence of probable depression/anxiety based on PHQ-9/GAD-7 cut-off was significantly higher in the moderate-severe active group compared with those in the inactive-mild active group. (depression: OR 3.350, 95%CI 2.015, 5.570, p  < 0.001; anxiety: OR 4.085, 95%CI 2.493, 6.692, p  < 0.001).

Predicted value of SLEDAI for depression or anxiety in patients with SLE

ROC curve analysis demonstrated an AUC of 0.660 ( p  < 0.001) for SLEDAI as a predictor of depression (Table 5 , Fig.  2 ). The SLEDAI score greater than 8.5 achieved 50.5% sensitivity and 78.4% specificity for predicting depression. Thus, when the SLEDAI score of SLE patients was less than 8.5, patients had a low risk of depression for the present. What’s more, when the SLEDAI score was higher than 8.5 and less than 10.5, patients were prone to mild depression ( p  < 0.001). When the SLEDAI score of SLE patients was higher than 10.5 and less than 14.5, patients were prone to moderate depression ( p  < 0.001). When the SLEDAI score of SLE was greater than 14.5, patients were prone to severe depression ( p  < 0.001).

Receiver-operating characteristic (ROC) curve for SLEDAI in the diagnosis of depression or anxiety. ROC curve for SLEDAI in the diagnosis of mild/moderate/severe depression is shown in Fig. 2A, 2B, and 2C, respectively. ROC curves for SLEDAI in the diagnosis of mild/moderate/severe anxiety are shown in Fig. 2D, 2E, and 2F, respectively

As with ROC analysis for predicting anxiety, we found that the optimal SLEDAI cutoff value of 8.5 showed a sensitivity of 54.2% and a specificity of 78.4% (AUC 0.684, p  < 0.001) (Table 5 , Fig.  2 ). Thus, when the SLEDAI score of SLE patients was less than 8.5, patients had a low risk of anxiety in the present. What’s more, when the SLEDAI score was higher than 8.5 and lower than 10.5, patients were prone to mild anxiety ( p  < 0.001). When the SLEDAI score of SLE patients was higher than 10.5 and lower than 14.5, patients were prone to moderate anxiety ( p  < 0.001). When the SLEDAI score of SLE was higher than 14.5, patients are prone to severe anxiety ( p  < 0.001).

In the past years, depression and anxiety are rarely diagnosed early in their course in SLE, partially due to the lack of reliable and accepted screening metrics in this patient population, but also due to clinicians’ focus on the somatic symptoms. In a study by Mok et al., both depression and anxiety independently impacted the quality of life in SLE patients [ 10 ] . Therefore, finding out the prevalence of depression and anxiety in SLE patients allows us to make a better clinical decision with them. In this study, we analyzed depression and anxiety in SLE patients, and find that the prevalence of probable depression/anxiety based on PHQ-9/GAD-7 cut-off in SLE patients is 54.5% and 61.5%, respectively. These high ratios highlighted the importance of early diagnosis of these mental disorders in SLE patients.

In this study, we demonstrated that family income, disease activity, and manifestation in musculoskeletal and neuropsychiatric systems are related to depression. And in the meantime, disease activity, and manifestation in musculoskeletal and neuropsychiatric systems are associated with anxiety in patients with SLE. In previous studies, various factors have been linked to depression or anxiety in lupus, including age, antibody, fatigue, sleep quality, specific organ involvement, some cytokines, disease activity, glucocorticosteroid use, unemployment, and so on [ 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. These diverse findings indicate that depression and anxiety in lupus are likely mediated through a complex mixture of biological, social, economical, psychological, and environmental contributors.

Of the numerous disease-related factors, the association between SLE disease activity and depression or anxiety remains one of the most frequently studied, though the results between studies are inconsistent. We demonstrated that the ratio of depression and anxiety varies in patients with different levels of disease activity. In fact, the ratio of patients with depression or anxiety in the moderate-to-severe disease activity group is much higher than in the mild disease activity or inactivity group, indicating that lupus disease activity is a risk factor for the severity of depression and anxiety. In line with our study, Nery et al. reported that SLE disease activity measured by SLEDAI was associated with depression severity [ 18 ], and Tay et al.[ 19 ] and Mak et al. [ 20 ] both found that increased SLE activity can be a prediction of more severe anxiety even after adjusting for depressive symptoms. However, Parperis et al. reported that despite the higher SELENA-SLEDAI score in the major depression compared with the group without major depression, this observation was not statistically significant [ 14 ] . In contrast, Jarpa et al. conducted a study showing that common mental disorders including depression and anxiety were not associated with lupus disease activity evaluated by SLEDAI [ 21 ] . This discordance in studies surrounding the effect of disease activity on depression and anxiety may have been attributed to differences in study methodologies, the diversity in screening instruments employed by the different studies, as well as varying definitions used for depression and anxiety disorders [ 22 ] .

The most contributive discovery of our study is the use of the SLEDAI score to predict the likehood of depression and anxiety in patient with SLE. To the best of our knowledge, this is the first study to predict depression and anxiety in SLE patients by disease activity. The discovery of the relationship between depression, anxiety, and SLEDAI score definitely helped rheumatologists better and earlier recognize patients with high risk for mental disorders. In fact, we may estimate depression and anxiety with screening tools in patients with active SLE. And we recommend that screening of depression and anxiety could be a conventional process in SLE patients with SLEDAI scores greater than 8.5. If the GAD-7/PHQ-9 score indicates moderate-severe anxiety/depression, we probably should initiate treatment of anxiety/depression in addition to corticosteroids and immune-suppressive drugs.

Our study had several limitations. First of all, it lacked longitudinal observations of subjects included in this study. Secondly, potential selection bias in who participated in the survey. Thirdly, the correlation of depression/anxiety symptoms with major depression/anxiety was not conducted in this study. Despite the methodological limitations and mixed results presented by the aforementioned studies, our research provides a rationale for future investigations.

In summary, our study indicates that depression and anxiety are common in Chinese SLE patients. Disease activity is positively related to the severity of depression and anxiety. Those patients whose SLEDAI scores are greater than 8.5 are more likely to suffer from mental disorders which may need conventional depression/anxiety screening and corresponding treatment.

Availability of data and materials

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

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This research was supported by the National Natural Science Foundation of China (81873882) and the Hunan Province Natural Science Foundation for Youths (2021JJ40841).

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Department of Rheumatology, the Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China

Jiafen Liao, Jin Kang, Fen Li, Jia Wang, Qi Tang, Ni Mao, Shu Li & Xi Xie

Department of Cardiology, Heart Center of Henan Provincial People’s Hospital, Henan Key Laboratory for Coronary Heart Disease Prevention and Control, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, Henan, China

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XX, JL, JK designed this study, JL, JK, FL, JW collected this data. JL, JK, XX, QL, QT, NM, and SL analyzed data. JL, JK, and XX mainly wrote this manuscript. JW, QT, NM, QL, and SL helped in writing the manuscript. All authors have read and approved the final manuscript.

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Correspondence to Xi Xie .

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The study was approved by the Ethics Committee of the Second Xiangya Hospital of Central South University (XX20200607). All participants gave their written informed consent prior to enrolment in the study. All methods were performed in accordance with the relevant local and national guidelines and regulations.

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Liao, J., Kang, J., Li, F. et al. A cross-sectional study on the association of anxiety and depression with the disease activity of systemic lupus erythematosus. BMC Psychiatry 22 , 591 (2022). https://doi.org/10.1186/s12888-022-04236-z

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Published : 05 September 2022

DOI : https://doi.org/10.1186/s12888-022-04236-z

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• http://orcid.org/0000-0002-2943-0229 Qian Zhao 1 ,
• Haoyang Chen 3 ,
• Lili Wang 1 ,
• Ning Wu 1 ,
• http://orcid.org/0000-0003-2346-8135 Ji Ma 4 ,
• http://orcid.org/0000-0002-1991-8968 Biyu Shen 5 , 6
• 1 Department of Nursing , Shanxi Provincial People's Hospital , Taiyuan , China
• 2 Department of Respiratory and Critical Care Medicine , Liaocheng People's Hospital , Liaocheng , Shandong , China
• 3 Department of Nursing , Nantong University Affiliated Rehabilitation Hospital , Nantong , China
• 4 The Orthopaedic Spinal Ward , Shanxi Provincial People’s hospital , Taiyuan , China
• 5 Department of Nursing , Shanghai Children's Medical Center , Shanghai , China
• 6 School of Nursing , Shanghai Jiaotong University School of Medicine , Shanghai , China
• Correspondence to Ji Ma; Majisxty{at}163.com ; Dr Biyu Shen; shenbiyu{at}126.com

Objective The aim of this study was to explore the effect of depression on pain, disease activity, functional disability and health-related quality of life measured by Visual Analogue Scale, Systemic Lupus Erythematosus Disease Activity Index, Health Assessment Questionnaire and Short Form-36 in patients with systemic lupus erythematosus.

Design Meta-analysis.

Data sources The PubMed, EMBASE, Cochrane Library and Web of Science were searched for obtaining available studies from inception to 7 March 2023.

Eligibility criteria for selecting studies Studies evaluating the impact of depression on pain, disease activity, functional disability and quality of life were included.

Data extraction and synthesis Two authors independently screened publications and extracted data according to set inclusion and exclusion criteria. Statistical analyses were conducted with RevMan V.5.3.0. Data were pooled using a fixed-effects or random-effects model according to heterogeneity.

Results A total of 13 identified studies met the inclusion criteria, reporting on a total of 1911 patients with systemic lupus erythematosus. The Visual Analogue Scale score was significantly higher in patients with depression than those without depression (standardised mean difference (SMD)=0.84 (95% CI 0.27 to 1.42), p=0.004). The Health Assessment Questionnaire score was significantly higher in patients with depression than those without depression (SMD=1.05 (95% CI 0.14 to 1.95), p<0.05). The Systemic Lupus Erythematosus Disease Activity Index score was significantly higher in patients with depression than those without depression (SMD=0.46 (95% CI 0.27 to 0.64), p<0.00001). Scores in most Short Form-36 dimensions (physical function, role physical function, emotional role function, vitality, mental health, social function, general health, physical component scale, mental component scale) were lower in patients with depression than those without depression.

Conclusion This meta-analysis showed that depression was associated with increased in pain, functional disability and disease activity, and decline in health-related quality of life in patients with systemic lupus erythematosus. Awareness of the importance of the relationship between depression in systemic lupus erythematosus patients and pain, functional disability and the quality of life might assist rheumatology physicians and nurses in assessing and preventing these symptoms.

PROSPERO registration number CRD42021265694.

• MENTAL HEALTH
• RHEUMATOLOGY
• Quality of Life

Data availability statement

All data relevant to the study are included in the article or uploaded as supplemental information.

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https://doi.org/10.1136/bmjopen-2022-068683

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STRENGTHS AND LIMITATIONS OF THIS STUDY

A greater number of potentially eligible articles were screened and included in the review.

The study selection, data extraction and quality assessment will be performed by two independent investigators. Disagreements, if any, will be resolved by consulting a third investigator.

The study quality and risk of bias will be comprehensively examined by adopting the Newcastle–Ottawa Quality Scale.

The differences in sample size and population sources between studies may be the reason for the heterogeneity.

Due to the limited number of studies, it is impossible to unify the diagnostic methods of depression.

Introduction

As a chronic inflammatory autoimmune disease, systemic lupus erythematosus (SLE) is characterised by loss of self-tolerance, formation of nuclear autoantibodies and immune complexes, and inflammation of multiple organs. The clinical manifestations of SLE are heterogeneous and can involve one or more organs, including lungs, kidneys and central nervous system, 1–5 which undoubtedly has a negative impact on the quality of life of patients.

In addition to organic symptoms, mental health problems are also common in patients with SLE. 6–16 Nevertheless, mental health problems are often under-recognised and undertreated in patients with SLE. Studies have shown that depression is one of the most common mental illnesses in patients with SLE, and its prevalence ranges from 17% to 75%. 17 The reasons why its prevalence is inconsistent may be the heterogeneity of the population, the difference in sample size and the different evaluation tools. Depression in patients with SLE may be related to high-dose prednisone and lymphocyte abnormalities. 18 19 What is more, depression affects patients’ perception of their symptoms and physical function, and aggravates fatigue, pain and psychological stress, 8 20 which lead to physical disability and decrease quality of life in patients with SLE. 14 21 Due to the long course of the disease and its proneness to recurrent episodes, for depression in SLE, early and accurate diagnosis and reasonable treatment should be carried out which have great significance for controlling the progression of the disease and improving the quality of life of patients.

At present, the relationship between depression and treatment outcomes such as pain, disease activity, functional disability and quality of life has not been widely explored. Studies indicated that depression was associated with poor disease activity 14 ; however, another study found that depression had nothing to do with disease activity. 20 Therefore, we conducted this meta-analysis to assess the relationship between depression and pain, disease activity, functional disability and quality of life in patients with SLE, so that valuable information for the best management of the disease could be provided.

We conducted a literature search for studies that assessed the effect of depression on disease activity and health-related quality of life (HRQoL) among patients with SLE. The systematic review and meta-analysis is reported based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement provided by the Cochrane Collaborative. 22 23 The selected search strategy and analysis method have been registered in the PROSPERO database (CRD42021265694) and the last search was conducted on 7 March 2023.

Search strategy

The PubMed, EMBASE, Cochrane Library and Web of Science were searched for obtaining available studies from inception to 7 March 2023. In the search, the following keywords and subject words were used: (Depress* OR Depress* disorders OR Dysthymi* OR Mood disorders) AND (Systemic lupus erythematosus OR SLE). See online supplemental appendix 2 for detailed search strategy.

Supplemental material

Inclusion and exclusion criteria.

The study inclusion criteria were as follows: (a) studies on patients with SLE diagnosed on the basis of American College of Rheumatology and/or Systemic Lupus International Collaborating Clinic (SLICC) 2012 classification criteria for SLE; (b) studies that enrolled participants aged ≥18 years; (c) studies that use validated methods to evaluate depression, pain, disease activity, functional disability and quality of life; (d) outcome variables must include at least one of the following variables: depression, pain, disease activity, functional disability and quality of life; (e) the type of studies was cross-sectional, cohort or longitudinal; (f) the article was published in English.

Different evaluation tools for the outcome indicators are used. The pain Visual Analogue Scale (VAS) is a self-reported measure of pain intensity which uses a straight line without any division, and marks the pain at both ends of the straight line with scores ranging from 0 (‘no pain’) to 10 (‘worst pain in my life’). 24 The disease activity was assessed by SLE Disease Activity Index (SLEDAI), which ranges between 0 and 105: 0, no activity; 1–5, mild activity; 6–10, moderate activity; 11–19, high activity; and ≥20, very high activity. 25 Quality of life was evaluated with Short Form-36 (SF-36). It is composed of eight domains, four of which are physical (physical function, role physical function, body pain and general health) and the other four are mental (social function, role emotional function, mental health and vitality) components. The scales physical and mental component summary (PCS, MCS) scores range from 0 (means the worst quality of life) to 100 (means the best quality of life). Impaired SF-36 subscale scores on each SF-36 domain were determined as values lower than the mean values observed for the entire study population. 26

The study exclusion criteria were as follows: (a) studies with overlapping or insufficient data; (b) the types of study were review, conference and case reports; (c) the type of study was not cross-sectional design.

Data extraction and study quality assessment

Two independent researchers searched and eliminated duplicate studies. They independently read the title and abstract of the articles so that they could exclude articles that did not meet the inclusion criteria. Then, they read the full text of the remaining studies mentioned above to determine the final article to be included. If it was unclear whether the study met the inclusion criteria, a third investigator was asked for their opinion and an agreement was reached afterwards. The following information was extracted from each study: author, year of publication, country, number of participants, age of participants, disease duration, type of study, assessment tool of depression, diagnostic criteria for SLE and main outcomes.

The quality of each included study was assessed by two independent reviewers through the Newcastle–Ottawa Scale (NOS). 27 It evaluates the quality of primary research based on the three areas used in the research: selection, comparability and exposure. NOS is a 9-point scale that identifies the risk of bias associated with the study design. The ‘star system’ is used to judge research from three broad perspectives: (1) selection of study group (0–4 points for case studies, 0–5 points for cross-sectional studies and cohort studies); (2) comparability of groups (0–2 points for case–control, cohort and cross-sectional studies); (3) determining results (0–3 points for case–control, cohort and cross-sectional studies). The NOS is scored separately according to the study design (case–control/cross-sectional study and cohort study). Studies scoring >7 were considered at low risk of bias, scores of 5–7 indicated moderate risk of bias and scores of <5 indicated high risk of bias. If there were any disagreements between the reviewers, the third reviewer was consulted. A consensus was reached through discussion.

Statistical analyses

The meta-analysis used the RevMan software (V.5.3.0) to analyse data. The standardised mean difference (SMD) and 95% CI of the continuous data were calculated to evaluate the change. The heterogeneity between studies was assessed by I 2 . If I 2 ≥50%, it can be considered that there was heterogeneity between the articles and the random-effects model was used; otherwise, the fixed-effects model was used (I 2 <50%). The Z test was used to assess for overall effect and p<0.05 was considered statistically significant.

Patient and public involvement

Patients and the public were not involved in this study.

Study selection and characteristics of study

A total of 11 717 articles were identified through our search strategy: 1672 articles in PubMed, 4829 articles in EMBASE, 230 articles in the Cochrane Library and 4986 articles in Web of Science ( figure 1 ). Additionally, six articles were identified by searching the reference lists of selected publications. After removing duplicates, the title and abstract of 7126 articles were screened, and 132 were considered eligible for full-text assessment. After further review of the full text, 119 articles were excluded (32 studies had no appropriate outcomes, 11 studies enrolled participants aged below 18 years, 56 studies did not provide sufficient or useful data, 13 studies were reviews or meta-analyses, 7 studies did not have full text available) and 13 studies were included finally, which involved a total of 1911 participants. 14 15 20 21 28–36 The characteristics of the included articles are summarised in the online supplemental table . Four studies were conducted in the America, 20 28–30 two in Egypt, 21 31 three in China, 15 32 36 one in Brazil, 14 one in Turkey, 34 one in Korea 35 and one in Thailand. 33 In terms of outcomes, 12 studies assessed disease activity, 14 15 20 21 28–33 35 36 5 assessed quality of life, 15 28 30 31 34 4 assessed pain by VAS 20 28 29 36 and 2 assessed functional disability by Health Assessment Questionnaire (HAQ). 14 21 The quality assessment using the NOS is shown in table 1 ; NOS ranges from 0 to 9 points—one received 8 points, 32 four received 7 points, 14 18 20 33 six received 6 points 29–31 34–36 and two received 5 points, 15 21 indicating that most studies have moderate methodological quality.

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Quality assessment of the included studies measured by NOS

Four studies 20 28 29 36 involving 666 patients reported pain measured by VAS. A random-effects model was used because the heterogeneity test showed an I 2 of 90% among the studies. There is a significant difference between patients with and without depression with SLE (SMD=0.84 (95% CI 0.27 to 1.42), p=0.004) ( figure 2 ).

Forest plot of pain in patients with depression versus patients without depression with systemic lupus erythematosus.

Functional disability

Two studies 14 21 involving 121 patients reported functional disability measured by HAQ. A random-effects model was used because the heterogeneity test showed an I 2 of 78% among the studies. There is a significant difference between patients with and without depression with SLE (SMD=1.05 (95% CI 0.14 to 1.95), p=0.02) ( figure 3 ).

Forest plot of functional disability in patients with depression versus patients without depression with systemic lupus erythematosus.

Disease activity

Twelve studies 14 15 20 21 28–33 35 36 involving 1798 patients reported disease activity measured by SLEDAI. A random-effects model was used because the heterogeneity test showed an I 2 of 64% among the studies. There is a significant difference between patients with and without depression with SLE (SMD =0.46 (95% CI 0.27 to 0.64), p<0.00001) ( figure 4 ).

Forest plot of disease activity in patients with depression versus patients without depression with systemic lupus erythematosus.

Health-related quality of life

As shown in figure 5 , three studies 15 31 34 were included in this review for physical function, role physical function, body pain, general health, social function, vitality, role emotional function and mental health dimensions of HRQoL in patients with SLE. They were all significantly lower in most domains, with an overall SMD of −1.08 for physical function (95% CI −1.33 to −0.82), –0.81 for role physical function (95% CI −1.24 to −0.38), –0.52 for body pain (95% CI −1.13 to 0.09), −0.75 for general health (95% CI −0.99 to −0.50), –3.31 for PCS (95% CI −5.79 to −0.83), –1.09 for social function (95% CI −1.54 to −0.63), –1.12 for vitality (95% CI −1.37 to −0.87), –1.25 for role emotional function (95% CI −2.06 to −0.44), –0.94 for mental health (95% CI −1.43 to −0.46) and −4.98 for MCS (95% CI −7.79 to −2.17). Due to the heterogeneity between various aspects, the random-effects model is used to estimate the overall effect, instead of the fixed-effects model.

Forest plot of health-related quality of life in patients with depression versus patients without depression with systemic lupus erythematosus. (A) Four domains of PCS (PF, RP, BP and GH) and PCS. (B) Four domains of MCS (SF, VT, RE and MH) and MCS. BP, body pain; GH, general health; MCS, mental component summary; MH, mental health; PCS, physical component summary; PF, physical function; RE, role emotional function; RP, role physical function; SF, social function; VT, vitality.

This is the first meta-analysis to explore the relationship between depression and pain, disease activity, functional disability and HRQoL in patients with SLE. Findings suggest that depression is associated with increased pain, disease activity and functional disability, and reduced quality of life.

The quality of the 13 types of research included in this study is medium, of which 11 display a quality score of ≥6 points, and only 2 researches display 5 points. The inclusion and exclusion criteria of the subjects were clearly stated in the original research, and the diagnostic methods of depression were clearly pointed out in 13 articles. The main outcome indicators and evaluation methods were relatively consistent among the studies, and the heterogeneity was relatively low. Therefore, the quality of the original research included in this study is acceptable. The final meta-analysis results of the outcome indicators are of high reliability and stability, but the methodological quality of some of the original research included is low, which may affect the reliability of the final results.

This systematic review demonstrates that depression is associated with increased pain, which is in line with previous studies. 20 29 The link between pain and mood disorders in rheumatism has long been established. The latest understanding of this interface shows the contribution of biological and psychological factors. The relationship between pain and depression is complex and is likely to be two way. The presence of pain can cause many depressive symptoms, including lack of happiness, poor sleep quality, fatigue, etc. 37 , 38 Furthermore, research had indicated that in terms of treatment, for arthritis patients with depression, improvements could be made not only in emotional well-being but also in reducing pain, enhancing functional status, and increasing quality of life.

In previous studies, the relationship between disease activity and depression is not quite clear. Some scholars believe that depression is related to increased disease activity, 14 15 21 while some studies have shown that depression has nothing to do with disease activity. 20 The results of this study show that depression is associated with higher disease activity. The reason for such a result is that increased disease activity may lead to pain and depression, which in turn increases fatigue. What is more, studies have shown that the SLEDAI scores were a strong predictor of depression in patients with SLE. 15

It was found in this study that patients with depression with SLE have poorer SF-36 scores than those without depression with SLE, particularly in physical function, limited emotions, energy, fatigue and emotional well-being, all of which have an impact on quality of life. Dietz et al have the same discovery and documented that depression is associated with low HRQoL. 30 A strategy was proposed for coping with this disease: expressing it with daily tasks and hoping for a better life. Therefore, in daily clinical practice, the high quality of life of patients with SLE is related to depression and fatigue to varying degrees.

There are several limitations in the current meta-analysis. This meta-analysis is limited by a small number of studies that provide appropriate data to allow statistics to aggregate the results. When a summary estimate of correlation is obtained, and there is heterogeneity, it should be interpreted with caution. The potential sources of heterogeneity are differences in source populations, sampling methods and adjustments to confounding factors between different studies. The heterogeneity may reduce the generalisation of results. Therefore, a random-effects model is used. Thus, high-quality and more rigorously designed research with a large sample size will be needed in the future.

Ethics statements

Patient consent for publication.

Not required.

Ethics approval

Not applicable.

Acknowledgments

We would like to thank Xiaoyu Chen and Teng Zhang for their assistance with this study.

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Supplementary materials

Supplementary data.

This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

• Data supplement 1
• Data supplement 2

QZ, XL and HC are joint first authors.

QZ, XL and HC contributed equally.

JM and BS contributed equally.

Contributors QZ, XL and HC—data curation, formal analysis, methodology, writing (original draft) and writing (review and editing). LW—conceptualisation, formal analysis and writing (review and editing). NW—conceptualisation and writing (review and editing). JM and BS—resources, writing (review and editing), supervision and funding acquisition. BS is responsible for the overall content as the guarantor.

Funding This work was supported by the Jiangsu Provincial Commission of Health and Family Planning Foundation (grant number Z201622); Jiangsu Province ‘333 high-level talent training project’ Foundation (grant number BRA2016198); Jiangsu Province Youth Medical Talent Foundation (grant number QNRC2016409); Jiangsu Province six talent peak high-level personnel training project Foundation (grant number WSN-234); and Nantong Science and Technology Plan Project (grant number MS12019007).

Competing interests None declared.

Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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Anxiety and Mood Disorders in Systemic Lupus Erythematosus: Current Insights and Future Directions

• Health Economics and Quality of Life (N Tsao, Section Editor)
• Published: 12 November 2018
• Volume 20 , article number  85 , ( 2018 )

Cite this article

• Annaliese Tisseverasinghe 1 ,
• Christine Peschken 1 , 2 &
• Carol Hitchon 1  

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33 Citations

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Purpose of Review

Optimal management of anxiety and mood disorders in patients with systemic lupus erythematosus (SLE) is limited by an incomplete understanding of their pathophysiology and a lack of treatment guidelines. This review aims to critically synthesize recent literature on these conditions in adults with SLE, focusing on their etiology, assessment, and management.

Recent Findings

Along with psychosocial factors, there is growing evidence for a bidirectional interaction between inflammatory pathways and SLE-associated anxiety and mood disorders. Direct immune-mediated mechanisms via autoantibodies may also play a role in some cases. With a growing number of tools used in SLE for the assessment of these conditions, the search continues for the ideal instrument to use in all future investigations to allow comparisons across studies. There is data supporting psychological interventions, but a dearth of literature on pharmacotherapy for the treatment of anxiety and mood disorders in SLE.

There is a clear need for further research in anxiety and mood disorders in SLE, particularly with respect to diagnostic tools and medications, which could inform much-needed updates to current guidelines.

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Annaliese Tisseverasinghe, Christine Peschken & Carol Hitchon

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Tisseverasinghe, A., Peschken, C. & Hitchon, C. Anxiety and Mood Disorders in Systemic Lupus Erythematosus: Current Insights and Future Directions. Curr Rheumatol Rep 20 , 85 (2018). https://doi.org/10.1007/s11926-018-0797-2

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Predictors of Incident Depression in Systemic Lupus Erythematosus

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Objective. Findings from previous studies of predictors of depression among patients with systemic lupus erythematosus (SLE) have been inconsistent. The aim of our study was to identify risk factors that preceded incident depression based on a large, closely followed longitudinal cohort.

Methods. Data regarding 1609 patients with SLE in the Hopkins Lupus Cohort who had no history of depression prior to cohort entry were analyzed. Demographic variables, SLE manifestations, laboratory tests, physician’s global assessment, Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI), cumulative organ damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index), and onset of depression were recorded at enrollment and each quarterly visit. Rates of incident depression were calculated overall, and in subgroups defined by demographic and clinical variables. Adjusted estimates of association were derived using pooled logistic regression.

Results. The incidence of depression was 29.7 episodes per 1000 person-years. In the multivariable analysis, these variables remained as independent predictors of incident depression: recent SLE diagnosis, non-Asian ethnicity, disability, cutaneous activity, longitudinal myelitis, and current prednisone use of 20 mg/day or higher. Global disease activity (SELENA-SLEDAI) was not a significant predictor after controlling for prednisone use.

Conclusion. Depression in SLE is multifactorial. Higher-dose prednisone (≥ 20 mg daily) is 1 important independent risk factor. Global disease activity is not a risk factor, but cutaneous activity and certain types of neurologic activity (myelitis) are predictive of depression. The independent effect of prednisone provides clinicians with an additional incentive to avoid and reduce high-dose prednisone exposure in SLE.

• RISK FACTORS
• SYSTEMIC LUPUS ERYTHEMATOSUS

Neuropsychiatric systemic lupus erythematosus (NPSLE) develops in 17%–75% of patients with SLE during the course of their disease 1 . Although multiple neuropsychiatric manifestations occur in SLE, major depression and cognitive dysfunction are the most common 2 . Depression is frequent in SLE 3 , 4 , 5 , 6 , 7 , 8 , and is more common than in the general population 9 . A diagnosis of depression ranges from 2% to 60%, whereas a diagnosis of major depression ranges from 20% to 47% in SLE 1 . The variability in reported frequency of depression is predominantly attributed to the variety of assessment methods and length of followup 3 . Depression has been linked to poor clinical outcomes in SLE, including increased work disability 10 .

The risk factors for depression in SLE are not adequately understood 4 , 5 , 6 , 7 , 8 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 . SLE activity 7 , 10 , 13 , other neuropsychiatric manifestations 3 , 8 , 15 , 17 , or autoantibodies such as anticardiolipin (aCL) or anti-P lupus antibody 12 , 16 could directly predispose to depression. Depression could also be a secondary phenomenon caused by other manifestations of the disease (for instance, pain and arthritis 19 ), by corticosteroid therapy 24 , or as an emotional reaction to the chronicity or social stress caused by having SLE 1 . The results from past studies are inconsistent, with some studies finding no association between depression and disease activity 4 , 6 , 11 , 18 , 20 , other neuropsychiatric manifestations 6 , autoantibodies [e.g., anti-P 6 , 20 , antiphospholipid antibodies (aPL) 23 ], or corticosteroid usage 10 , 18 . One previous analysis found that depression was associated with secondary Sjögren syndrome 8 .

Besides the inconsistencies in previous studies, most prior studies have been cross-sectional, making it difficult to distinguish between the factors that preceded depression versus those that occurred after depression. Here, we report the results of a longitudinal study of incident depression in a large prospective cohort of patients with SLE without prior depression. Using this cohort, we estimated the incidence rate of first depression occurrence, and compared the incidence in subsets of SLE defined by candidate risk factors, including socioeconomic status, SLE disease activity, clinical manifestations, autoantibodies, and medication use.

• MATERIALS AND METHODS

Patients and study design

The analysis was based on data from the Hopkins Lupus Cohort, begun in 1987. The study was approved on a yearly basis by the Johns Hopkins University School of Medicine Institutional Review Board. All patients gave written informed consent. At cohort entry, a comprehensive medical history, including demographic variables, clinical manifestations, laboratory tests, and treatment was obtained from the medical records and the patient. At each quarterly clinic visit, a battery of laboratory tests were performed, including a complete blood count, urinalysis and urine protein/creatinine ratio, comprehensive metabolic panel, erythrocyte sedimentation rate, serum creatinine, complement factor 3 (C3) and C4 levels, anti-dsDNA, and multiple measures of aPL (lupus anticoagulant by dilute Russell’s viper venom time with confirmatory studies, and aCL IgG, IgM, and IgA). In addition, cohort members had 1 or more measurements of other immunologic markers related to SLE, including antinuclear antibody, anti-Sm, anti-RNP, anti-Ro, anti-La, and anti-β2 glycoprotein I. At each visit, clinical assessment of disease activity was done using the physician’s global assessment 25 and the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) 26 . The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index 27 was also similarly recorded at the first visit and updated at least every 3 months. This analysis is based on the cohort experience through June 2013.

A patient was considered to have depression if (1) there was a record of persistent depression (2 or more mentions of depression separated by several weeks in rheumatology clinic notes) and/or a diagnosis of affective disorder was made by a psychiatric professional; and (2) treatment for those symptoms with psychotherapy or antidepressant medications was documented. Antidepressant use for reasons other than depression was not counted. All Johns Hopkins Hospital records, outpatient rheumatology records, and psychiatric records were reviewed by 1 rheumatologist. All patients met the ACR neuropsychiatric case definition of major depressive-like episode or mood disorder with depressive features 28 . Other neuropsychiatric manifestations of SLE were defined by the ACR neuropsychiatric case definitions 28 and included seizures, stroke or transient ischemic attack, aseptic meningitis, organic brain syndrome, psychosis, and longitudinal myelitis.

From 1987 to 2013, 2104 patients were in the cohort. Patients who had an episode of depression prior to cohort entry were excluded. Those who had a history of depression, but for whom the onset year was uncertain, were also excluded. For those included, the study was based on the experience of each patient from cohort entry until the patient’s last cohort visit, or at the time of the first episode of depression (whichever came first).

Statistical analysis

To facilitate the analysis, the dataset was formatted to consist of 1 record for every month of followup for each patient. Each record contained the clinical and medication history of the patient up until that time based on information from the most recent quarterly visit. Each person-month record also contained a variable indicating whether new depression had occurred during that month. For some variables (such as anti-Sm, anti-Ro, and anti-La), which were not part of the quarterly battery of tests and were measured only once, we assigned the value of the measurement at that time to all of a patient’s person-months.

To estimate the association between a predictor (e.g., age) and incidence rates of depression, each month was classified into a subgroup based on that predictor (e.g., age 18–39 yrs). Then we estimated the rate of depression per month in each subgroup by calculating the number of incident events of depression divided by the number of person-months observed in that subgroup. Results were converted to rates per person-year. To assess whether associations between risk factors and rates of depression persisted after controlling for potential confounding variables (e.g., age), we applied pooled logistic regression to the monthly data. Pooled logistic regression is a form of discrete survival analysis that is about equivalent to a Cox model. An advantage of this approach is that it facilitates data exploration and incorporation of time-varying predictors 29 . Using this approach, we fit multiple regression models for specific variables, controlling for additional confounders relevant to those specific variables. Finally, we fit a final multivariable model including the variables that were most important in the univariate and multivariate models.

Characteristics of the patients with SLE

The analysis was based on 1609 patients with SLE recruited between 1987 and June 2013. The majority (92%) of this cohort were women, and most were either white (51%) or African American (41%). About 76% of the patients were less than 40 years of age at cohort entry. Over the study, 46% of patients in the cohort were followed up for more than 5 years. The SLICC/ACR Damage Index indicated minimal cumulative organ damage with a score of 0 in 940 patients (58%), 1 in 357 patients (22%), 2–3 in 250 patients (15%), and more than 4 in 62 patients (5%) at cohort entry ( Table 1 ).

• View inline

Characteristics of patients in the Hopkins Lupus Cohort who did not have precohort history of depression.

Rate of incident depression

In our study, 282 (17%) of 1609 patients had a first depression occurrence during the followup. The 1609 patients were observed for a total of 9487 person-years. This equates to an incidence rate of 29.7 episodes per 1000 person-years (95% CI, 26.4 to 33.4; Table 2 ).

Relationship between demographic factors and incident episodes of depression in the Hopkins Lupus Cohort.

Association between demographic factors and depression in the univariate analysis

Rates of incident depression declined consistently with age ( Table 2 ). The rates of depression were found to be 1.4 times higher in patients with disability than in those without (p = 0.0084), and 1.5 times higher in those separated or divorced compared to married individuals (p = 0.021). The rate of depression was significantly lower in patients with college education [rate ratio (RR) = 0.6, p = 0.031], or family income more than $100,000 US (RR = 0.6, p = 0.014). Importantly, depression was substantially (90%) less frequent in those of Asian ethnicity than in others (RR = 0.1, p = 0.018; Table 2 ).

Association between SLE disease duration, activity, non-neuropsychiatric symptoms, and depression in the univariate analysis

The association of SLE disease-related variables and depression is summarized in Table 3 . The rate of incident depression in patients with SLE disease duration more than 3 years was 40% to 60% lower than in those with disease duration less than 3 years (p < 0.0001). The rate of incident depression was 1.6 times higher in patients with SLE with higher current SLE disease activity as measured by a SELENA-SLEDAI score of 5 or more versus 0 (p = 0.0077). The rate of incident depression in patients with SLE with current cutaneous SLE activity was 1.5 times higher than in those without (p = 0.0031). Moreover, the rate of incident depression in patients with SLE with cutaneous SLE activity over the last 12 months was also 1.5 times higher than in those without (p = 0.027). In contrast, there was no significant association between depression and either musculoskeletal activity or renal SLE (p > 0.05).

Relationship between SLE–related disease activities or symptoms and incident episodes of depression in the Hopkins Lupus Cohort.

Association between NPSLE symptoms and depression in the univariate analysis

Of the 282 incident depressions, 183 (65%) occurred in the absence of other neuropsychiatric conditions within the same period of observation. As noted in Table 4 , the rate of incident depression in the months after onset of longitudinal myelitis was 4 times higher than in the other months without a history of myelitis (p = 0.0064). This finding is based on 8 patients with longitudinal myelitis in our cohort, of whom 4 developed depression. We found no association between depression and prior history of any other neuropsychiatric disorders, including seizure, psychosis, organic brain syndrome (encephalopathy), aseptic meningitis, stroke, SLE headache, mononeuritis multiplex, cognitive impairment, cranial or peripheral neuropathy (p > 0.05). Abnormal brain computed tomography (CT) and magnetic resonance imaging (MRI) scans were also not associated with depression (p > 0.05; Table 4 ).

Relationship between neurologic manifestation of SLE and incident episodes of depression in the Hopkins Lupus Cohort.

Association of SLE immunological markers and SLE medication use with depression in the univariate analysis

As noted in Table 5 , we found no significant association between depression and lower C3/C4, anti-dsDNA, anti-Sm, anti-RNP, anti-Ro, anti-La, aCL, or lupus anticoagulant. The rate of incident depression during months with low C3 was 1.3 times higher than during those without low C3, but it did not quite reach statistical significance (p = 0.066). Notably, the rate of incident depression increased significantly as the dose of current prednisone increased. Among those taking 20–39 mg/day, the rate of incident depression was 2.3 times higher than the rate among those not taking prednisone (p = 0.0002). Among those taking 40 or more mg/day, the rate was increased by a factor of 3.1 (RR = 3.1, p = 0.0001). Hydroxychloroquine or immunosuppressive drug use was not associated with and was not protective against depression ( Table 5 ).

Relationship between immunologic variables, medication use, and incident episodes of depression in the Hopkins Lupus Cohort.

Multivariable analyses of independent predictors of incident depression in the Hopkins Lupus Cohort

To tease out the relative importance of correlated risk factors, we fit multivariable models that estimated the association between risk factors and depression, controlling for other variables. In separate multivariate analyses, we found the following results: (1) age was not a significant predictor of depression after controlling for SLE duration; (2) global disease activity (SELENA-SLEDAI) was not a significant predictor after controlling for prednisone use; (3) education and income were strongly related to each other, and neither was a significant predictor after adjusting for the other; and (4) smoking was not a significant predictor after controlling for education and/or income. Thus, in a single full multivariable model, we did not include age, SELENA-SLEDAI, education, and smoking. Estimates from the final multivariate model are shown in Table 6 . We found that the rate of incident depression appeared to decline as the time since SLE diagnosis increased (RR = 0.7, p = 0.0006). East Asians had a significantly lower rate of depression (RR = 0.1, p = 0.031). The incidence of depression declined within recent cohort years (RR = 0.6, p = 0.0008). Notably, disability (RR = 1.4, p = 0.034), cutaneous activity (RR = 1.7, p = 0.0008), history of myelitis (RR = 4.5, p = 0.0033), and prednisone (RR = 2.0, p = 0.0006) were independently associated with a higher risk of incident depression ( Table 6 ).

Independent predictors of incident depression in the Hopkins Lupus Cohort based on a multivariate model.

Depression is frequent in SLE. We observed an incidence rate of 29.7 episodes of depression per 1000 person-years. This rate is substantially higher than the rate reported of 15.9 cases per 1000 person-years based on a study by Eaton, et al 30 of 4 urban sites in the United States (1 of which was Baltimore).

In multivariable analyses, we found that the rate of incident depression was higher within the first 3 years of diagnosis of SLE, after periods of cutaneous disease activity, with current prednisone use, and among those with a history of longitudinal myelitis. It was lower among those who were East Asian or had high socioeconomic status.

Our results showed that depression tended to occur early in the course of SLE. A similar finding was observed with seizure in SLE 31 . The incidence of depression might decline later in the course of SLE as a result of better control of disease activity, less prednisone use, and increased ability to cope over time.

We observed a decline in the incidence of first depression occurrence with older age. Our findings suggest that older patients with SLE who have not had a prior episode of depression are at relatively low risk of developing a first occurrence of depression. Because we were describing incidence of a first episode of depression, it should be noted that this does not imply that depression was less frequent or less prevalent among older patients in our cohort. Also, in this cohort, the association between incidence of depression and younger age appears to be explained by the fact that the rates of depression are highest in the years close to the diagnosis of SLE.

Consistent with a prior study 32 , we found that depression was independently associated with disability in patients with SLE. A previous study showed that patients with SLE and work disability were more likely to have depression, fibromyalgia, and arthralgia 32 . Our multivariate analysis confirmed that disability was associated with depression 10 . Depression was also associated with disability in systemic sclerosis 33 and multiple sclerosis 34 .

We found that East Asians had a significantly lower rate of depression compared with other ethnicities. To our knowledge, this is the first study to find this protective effect of East Asian ethnicity in SLE. The findings of a protective effect of East Asian ethnicity will require independent confirmation, because the East Asian ethnic subgroup in our cohort was small (< 8%) compared to the white and African American groups, and there was only 1 incident depression event in the East Asian group. However, our finding is supported by other studies that found a lower level of depression in East Asians with rheumatoid arthritis (RA) 35 and in the general population 36 , 37 , 38 , 39 . Cross-national comparative community studies found that the prevalence of lifetime depression in Taiwan and Korea was 1.5% and 2.9%, respectively, as opposed to 5.2% in the United States 36 . One study examined data from 10 countries and found that East Asian countries reported the lowest rates (3.0% in Japan), while Western countries reported the highest prevalence of depression (16.9% in the United States) 37 . Pacific Islanders were 3 times more likely to have severe or moderately severe depression compared to East Asians (4.8% vs 1.5%) 38 . The reduced incidence of depression in East Asian patients with SLE, both in our study and in other non-SLE studies cited, might be related to cultural factors affecting the likelihood of acknowledging depression. East Asians who have depression could be less likely to have the disorder detected and treated, which may result in a lower prevalence of depression. However, genetic, biologic, social, and other causative factors require further study 40 .

Prior research 19 showed an association of depression with other symptoms and signs in patients with SLE. The most significant variables associated with depression were pain and arthritis 19 . In our cohort, cutaneous SLE activity was an independent predictor of incident depression in SLE, but we did not observe a strong association between depression and musculoskeletal activity, renal SLE, or global disease activity, after adjustment for corticosteroid exposure in multivariate analysis. The reasons that cutaneous manifestations are most strongly related to depression are unclear. It is possible that cutaneous SLE activity (or sequelae thereof) could lead to psychosocial stress as a precipitant of depression.

We found that longitudinal myelitis was independently associated with a higher risk of incident depression. The independent effect of longitudinal myelitis on depression was based on 4 cases of depression in 8 patients with myelitis. Because myelitis is so rare in SLE, it will be difficult to independently confirm our finding. This statistically significant finding is the first documentation of the association of longitudinal myelitis and depression, although an association of depression with other neuropsychiatric SLE manifestations was found in several studies 3 , 8 , 15 , 17 . Hanly, et al 15 found that patients with SLE with neuropsychiatric syndromes reported more symptoms of depression compared to patients with RA with neuropsychiatric syndromes 15 . Patients with SLE with clinical evidence of recent or previous central nervous system disorder scored significantly higher (more pathology) than did other patients with SLE on the subscales that measure psychotic depression 41 . Utset, et al found that some types of neuropsychiatric SLE (such as seizures, psychosis, aseptic meningitis, poorer cognitive function, and encephalopathy) were independently associated with depression 8 . Lim, et al 4 failed to find a significant association between current and previous neurological disease and psychiatric symptoms.

Depression in the general population (in particular, major depression) has been shown to be accompanied by signs of an immune response and cell-mediated immune activation 42 , which include increased serum levels of soluble CD8 molecule, interleukin 1 (IL-1)-β, the soluble IL-2 receptor, tumor necrosis factor-α, increased numbers of T cell activation markers such as CD3+CD25+, and higher neopterin 42 . In our study, depression was associated only with myelitis and cutaneous activity, and not global activity, serologic activity, or aPL. We found that abnormalities in MRI or CT scans were not associated with depression, confirming a previous study 4 .

The association of disease activity with depression had been previously investigated with conflicting results. Although some prior studies found an association between depression and SLE disease activity 7 , 10 , 13 , other studies found no relation between disease activity and depression 4 , 6 , 11 , 18 , 20 . In our univariate analysis, we found an association of disease activity with depression. However, our multivariable analysis concluded that SLE disease activity was not a significant independent predictor after controlling for prednisone use, which was consistent with the majority of the prior studies 4 , 6 , 11 , 18 , 20 .

The most striking finding in our study was the association of incident depression in SLE with prednisone, in a dose-dependent manner. The effect of corticosteroids on mood (including depression) has been well recognized and suggested to be dose-dependent to some extent in non-SLE disease 43 , 44 , 45 , 46 . The Boston Collaborative Drug Surveillance Program examined psychiatric symptoms in 676 patients free of psychiatric disease prior to steroid treatment and found that severe psychiatric symptoms (psychosis, profound depression, mania) were less frequent (1.3%) at doses of < 40 mg of prednisone daily, but increased to 18.4% at doses > 80 mg of prednisone daily 44 , strongly suggesting that these psychiatric symptoms are dose-dependent. Naber, et al found that 10% of 50 ophthalmologic patients developed depression after receiving high doses of corticosteroids (methylprednisolone and fluocortolone at doses of 119 ± 41 mg/day at baseline and 75 ± 22 mg after 8 days of treatment) 45 . Compared with short-term higher prednisone therapy, longterm therapy might be more associated with depressive than with manic symptoms 47 , 48 .

However, previous studies have been inconsistent with respect to the association of corticosteroids and depression in SLE. In a study of 70 patients, Nery, et al found that patients with SLE with major depression did not differ significantly from patients without major depression based on the mean dose of prednisone 10 . In fact, Denburg, et al found actual improvement in mood following exposure to corticosteroid use (a dose of 0.5 mg/kg of prednisone daily for at least 6 months), but that small study included only 10 women with SLE 49 . In contrast, Shah, et al found an association of depression with corticosteroid use in a retrospective study of claims data in 2717 patients with SLE (p = 0.0443) 24 . Karol, et al found that a current prednisone dose higher than 7.5 mg per day was perhaps associated with depression in patients with SLE, although the association did not reach statistical significance (p = 0.07) 19 . Our findings showed that current prednisone therapy was associated with incident depression in a dose-dependent manner, with the statistical effect of current prednisone dose seen at or above 20 mg/day. Because these higher doses of prednisone are generally used in patients with SLE with higher disease activity, especially renal, central nervous system, and hematologic involvement, our results reinforce the need for noncorticosteroid approaches to control SLE activity, to avoid inducing depression.

The mechanism of the association of depression and corticosteroid use is not well understood. Compared with controls of similar age, sex, ethnicity, education, height, and medical history, the patients treated with corticosteroid may have lower N-acetyl aspartate ratios (a putative marker of neuronal viability) and smaller hippocampal volumes, and greater depressive symptom severity 48 . Increased levels of glucocorticoid hormones — the main product of the hypothalamic pituitary adrenal (HPA) axis — have been considered “depressogenic”. Abnormalities of the HPA axis with hypercortisolemia and elevated plasma cortisol concentrations are found in patients with major depressive disorder, and the effect of corticosteroids on the HPA axis might be a mechanism that induces depression 50 .

We did not find any association of SLE autoantibodies or of low complement with depression. In previous studies, depression has been linked to anti-P 16 . We could not address anti-P, as it was not part of our cohort protocol. In spite of an association of aPL with seizures and headache, Sanna, et al similarly found no association between aPL and depression 23 , which was consistent with our results.

A limitation of our study was that some of the major findings were based on very small numbers of actual events (such as East Asian ethnicity and longitudinal myelitis). In addition, our case finding was based on the ACR neuropsychiatric case definition and not on a prospective DSM-IV interview at every visit. The strengths of our study, including large size, the standardized approach to data collection, and the prospective multiethnic cohort analyses, enabled us to estimate the incidence rate of first occurrence of depression, to assess risk factors before the onset of depression, and to detect the important association with prednisone.

Our results showed that depression in SLE was multifactorial. Depression usually occurred early in the course of SLE, in patients with non-East Asian ethnicity, and was independently associated with prior cutaneous lupus and myelitis activity. Current prednisone therapy was associated with incident depression in a dose-dependent manner. Our findings may help to guide prevention of and management of depression in SLE.

Published online before print August 15, 2014

Supported by a grant from the US National Institutes of Health (NIH AR 43727). Also supported by Grant Number UL1 RR 025005 from the US National Center for Research Resources.

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• Published: 01 November 2022

Mendelian randomization study on the causal effects of systemic lupus erythematosus on major depressive disorder

• Wenchang Li 1 , 2   na1 ,
• Hoktim Kan 3   na1 ,
• Weizhe Zhang 1 , 2 ,
• Yanlin Zhong 1 , 2 ,
• Weiming Liao 1 , 2 ,
• Guiwu Huang 1 , 2 &
• Peihui Wu 1 , 2  

Journal of Human Genetics volume  68 ,  pages 11–16 ( 2023 ) Cite this article

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• Genome-wide association studies
• Systemic lupus erythematosus

The vast majority of epidemiological studies suggested a link between systemic lupus erythematosus (SLE) and major depressive disorder (MDD). However, the causality for SLE on the risk of MDD remained unknown due to confounding factors or reverse causality. Herein, we investigated the causality between SLE and MDD in those of European ancestry by a Mendelian randomization (MR) approach. Summary genetic data of cases with SLE/MDD were derived from independent largest public genome-wide association study. Forty-six single nucleotide polymorphisms associated with SLE were used as instrumental variables. The main causal inference was carried out using the MRE-IVW method. Additional, reverse-direction MR and multivariable MR analyses were further performed. Result indicated that SLE was causally associated with a lower risk of MDD (using the MRE-IVW method, odds ratio [OR] = 0.983, 95% confidence interval [CI] = 0.974–0.991, p  = 1.18 × 10 −4 ). Complementary analysis found no heterogeneity or horizontal pleiotropy. Multivariate MR analysis yielded consistent results (OR =  0.981; 95% CI = 0.969–0.993; p  = 2.75 × 10 −3 ). Reverse-direction MR analysis suggested non-causal relationship of MDD on the risk of SLE (using the IVW method, OR = 0.846, 95% CI = 0.345–2.072; p  = 0.714). Thus, this is the first study providing evidence of potential causal links between SLE and MDD and further related research is needed.

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Introduction.

Major depressive disorder (MDD) is one of the most severe and common disorders in psychiatry globally and has long been a major societal concern [ 1 ]. MDD affects more than 300 million people of all ages worldwide, and is currently a major contributor to the global disease burden in the general population [ 2 , 3 ]. However, the pathogenesis of MDD is unclear. Twin studies have shown that 30–40% of the variation in MDD can be attributed to genetic factors [ 4 ]. Notably, MDD has long been regarded as a “comorbidity” of several chronic diseases, such as angina, systemic lupus erythematosus (SLE), arthritis and diabetes, which worsens the quality of health substantially compared with when these diseases occur alone [ 5 ].

Psychological disorders in SLE have been investigated in recent decades. The reported prevalence varied widely across several published SLE cross-sectional studies, from 2.1% to 78.6% depending on factors such as study design and diagnostic criteria [ 6 , 7 , 8 , 9 ]. In the vast majority of epidemiological reports, the prevalence of depression in SLE patients was approximately twice that in the general healthy population in clinical and community samples [ 10 ]. SLE accompanied by depression is associated with markedly worse prognosis in physical, mental, and social domains. Given this very close relationship between SLE and MDD, diagnosing and treating MDD may help improve health-related quality of life in individuals with SLE [ 11 ]. However, research and evaluation from observational studies are insufficient to draw conclusions on the cause–effect relationships due to spurious correlations caused by confounders and reverse causality.

Well-designed randomized controlled trials (RCTs)—the gold standard to imply causality—can tackle the potential confounders effectively. However, RCTs take considerable time and might be impractical to initiate due to ethical concerns and financial limitations. As an important complementary causal research approach, Mendelian randomization (MR) uses genetic variants that associate with the exposure as instrumental variables to robustly assess the causality between exposure and outcome, given that certain assumptions including the absence of pleiotropy are met [ 12 ]. Against this background, the purpose of this study is to investigate lifetime prevalence rates of MDD in patients with SLE, which extends previous work by simultaneously assessing the largest GWAS data of MDD in a large sample of SLE patients, using a reliable and validated structured MR approach.

GWAS data sources

This two-sample MR study using publicly available summary statistics of GWAS data on SLE [ 13 ] and MDD [ 14 ]. SLE-related instrumental variables were derived from independent genome-wide relationship studies (GWAS), including 7219 cases and 15,991 controls with European ancestry. Genetic relationships with MDD were obtained from the GWAS data among individuals of European ancestry from the Psychiatric Genomics Consortium database, which comprises 135,458 major depression cases and 344,901 controls. Among them, 59,851 patients with MDD and 113,154 controls were included in the present MR analysis, because genome-wide summary statistics of 23andMe data were not public available (75,607 cases and 231,747 controls). Further details concerning the above studies have been published previously [ 13 , 14 ].

Genetic instrument selection process

SNPs are considered to meet the following three key assumptions [ 15 ]. (1) Genetic variants should be strongly associated with the exposure. The selection of instrumental variables should satisfy the association between SNPs and the corresponding phenotype (systemic lupus erythematosus) ( p  < 5 × 10 −8 ). (2) Genetic variants extracted for exposure should be independent of any confounder. (3) The genetic variants only affect the outcome only through the exposure. In order to meet the following assumptions, SNPs are then filtered through the following steps. Candidate genetic instrumental variables (IVs) that surpassed a conventional genome-wide significance threshold ( p  < 5  ×  10 −8 ) were obtained from a recent GWAS of SLE comprising data on participants with European ancestry. Proxy SNPs were identified at a cut-off of R 2  > 0.8 to replace missing SNPs in the outcome GWAS dataset. If no suitable proxy was available, SNPs were discarded. Linkage disequilibrium (LD) clumping with a clumping window of 10 MB was applied to ensure that these SNPs were individually, and cumulatively, considered as valid instruments for MR analysis (LD R 2  > 0.01) [ 16 ]. F-statistic was used to confirm the strength of IVs, with weak IVs (F-statistic <10) being discarded. In the harmonization process, ambiguous and palindromic SNPs (minor allele frequency >0.42) were excluded. Outlier SNPs with potential pleiotropy was detected by the MR-pleiotropy residual sum and outlier (MR-PRESSO) test and then discard.

Two-sample Mendelian randomization

To perform a robust and reliable inference of the causal relationship between SLE and MDD, in the main analysis, we performed multiplicative random-effect inverse variance weighted (MRE-IVW) analysis [ 17 ]. MR-Egger regression and weighted median constitute statistical tests for the presence of pleiotropic effects of SNPs under analysis and provide a complementary causal estimate [ 18 , 19 ]. The Cochran Q test for the IVW method was implemented to detect heterogeneity [ 20 ]. In detail, no heterogeneity was detected if the p value of the Cochran Q was >0.05 and I 2 was <25%. The leave-one-out test was then performed to assess whether the IVW estimate was biased by the influence of particular single SNPs. Additionally, reverse-direction MR analysis was conducted to examine whether there existed reverse-direction causal relationship. Statistical analyses were performed using R software version 4.0.2 ( https://www.r-project.org/ ) with the two-sample MR package (version 0.5.5).

In addition, each SNP was looked up in the genetic instrument in Phenoscanner ( http://www.phenoscanner.medschl.cam.ac.uk/ ) to determine whether the estimate was violated by potential risk factors verified by other MR studies, including periodontitis [ 21 ], plasma cathepsin B level [ 22 ], gut microbiome [ 23 ], selenium [ 24 ], circulating GDF-15 level [ 25 ], and high serum iron status [ 26 ].

Power calculation

An online publicly available power calculator (mRnd, http://cnsgenomics.com/shiny/mRnd/ ) was utilized to evaluate the power of our study [ 27 ]. For binary outcomes (MDD), after we inputted the required parameters in mRnd (α = 0.05, R 2  = 0.983 in this study), the power of our study was roughly estimated.

Multivariable Mendelian randomization

Taking critical impact of several confounding factors linking SLE to the MDD onset into account, a multivariable MR analysis was applied to estimate the effect of multiple exposure variables on an outcome (MDD in this study). For MVMR analyses, we constructed instruments using SNPs in each of the GWASs meeting our single-variable MR selection criteria, described previously. We combined the SNPs from the relevant GWASs (Body mass index [ 28 ], smoking [ 29 ], drinking [ 29 ] and physical activity [ 30 ]) and removed those SNPs which was missed in one or more datasets, then extracted the SNP effects and corresponding standard errors from the exposures and outcome GWASs. Notably, SNPs with robust information related to both causal SLE and four several confounders (see Supplement table  S4 ) were utilized as IVs for multivariable MR analysis. Inverse-variance weighted method was further used to estimate the causal effect.

Two-sample Mendelian randomization analysis for causal link of SLE with MDD

After the clumping process, 52 LD-independent SNPs for exposure (SLE) remained for further analysis. Among them, 4 outlying SNP (rs1270942, rs13136219, rs501480, rs7768653) in the causality inference was detected based on MR-PRESSO analysis and excluded. Two palindromic SNPs (rs115531193, rs2736332) were detected and removed in the harmonization process. 46 SNP selected as instrumental variables were listed in Supplementary Table  S1 . As shown in Fig.  1 , the overall causal relationship between SLE and MDD (IVW method, OR = 0.983; 95% CI, 0.974 to 0.991; p  = 1.18 × 10 −4 ) was significant. In addition, results from the “leave-one-out” analysis (Fig.  2A ) demonstrated that no single SNP was driving the IVW point estimate. These results indicated that SLE was negatively associated with the risk of MDD. Figure  2B showed the forest plot of pooled MR estimates and individual estimates between SLE-associated IV and the risk for MDD. Finally, conducting reverse MR analysis with available SNPs listed in Supplementary Table  S2 , we gave the evidence that there is not causal effect of MDD on the risk of SLE (IVW method, OR = 0.846; 95% CI, 0.345 to 2.072; p  = 0.714). However, we had limited power (27%) to test significant causal effect of SLE on the risk of MDD, possibly due to small sample size of the MDD GWAS and the ORs for the relationship was relatively limited.

Forest plot of Mendelian randomization analyses for the relevance of systemic lupus erythematosus with risk of major depressive disorder. OR odds ratio, CI confidence interval, MREIVW multiplicative random effects inverse variance weighted method, MR Mendelian randomization, SNP single-nucleotide polymorphism

A Plots of “leave-one-out” analyses for MR analyses of the causal effect of systemic lupus erythematosus with the risk of major depressive disorder (MDD). B Forest plots of instrumental variable Wald ratios and causal effect assesses of the relationship between systemic lupus erythematosus and the risk of MDD observed in the multiplicative random effects inverse variance weighted (MRE-IVW) method-based MR approach. The horizontal lines in the figure represents beta value and its 95% confidence interval [CI] of causal inference, which indicates the genetic effect of the SNP on MDD

Sensitivity analysis

Assessment of sensitivity analysis scores based on IVW analysis were consistent with weighted median and MR-Egger results. Figure  3 shows the scatter plot of the causal effect given by each MR estimator. The MR-Egger regression revealed that directional pleiotropy was unlikely to bias the result (Egger_intercept = −0.004, p  = 0.283). Cochran Q test and the funnel test (Fig.  4 ) indicated no heterogeneity between SLE and MDD (Q value = 43.306, p  = 0.544). And the result of the weighted median further supported the positive relationship, which confirmed that the results were not biased by heterogeneity. Moreover, our results of I 2 value showed the absence of heterogeneity ( I 2  = 0%), indicating increased reliability of MR estimates. The Phenoscanner results of each SNP with the genetic traits are shown in Supplementary Table  S3 . No potential risk factors were detected to violate the robustness of our MR causality estimate.

Single-nucleotide polymorphism (SNP) exposure relationship estimates for systemic lupus erythematosus (SLE) against the SNP-outcome relationship estimates for major depressive disorder (MDD). Causal effect given by each Mendelian randomization (MR) estimator, caveated by issues discussed in the main text. MRE-IVW multiplicative random effects inverse variance weighted method, SNP singlenucleotide polymorphism. The X-axis and Y-axis scale represent the beta value (genetic effect) of the SNP on the risk of SLE and MDD, respectively

Funnel plot showing the inverse variance weighted MR estimate of each systemic lupus erythematosus SNP with estimated major depressive disorder versus 1/standard error (1/SEIV)

Using a threshold of p  < 5 × 10 –8 , those IVs after quality control were utilized to estimate the causal effect in MVMR were listed in Supplement table  S4 . There was strong evidence that SLE was causally associated with a lower risk of MDD, and with MVMR after conditioning with other four traits, the causal relationships was still robust (IVW method, OR = 0.981; 95% CI, 0.969 to 0.993; p  = 2.75 × 10 −3 ). Smoking and BMI was also causally associated with the risk of MDD (IVW method, BMI: OR = 1.085; 95% CI, 1.016 to 1.159; p  = 0.016; Smoking: OR = 1.468; 95% CI, 1.236 to 1.744; p  = 1.23 × 10 −5 ). However, drinking and physical activity were detected insignificant causal effect on the risk of MDD ( p value for drinking is 0.514 and for physical activity is 0.056). In a conclusion, known from the result of MVMR, the causal relationship between SLE and MDD was robust and it wouldn’t be biaed by these confounding factors.

This study obtained partly genetic evidence in support of the potential causal links between SLE and the lower risk of MDD by applying a validated structured MR approach. This relationship was significant in the main MR analyses and consistent across follow-up sensitivity analyses. These findings demonstrated that SLE patients tended to have a lower prevalence of MDD in genetics, which might be contrary to previous observational studies.

Observational studies have reported inconsistent findings on the relationship between SLE and MDD. That MDD was a risk factor on SLE disease activity have been reported in some cohorts, but in other cohorts, MDD prevalence was independent to SLE disease activity [ 31 , 32 , 33 , 34 , 35 ]. Study of Roberts et al. suggested that MDD increases the risk of SLE [ 36 ]. However, another study demonstrated that improving patients’ mood did not significantly ameliorate the disease activity of SLE [ 37 ]. Previous studies reported that serum anti-ribosomal P (anti-RP) titers were significantly more likely to be positive in SLE with MDD than without, implying that anti-RP plays a role in SLE-mediated depression [ 38 ]. In addition, the regulatory relationship of SLE on depression may also be related to neuroinflammation and brain serotonin levels [ 39 , 40 ]. Huang et al. analyzed data from a cohort of 1609 SLE patients who had no history of MDD prior and made a multivariate analysis, suggested that glucocorticoid use and skin manifestations were predictors of depression, but global disease activity of SLE was not. Interestingly, the authors found that the incidence of depression decreased as the time to SLE diagnosis increased, which may be due to better control of disease activity, less prednisone used and coping ability increased over time [ 41 ]. Stojan et al. reported that 59% of SLE patients experienced a significant decrease in BMI within 5 years [ 42 ]. Our study demonstrated that smoking and BMI are clear predictors of MDD and the relationship between lower BMI and lower risk of MDD was verified in our multivariable MR. Undoubtedly, it is necessary to explore the potential causal relationship of MDD to SLE at the gene level.

Some limitations could potentially bias the results of observational studies. Firstly, these observational studies cannot be used as direct evidence of the causal relationship between SLE and depression because of its design. Secondly, most studies used questionnaire reports to define depression, which may deviate from the strict definition of “major depression disorder”. Thirdly, most original reports lacked the assessment of attribution to MDD and fail to exclude confounding factors (such as drugs, smoking, BMI, etc.). Mental and physical health are tightly connected. When depressive symptom coexists with the development of SLE, health-related quality of life, disability, and costs tend to be much worse [ 11 , 43 , 44 ]. The relationship between MDD and SLE may be related to social income and compliance [ 45 , 46 , 47 ].

MR studies use genetic variation as a statistical tool and has been widely used for evaluating causal inference between disease risk factors and exposure outcomes. Our results showed that SLE was associated with the lower risk of MDD and MDD had no significant causal relationship with SLE. To date, this is the first MR study to explore the causal relationship between SLE and MDD. In this two-sample MR study, the potential causal relationship between genetically predicted SLE and MDD was investigated thoroughly. Instrumental variables were chosen from corresponding largest summary statistics of GWAS datasets after a set of rigorous process. Moreover, the absence of pleiotropic and heterogeneity minimized the effects of confounded estimates caused by single SNPs that could affect the outcome on different pathways. In addition, ancestry was controlled by selecting European samples in this MR study may help to minimize bias of the unmatched genetic variants frequencies among different ancestry. This MR analysis showed that SLE may have a mild protective causal relationship with MDD. This contrasts sharply with previous observational studies, thus, the mechanism of the potential protective effect of SLE on MDD needs further exploration.

Several limitations also exit in this study. First, only Europeans ancestry were included, and additional studies should be conducted to confirm whether our findings are generalizable in ethnically. Second, although we have performed multivariate MR analysis for possible potential confounders such as BMI, smoking, drinking, physical activity, we did not obtain gender or drugs information because of using summary data, so the impact of sex hormone or drugs differences on the results cannot be excluded. Although our results are contrary to previous observational studies, it shows that the relationship between SLE and MDD is still very complex, which needs further rigorous disease diagnosis and more detailed classification research.

Data availability

The original contributions presented in the study are included in the article/ Supplementary Material , further inquiries can be directed to the corresponding author.

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Acknowledgements

We thank the authors for providing GWAS data and making the GWAS summary data publicly available.

This study was supported by Science and Technology Planning Project of Guangdong Province (2017B020227005) and Science and Technology Planning Project of Guangdong Province (2019A141401002).

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These authors contributed equally: Wenchang Li, Hoktim Kan.

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Department of Joint Surgery, The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, China

Wenchang Li, Weizhe Zhang, Yanlin Zhong, Weiming Liao, Guiwu Huang & Peihui Wu

Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, China

Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

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WCL, HTK, GWH, and PHW designed the study and drafted the first version of the manuscript. HTK, WCL, GWH, YLZ, and WML conducted data analysis. All authors revised and approved the final version of the manuscript. PHW takes full responsibility for the integrity of the study.

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Correspondence to Guiwu Huang or Peihui Wu .

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Li, W., Kan, H., Zhang, W. et al. Mendelian randomization study on the causal effects of systemic lupus erythematosus on major depressive disorder. J Hum Genet 68 , 11–16 (2023). https://doi.org/10.1038/s10038-022-01080-7

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DOI : https://doi.org/10.1038/s10038-022-01080-7

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Increased risk of depression in patients with discoid lupus erythematosus: a nested, case–control study in the All of Us Research Program

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Gloria F Chen, Katharina S Shaw, Stephanie Sanchez-Melendez, Ruth Ann Vleugels, Jeffrey M Cohen, Increased risk of depression in patients with discoid lupus erythematosus: a nested, case–control study in the All of Us Research Program, British Journal of Dermatology , Volume 189, Issue 5, November 2023, Pages 628–629, https://doi.org/10.1093/bjd/ljad239

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https://doi.org/10.1093/bjd/ljad239

Dear Editor, Discoid lupus erythematosus (DLE) is a chronic, autoimmune skin disease characterized by its ability to cause irreversible scarring, alopecia and disfigurement. While DLE is known to severely impact patients’ quality of life, particularly as it pertains to emotional wellbeing, 1 the association between DLE and clinically diagnosed depression remains poorly characterized as large-scale studies in heterogeneous patient populations are lacking. 2, 3

To bridge this knowledge gap, we performed a nested case–control study of US adults from the All of Us Research Program, a National Institutes of Health database that provides clinical data on a socioeconomically diverse cohort of > 300 000 participants. Using electronic health record (EHR) data shared in All of Us , DLE cases were identified by SNOMED code 200938002, which corresponds to a clinician-assigned diagnosis of DLE. Cases of depression were similarly identified using SNOMED code 370143000. Hypothyroidism, systemic lupus erythematosus (SLE) and anxiety were identified by SNOMED codes 40930008, 55464009 and 21897009, respectively. Smoking status and demographic data were collected from participant-provided survey data.

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Anxiety, Depression Common in People With SLE and Lupus Nephritis

A new study finds anxiety and depression are more common in people with systemic lupus erythematosus (SLE) if they also have nephritis.

Several studies have shown that anxiety and depression are more common in people with systemic lupus erythematosus (SLE), but a new study suggests those mental disorders are even more common in people who have lupus nephritis (LN).

Co-authors Ying Hu, PhD, of the First Affiliated Hospital of Harbin (China) Medical University, and Ge Zhan, PhD, of the First Specialized Hospital of Harbin, said LN remains a major, life-threatening complication of SLE, with as many as 30% of people with LN eventually developing end-stage renal disease (ESRD). In addition, they said it is not uncommon for people with LN to experience anxiety, depression, and suicidality, all of which can affect treatment success and quality of life.

Previous studies have suggested that between one-third and one-half of people with SLE suffer from anxiety and/or depression. But Hu and Zhan said there is limited evidence to describe rates of those disorders among people with LN.

In their new study, published in the journal Immunity, Inflammation and Disease, the 2 investigators outlined the findings from the case-control study, in which they compared 3 cohorts of 50 patients: 1 cohort of people with SLE and LN, 1 cohort of people with SLE without LN, and 1 cohort of healthy controls. All participants were assessed using the Hospital Anxiety and Depression Scales for anxiety (HADS-A) and for depression (HADS-D). The investigators then compared rates to see whether LN increased the odds of anxiety or depression.

The answer, based on these participants, appeared to be “yes.” On the HADS-A, the median score among people with LN was 7.0, with an interquartile range of 6.0-10.0. On the HADS, scores of 7 and below are considered normal; scores of 8-10 represent borderline or mild cases. For people with non-LN SLE, the median score was 6.0. For the control group, the median score was 5.0. The rate of anxiety based on those scales was 38.0%, 28.0%, and 12.0% for people with SLE with LN, SLE without LN, and healthy controls, respectively.

Depression scores were even higher. The median HADS-D score for people with SLE and LN was 7.5, with an interquartile range of 6.0-11.0. The median score for people with SLE without LN was 6.0, and the median score for the control group was 4.0. The authors found a depression rate of 50% in the SLE-with-LN group, 30.0% in the non-LN SLE group, and 10.0% in the control group.

The investigators said possible reasons for the higher rates of anxiety and depression in people with LN could be that people with LN might be more likely to face events like pain, disability, discrimination, and social stress, or that LN brings with it the recruitment of pro-inflammaotry cytokines that could potentially raise the risk of anxiety and depression.

In the study, age, LN activity index scores, alopecia, 24-hour proteinuria, and C-reactive protein were all independently correlated with a higher risk of anxiety. Only 2 of those factors—age and LN activity index—were linked with a higher depression risk.

The authors said their study was limited in size, and it also did not attempt to investigate the underlying pathogenesis of anxiety and depression in these patients. Further studies will be needed in order to explore the pathogenesis of the conditions, Hu and Zhan said.

Still, they concluded that these data suggest that anxiety and depression are a significant concern for people with SLE, and particularly for those with both LN and SLE.

Hu Y, Zhan G. Anxiety and depression prevalence and their risk factors in lupus nephritis patients: a case-control study. ImmunInflamm Dis. 2022;10(9):e689. doi:10.1002/iid3.689

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The Assessment of Anxiety and Depression and its Associated Factors in SLE

Affiliations.

• 1 Queen's University, Kingston, Ontario, Canada.
• 2 University of Toronto Lupus Clinic, Toronto Western Hospital, Centre for Prognosis Studies in the Rheumatic Diseases, Toronto, Ontario, Canada.
• 3 Department of Medicine, UCSF, Philip R. Lee Institute for Health Policy Studies, St, San Francisco, CA 94117, United States.
• PMID: 30255761
• DOI: 10.2174/1573397114666180926101513

Background: Depression and anxiety are common neuropsychiatric complaints in patients with Systemic Lupus Erythematosus (SLE). While numerous studies have been performed to investigate the prevalence, impact, and associated factors of depression and anxiety, current literature presents mixed results. In particular, the prevalence of anxiety and depression varies substantially between studies due to methodological limitations, and heterogeneity in defining anxiety and depression, patient selection, and metrics used. Moreover, there is a lack of studies evaluating the validity, reliability, and interpretability of commonly used screening tools for depression and anxiety in SLE patients.

Result and conclusion: Further investigations should aim to reach a consensus surrounding the role of controversial associated factors in depression and anxiety of SLE patients, while also focusing on the identification of novel factors that have not yet been highlighted in the literature.

Keywords: Systemic lupus erythematosus; anxiety; autoimmune disease; depression; factors; patient-reported outcomes..

Copyright© Bentham Science Publishers; For any queries, please email at [email protected].

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• http://orcid.org/0000-0001-9299-0053 Cynthia Aranow 1 ,
• Cornelia F Allaart 2 ,
• http://orcid.org/0000-0003-0292-9043 Zahir Amoura 3 ,
• http://orcid.org/0000-0003-3047-500X Ian N Bruce 4 , 5 ,
• Patricia C Cagnoli 6 ,
• Walter W Chatham 7 ,
• Kenneth L Clark 8 ,
• http://orcid.org/0000-0001-6712-1585 Richard Furie 1 ,
• James Groark 9 ,
• http://orcid.org/0000-0001-7506-9166 Murray B Urowitz 10 ,
• http://orcid.org/0000-0001-6438-8663 Ronald van Vollenhoven 11 ,
• Mark Daniels 12 ,
• Norma Lynn Fox 9 ,
• Yun Irene Gregan 13 ,
• Robert B Henderson 14 ,
• André van Maurik 14 ,
• http://orcid.org/0000-0002-8413-131X Josephine C Ocran-Appiah 15 ,
• Mary Oldham 16 ,
• David A Roth 17 ,
• Don Shanahan 18 ,
• http://orcid.org/0000-0002-3532-5409 Paul P Tak 19 ,
• http://orcid.org/0000-0001-9920-2195 Yk Onno Teng 20
• 1 Feinstein Institutes for Medical Research, Northwell Health , Manhasset , New York , USA
• 2 Leids Universitair Medisch Centrum , Leiden , The Netherlands
• 3 Assistance Publique–Hôpitaux de Paris, Groupement Hospitalier Pitié–Salpêtrière, French National Referral Center for Systemic Lupus Erythematosus, Antiphospholipid Antibody Syndrome and Other Autoimmune Disorders, Service de Médecine Interne 2, Institut E3M, Inserm UMRS, Centre d’Immunologie et des Maladies Infectieuses (CIMI-Paris) , Sorbonne Université , Paris , France
• 4 Kellgren Centre for Rheumatology, Manchester University Hospitals NHS Trust , Manchester , UK
• 5 Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre , Manchester , UK
• 6 University of Michigan Medical Center , Ann Arbor , Michigan , USA
• 7 University of Alabama at Birmingham , Birmingham , Alabama , USA
• 8 Clinical Science, GSK , Stevenage , UK
• 9 Clinical Development, GSK , Collegeville , Pennsylvania , USA
• 10 Toronto Western Hospital, University of Toronto, Lupus Clinic , Toronto , Ontario , Canada
• 11 Amsterdam University Medical Center, Amsterdam Rheumatology Center , Amsterdam , The Netherlands
• 12 Global Medical Affairs, GSK , Brentford , UK
• 13 Clinical Science Immunology, GSK , Collegeville , Pennsylvania , USA
• 14 Clinical Biomarker Group, GSK , Stevenage , UK
• 15 Clinical Science, Respiratory and Immunology Clinical Research and Early Programs, GSK , Philadelphia , Pennsylvania , USA
• 16 Biostatistics, GSK , Stevenage , UK
• 17 Research and Development, GSK , Collegeville , Pennsylvania , USA
• 18 Development Biostatistics, GSK, GSK House , Brentford , UK
• 19 Research and Development, GSK , Stevenage , UK
• 20 Department of Nephrology, Leiden University Medical Center , Leiden , The Netherlands
• Correspondence to Dr Cynthia Aranow; caranow{at}northwell.edu

Objectives Disease activity control in patients with systemic lupus erythematosus (SLE) with corticosteroid and immunosuppressant withdrawal is a treatment goal. We evaluated whether this could be attained with sequential subcutaneous belimumab (BEL) and one cycle of rituximab (RTX).

Methods In this phase 3, double-blind BLISS-BELIEVE trial (GSK Study 205646), patients with active SLE initiating subcutaneous BEL 200 mg/week for 52 weeks were randomised to intravenous placebo (BEL/PBO) or intravenous RTX 1000 mg (BEL/RTX) at weeks 4 and 6 while stopping concomitant immunosuppressants/tapering corticosteroids; standard therapy for 104 weeks (BEL/ST; reference arm) was included. Primary endpoint: proportion of patients achieving disease control (SLE Disease Activity Index-2000 (SLEDAI-2K) ≤2; without immunosuppressants; prednisone equivalent ≤5 mg/day) at week 52 with BEL/RTX versus BEL/PBO. Major (alpha-controlled) secondary endpoints: proportion of patients with clinical remission (week 64; clinical SLEDAI-2K=0, without immunosuppressants/corticosteroids); proportion of patients with disease control (week 104). Other assessments: disease control duration, anti-dsDNA antibody, C3/C4 and B cells/B-cell subsets.

Results The modified intention-to-treat population included 263 patients. Overall, 16.7% (12/72) of BEL/PBO and 19.4% (28/144) of BEL/RTX patients achieved disease control (OR (95% CI) 1.27 (0.60 to 2.71); p=0.5342) at week 52. For major secondary endpoints, differences between BEL/RTX and BEL/PBO were not statistically significant. Anti-dsDNA antibodies and most assessed B cells/B-cell subsets were lower with BEL/RTX versus BEL/PBO. Mean disease control duration through 52 weeks was significantly greater with BEL/RTX versus BEL/PBO.

Conclusions BEL/RTX showed no superiority over BEL/PBO for most endpoints analysed; however, it led to significant improvements in disease activity markers compared with BEL/PBO. Further investigation of combination treatment is warranted.

Trial registration number NCT03312907 .

• Autoimmune Diseases
• Biological Therapy
• B-Lymphocytes
• Lupus Erythematosus, Systemic

Data availability statement

Data are available upon reasonable request. GSK is committed to publicly disclosing the results of GSK-sponsored clinical research that evaluates GSK medicines, and as such was involved in the decision to submit the results of this study (GSK Study 205646). Anonymised individual patient data and study documents can be requested for further research from https://www.gsk-studyregister.com/en/ .

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:  http://creativecommons.org/licenses/by-nc/4.0/ .

https://doi.org/10.1136/ard-2024-225686

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WHAT IS ALREADY KNOWN ON THIS TOPIC

Achieving low disease activity in the absence of corticosteroids remains an important treatment goal in patients with systemic lupus erythematosus (SLE).

Preliminary studies suggested that sequential therapy with belimumab and rituximab in patients with active SLE may provide clinical benefits with an acceptable safety profile.

WHAT THIS STUDY ADDS

In this robust phase 3 BLISS-BELIEVE study of sequential belimumab and rituximab administration, while the primary and major secondary endpoints were not met, the mean duration of longest disease control was nominally significantly greater in patients treated with belimumab and rituximab sequential therapy compared with belimumab and placebo.

Significant reductions in anti-dsDNA antibody levels, CD19+ B cells and B-cell subsets, were observed with belimumab and rituximab sequential therapy versus belimumab and placebo.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

This is the first randomised study in SLE to prospectively investigate a novel treatment regimen that incorporated a rapid reduction and withdrawal of standard immunosuppressants and thereby it sets the stage for future trials in SLE to aim for the stringent, clinically meaningful endpoint of remission off-therapy.

Introduction

Despite traditional standard therapy (ST), including medications such as corticosteroids, antimalarials and immunosuppressants, a significant proportion of patients with systemic lupus erythematosus (SLE) do not achieve long-term disease control. 1–3 As prolonged exposure to glucocorticoids increases the risk of organ damage accrual, 4 management guidelines recommend tapering corticosteroids to ≤5 mg/day or withdrawing entirely when possible. 3 Furthermore, the treat-to-target principle has been embraced by SLE experts where, besides achieving low disease activity, treatment goals should be remission on-therapy and, even more aspirational, remission off-therapy. 5 6 Notwithstanding these ambitious goals, achieving disease control without corticosteroids remains an unmet treatment goal, but no randomised trial has previously employed these endpoints. 2 These goals could be achieved with disease-modifying therapies targeting the underlying pathogenesis of SLE. 7

B cells play a key role in the pathogenesis of SLE. 8 B-lymphocyte stimulator (BLyS) promotes B-cell activation and differentiation, 9–11 and elevated serum BLyS is associated with higher disease activity, disease relapse and increased numbers of autoantibody-secreting plasma cells. 9 12

Belimumab, a human IgG1λ monoclonal antibody that selectively inhibits soluble BLyS, is approved in combination with ST for treating SLE and lupus nephritis (LN). 13 14 Rituximab, a B-cell-depleting anti-CD20 monoclonal antibody, is used off-label in clinical practice as clinical trials have not demonstrated clinical efficacy. 8 15–18

The scientific justification for sequential therapy with belimumab and rituximab is twofold. Elevated BLyS levels, which occur following B-cell depletion, promote the maturation of autoreactive B cells by allowing them to bypass tolerance checkpoints and enter the immune repertoire. 19–22 Conversely, B-cell reconstitution without high levels of BLyS might result in tolerised B cells without autoreactivity and an enhanced clinical response. This potentially explains the inability of rituximab alone to show superiority over ST in SLE studies. 23 A second rationale for dual therapy is that although rituximab rapidly depletes peripheral B cells, tissue-resident B cells are less affected. 24–26 Thus, since belimumab was shown to increase circulating B-cell levels by either disrupting lymphocyte trafficking and preventing B cells from transmigrating from the blood into tissue or by preventing B cells from being retained at the tissue level, greater B-cell depletion may occur when belimumab is administered before rituximab. 27–34

Three small phase 2 trials, Synbiose (in patients with severe, refractory SLE, of whom the majority had active LN), Belimumab after B cell depletion therapy in patients with SLE (BEAT-LUPUS; in refractory SLE) and The Combination of Antibodies in Lupus Nephritis: Belimumab and Rituximab Assessment of Tolerance and Efficacy (CALIBRATE; in LN), have evaluated the efficacy and safety of rituximab and belimumab sequential therapy in improving disease biomarkers and outcomes, including B-cell depletion. 31 32 35 We have therefore hypothesised that the belimumab/rituximab combination may result in greater B-cell depletion and thus yield better control of disease activity with less need for concomitant immunosuppressants and corticosteroids than belimumab alone. To test this hypothesis, we evaluated the efficacy, safety and tolerability of belimumab with or without a single cycle of rituximab while stopping concomitant immunosuppressants and tapering corticosteroids in adult patients with SLE, using novel and stringent disease control endpoints.

Study design

This phase 3, multicentre, randomised, double-blind, placebo-controlled, 104-week study (GSK Study 205646, NCT03312907 ) was conducted at 71 sites globally between March 2018 and July 2021 ( online supplemental figure S1 ). The study protocol has been published previously. 28

Supplemental material

Eligible patients were ≥18 years of age, fulfilled ≥4 of the 11 American College of Rheumatology classification criteria for SLE, 36 37 and were required to have serum positivity for anti-nuclear antibody (titre ≥1:80) and/or anti-dsDNA antibody (≥30 IU/mL) and an SLE Disease Activity Index-2000 (SLEDAI-2K) score ≥6. Patients with severe LN or severe, active central nervous system lupus were excluded. Full eligibility criteria have been published previously. 28

Randomisation and masking

Patients were centrally randomised in a 1:2:1 ratio to: (1) BEL/PBO arm: subcutaneous (SC) belimumab 200 mg/week for 52 weeks and intravenous placebo at weeks 4 and 6; (2) BEL/RTX arm: belimumab 200 mg/week SC for 52 weeks and rituximab 1000 mg/week intravenous at weeks 4 and 6; or (3) BEL/ST arm: open-label belimumab 200 mg/week SC and ST for 104 weeks. The BEL/ST arm was included to provide an exploratory reference for assessing the relative performance of BEL/RTX versus BEL/PBO. Patients were stratified by their screening SLEDAI-2K score (≤9 or ≥10), immunosuppressant use (yes/no) and corticosteroid dose (prednisone equivalent ≤10 or >10 mg/day).

BEL/PBO and BEL/RTX patients received study treatment until week 52 (primary efficacy endpoint assessment) and then entered a 52-week, treatment-free (no belimumab or rituximab) double-blind observational phase through week 104 to allow assessment of the durability of remission. During the double-blind observational phase, comprehensive clinical assessments were scheduled at week 60, week 64 and every 8 weeks thereafter up to week 104. Data were also collected at any unscheduled visits that occurred. Patients were considered to have failed treatment if they received, at the investigator’s discretion, corticosteroids (>5 mg/day), any immunosuppressants, and/or open-label belimumab ( online supplemental materials ). BEL/ST patients received belimumab and continued their ST throughout the 104 weeks.

Antimalarials, non-steroidal anti-inflammatory drugs (NSAIDs), and/or prednisone-equivalent doses of ≤5 mg/day were allowed within protocol-defined limits in weeks 53 through 104 in all treatment groups.

Discontinuation of immunosuppression and tapering of corticosteroids

All BEL/PBO and BEL/RTX patients discontinued immunosuppressants at or before week 4. Reinitiation of immunosuppressants post week 4 in BEL/PBO and BEL/RTX groups (on the physician discretion) resulted in treatment failure. In the BEL/ST group, an increase of immunosuppressant dose post week 12 resulted in treatment failure. After the initial 12 weeks of study treatment, all treatment groups were required to taper prednisone-equivalent dose to ≤5 mg/day by week 26. Patients were considered treatment failures if their dose exceeded 5 mg/day after week 26 ( online supplemental materials ).

Efficacy endpoints

The primary endpoint was the proportion of patients achieving a state of disease control at week 52, defined as a SLEDAI-2K score ≤2 achieved without immunosuppressants and with a prednisone-equivalent dose of ≤5 mg/day.

Major secondary endpoints were the proportion of patients in clinical remission at week 64, defined as a clinical SLEDAI-2K score of 0 (without a serological activity component) achieved without immunosuppressants and with a prednisone-equivalent dose of 0 mg/day, and the proportion of patients with a state of disease control (defined as per primary endpoint) at week 104. Additional secondary efficacy endpoints included analysis of the primary efficacy endpoint by baseline characteristics (age, race, sex, SLEDAI-2K, use of immunosuppressants, corticosteroid dose, complement 3/4 (C3/C4) and anti-dsDNA antibody levels, BLyS levels, and region). As the BEL/ST arm was open label, the primary and major secondary assessments were conducted by independent blinded assessors (IBA).

Secondary efficacy endpoints that were assessed by principal investigators (PI) included duration of disease control through 52 and 104 weeks in patients achieving disease control at ≥1 time point; time to disease control (defined as per primary endpoint); time to clinical remission (defined as per secondary endpoint); change from baseline in SLEDAI-2K score and the proportion of patients achieving Lupus Low Disease Activity State (LLDAS) 38 39 at weeks 52, 64 and 104.

Time-to-first severe flare was measured through week 104 by a modified SLE Flare Index (SFI), which did not consider severe flares that were triggered only by an increase in SLEDAI-2K score to >12, but included patients classified as a treatment failure by our stringent definition (eg, receiving corticosteroid dose >5 mg/day after week 26, restarting belimumab in year 2 (BEL/PBO or BEL/RTX)), as having a severe flare. Post hoc analyses were also performed to assess disease control at week 52 by baseline proteinuria (≤0.5 g/24 hours vs >0.5 g/24 hours), time to severe flare (modified SFI) without imputing treatment failures as a flare, proportions of patients with proteinuria shift from >0.5 g/24 hours to normal (≤0.5 g/24 hours) and prednisone-equivalent reduction by ≥25% from baseline to ≤7.5 mg/day during weeks 40 through 52.

Biomarker endpoints

Prespecified biomarker endpoints included changes from baseline in IgG, anti-dsDNA antibody and complement C3/C4 levels. Proportions of patients with anti-dsDNA antibody shift from positive at baseline to negative, and with C3/C4 shifts from low at baseline to normal/high were also assessed. B cells and B-cell subsets were assessed by flow cytometric characterisation. Central laboratory testing was used for all biomarker measurements. Biomarker endpoints were assessed statistically at weeks 52, 64 and 104.

Safety endpoints

Safety assessments included adverse events (AEs), serious AEs, AEs of special interest (malignant neoplasms; post-injection/infusion anaphylaxis/hypersensitivity reactions; all infections of special interest (opportunistic infections, herpes zoster, tuberculosis and sepsis); depression/suicide/self-injury) and deaths. AEs are reported on treatment for week 52 (year 1) and on study for week 104 (year 1+2).

Statistical analysis

The target sample size of 280 patients was expected to achieve ≥98% power to detect a treatment difference in the primary endpoint at the 5% two-sided level of significance, assuming response rates of 10% and 35% in the BEL/PBO and BEL/RTX groups (1:2 randomisation), respectively.

All randomised patients who received ≥1 dose of study treatment were included in the intention-to-treat (ITT) population. Efficacy endpoints were assessed using a modified ITT (mITT) population, which comprised the ITT population but excluded 29 patients from the BEL/ST group due to IBAs being potentially unblinded.

Primary and the two major secondary efficacy endpoints were alpha controlled using a prespecified testing order; endpoints could be tested in sequence (two-sided alpha=0.05), provided that statistical significance was achieved in all prior tests. These endpoints were analysed using logistic regression adjusted for baseline SLEDAI-2K score (≤9 or ≥10), immunosuppressant use (use or no use), prednisone-equivalent dose (≤10 mg/day or >10 mg/day) and treatment group. As the primary endpoint was not statistically significant, the p values for the two major secondary endpoints are nominal.

Other endpoints were not adjusted for multiplicity, and all associated p values are nominal.

Patients who met treatment-failure criteria, withdrew or missed assessments (and subsequent data collection was not possible) were regarded as non-responders for primary and secondary efficacy assessments and as experiencing a severe flare for the modified SFI flare endpoint. Other analyses were not alpha controlled; preplanned analyses were performed at weeks 52, 64 and 104.

The post hoc analysis for proteinuria is described in the online supplemental materials .

Biomarker outcomes were performed on observed data for ITT patients who were ongoing after 52 weeks and received both intravenous doses of rituximab or placebo or who remained on open-label belimumab through week 52 (for BEL/ST group) and did not have more than 28 consecutive days from baseline to week 51 without a belimumab dose. Year 1 and 2 analyses used data collected in year 1 before belimumab restart (BEL/PBO and BEL/RTX groups) or discontinuation (BEL/ST group) for patients who completed week 52 on treatment. No imputation was carried out for missing data in these analyses.

Safety endpoints were summarised descriptively.

Patient and public involvement

Patients and/or public were not involved in the design, conduct, reporting or dissemination of this research.

Role of the funding source

This study (GSK Study 205646) was funded by GSK. GSK was involved in designing the study, contributed to the collection, analysis and interpretation of the data, supported the authors in the manuscript development, and funded the medical writing assistance. All authors approved the content of the submitted manuscript and were involved in the decision to submit the manuscript for publication.

Patient disposition and baseline characteristics

Of 396 patients screened, 292 were included in the ITT population and 263 in the mITT population. Overall, 226/292 (77.4%) patients completed the study at week 104, with 215 of these patients having completed the scheduled study treatment up to Week 52. Across all groups, the most common reason for not completing the study was the patient’s decision to withdraw ( figure 1 ).

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Patient disposition summary. mITT population excludes 29 patients from the BEL/ST group, due to IBAs being potentially unblinded. BEL, belimumab; IBA, independent blinded assessor; ITT, intention-to-treat; mITT, modified intention-to-treat; RTX, rituximab; ST, standard therapy.

Baseline characteristics were similar across treatment groups. The mean (SD) glucocorticoid dose was 10.0 (10.49) mg/day; most patients (80.8%) were taking glucocorticoids, followed by antimalarials (79.8%; table 1 ).

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Patient baseline characteristics (ITT population, N=292)

Efficacy results

At week 52, 16.7% of BEL/PBO-treated and 19.4% of BEL/RTX-treated patients achieved disease control, which was not statistically significant ( table 2 ). Of note, 25.5% of BEL/ST-treated patients achieved disease control. The observed differences in individual components of disease control between BEL/RTX and BEL/PBO groups are summarised in online supplemental table S1 , and the first reasons for not achieving disease control at Week 52 in online supplemental table S2 .

Summary of primary and major secondary efficacy endpoints, based on IBA assessment (mITT population,* N=263)

Proportions of patients off-treatment achieving clinicalremission at week 64 or disease control at week 104 showed no statistically significant differences between BEL/RTX and BEL/PBO ( table 2 ). The most common first reason for not achieving disease control at week 104 was continuation or restart of belimumab at the investigator’s discretion ( online supplemental table S2 ). In the ITT population, including those for whom it was the first reason for not achieving disease control, 54.8% (n=34/62) of BEL/PBO and 50.0% (n=62/124) of BEL/RTX patients continued or restarted belimumab in year 2.

Few patients achieved disease control or clinical remission that was sustained for at least 24 weeks and maintained through week 104, with no significant difference between BEL/RTX and BEL/PBO ( online supplemental table S3 ).

Prespecified subgroup analyses by baseline characteristics for the primary endpoint, disease control at week 52, showed no significant differences. However, there were numerically higher ORs in favour of BEL/RTX versus BEL/PBO for achieving disease control in patients with low C3/C4 levels and anti-dsDNA antibodies ≥30 IU/mL or SLEDAI-2K score ≥10 at baseline ( figure 2 ). When analysed by baseline proteinuria (post hoc) at week 52, disease control was achieved by 18.0% (n=11/61) of BEL/PBO and 20.8% (n=25/120) of BEL/RTX patients with baseline proteinuria ≤0.5 g/24 hours (OR (95% CI) 1.21 (0.54 to 2.71), p=0.6353), and by 9.1% (n=1/11) of BEL/PBO and 12.5% (n=3/24) of BEL/RTX patients with baseline proteinuria >0.5 g/24 hours (OR (95% CI) 1.74 (0.12 to 25.15), p=0.6845).

Disease control* by baseline characteristics subgroups at week 52, based on IBA assessment (mITT population † ; N=263). Note: OR (95% CI) and p value are from a logistic regression model with covariates: baseline SLEDAI-2K, baseline immunosuppressants, baseline prednisone-equivalent dose and treatment group (however, covariates were excluded from the corresponding subgroup models, for example, baseline SLEDAI-2K was not included in analysis by baseline SLEDAI-2K). *Disease control is defined as a SLEDAI-2K score ≤2 achieved without immunosuppressants and with a prednisone-equivalent dose of ≤5 mg/day. † mITT population excludes 29 patients from the BEL/ST group, due to IBAs being potentially unblinded. BEL, belimumab; BLyS, B-lymphocyte stimulator; C3/4, complement 3/4; IBA, independent blinded assessor; mITT, modified intention-to-treat; PBO, placebo; RTX, rituximab; SLEDAI-2K, SLE Disease Activity Index-2000; SLE, systemic lupus erythematosus; ST, standard therapy.

The mean duration of the longest disease control response (prespecified analysis) was significantly greater in BEL/RTX versus BEL/PBO patients through 52 weeks (adjusted treatment difference (95% CI) 47.0 (8.0 to 86.0) days, p=0.0188). Duration of disease control over 104 weeks, including the observational phase where all immunosuppression was stopped, was not significantly different between treatments ( table 3 ). Reductions in SLEDAI-2K scores through 104 weeks were observed in all treatment groups, with a significantly larger reduction observed with BEL/RTX versus BEL/PBO (adjusted treatment difference (95% CI) −1.6 (−2.4 to –0.7), p=0.0003; online supplemental figure S2A ). The odds of achieving LLDAS were not significantly different for BEL/RTX versus BEL/PBO at week 52 or 104 ( online supplemental figure S2B ).

Duration of disease control,* based on PI assessment (mITT population, † N=263)

Reduction from baseline in SLEDAI-2K ≥4 at week 52 by anti-dsDNA antibody and C3/C4 levels is shown in online supplemental table S4 .

SLE severe flares were assessed using a modified SFI as defined. As such, through week 52, 37.5% of BEL/PBO and 36.1% of BEL/RTX patients had a severe SFI flare. Over 104 weeks, this increased to 75.0% and 64.6%, respectively (HR (95% CI) 0.81 (0.57 to 1.13), p=0.2150) ( online supplemental figure S2C ). The median number of days to the first severe SFI flare was 372 in the BEL/PBO group and 379 in the BEL/RTX group. In post hoc analysis of severe flares that did not impute treatment failure, 20.8% of BEL/PBO-treated patients and 15.3% of BEL/RTX-treated patients experienced severe SFI flares over 104 weeks (HR (95% CI) 0.69 (0.36 to 1.34), p=0.2745). Among these patients, the median number of days to first severe flare was 202.0 and 226.5 in the BEL/PBO and BEL/RTX groups, respectively.

Within the small number of patients with proteinuria >0.5 g/24 hours at baseline (BEL/PBO, n=11; BEL/RTX, n=24; BEL/ST, n=9), at week 52, a numerically greater proportion of BEL/RTX-treated patients versus BEL/PBO-treated patients shifted from high (>0.5 g/24 hours) to normal (≤0.5 g/24 hours), but the difference was not significant (p=0.1318; post hoc analysis; online supplemental figure S3A ).

In a post hoc analysis, among patients with baseline prednisone-equivalent corticosteroid dose of >7.5 mg/day, dose reduction by ≥25% from baseline to ≤7.5 mg/day during week 40 through week 52 was observed in 50.0% (n=18/36) of BEL/PBO and 54.7% (n=41/75) of BEL/RTX patients, with no statistical difference (OR (95% CI) 1.29 (0.57 to 2.90), p=0.5379).

By week 52, a decrease from baseline in IgG was observed in all groups, with the greatest decreases observed with BEL/RTX. On belimumab discontinuation from week 52, IgG levels gradually increased but remained below baseline ( online supplemental figure S3B ).

A significantly greater decrease in anti-dsDNA antibodies from baseline was observed with BEL/RTX versus BEL/PBO at weeks 52 (p=0.0495) and 64 (p=0.0230), but not at week 104 (p=0.2501; online supplemental figure S3C ). Among anti-dsDNA antibody-positive patients at baseline (BEL/PBO, 63.6%; BEL/RTX, 71.4%), a significantly greater proportion of BEL/RTX versus BEL/PBO patients shifted to negative at week 52 only (n=18/74, 24.3% vs n=2/35, 5.7%; p=0.0186).

Increases from baseline in median C3 and C4 levels were observed in all groups, particularly BEL/RTX; levels were generally maintained above baseline during the observation phase ( online supplemental figure S3D, E ). Significant differences between BEL/RTX and BEL/PBO for median change from baseline were observed only for C3 levels at week 64 (p=0.0315). Among patients with low C3 levels (BEL/PBO, 43.6%; BEL/RTX, 44.8%) and those with low C4 levels (BEL/PBO, 18.2%; BEL/RTX, 32.4%) at baseline, there was no difference in the shift to normal/high levels between BEL/RTX and BEL/PBO groups.

At week 52, decreases in B cells and B-cell subsets were observed across all three groups, with significantly greater decreases observed with BEL/RTX versus BEL/PBO (p <0.0001) for all assessed B cells and B-cell subsets ( online supplemental figure S4 ). At week 104, the only statistically significant BEL/RTX versus BEL/PBO treatment difference was for memory CD20+ CD27+ B cells (p=0.0026).

Similar proportions of patients across treatment groups experienced on-treatment AEs (year 1) and on-study AEs (years 1+2; table 4 ). Proportions of patients experiencing belimumab-related AEs on-study were 34.7%–38.2% across all treatment groups and study periods ( table 4 ). Infections and infestations were the most frequently reported serious and non-serious AEs by system organ class, experienced by a higher proportion of the BEL/RTX group than other treatment groups ( table 4 ). In year 1, serious infections and infestations occurred in eight, two and one patients in the BEL/RTX, BEL/PBO and BEL/ST groups, respectively.

Summary of AEs and AESI for year 1 and years 1 + 2 (ITT population; N=292)

The incidence of infections of special interest was low, with one patient reporting sepsis in the BEL/RTX group.

Overall, 9 (12.5%) BEL/PBO-treated patients, 16 (11.1%) BEL/RTX-treated patients, and 5 (6.6%) BEL/ST-treated patients experienced psychiatric disorders of special interest and events of depression/suicide/self-injury ( table 4 ). Suicidal behaviour was reported in one patient in each group. No completed suicides were reported. Three deaths were recorded: one in the BEL/PBO group due to cholangiocarcinoma (fatal SAE started on study, but death occurred after study withdrawal) and two on study in the BEL/RTX group (one due to pneumonia and one attributed to ‘sudden death’).

This study addressed a novel treatment approach of adding rituximab to belimumab in patients with active SLE while investigating a rigorous withdrawal of background immunosuppressants and tapering corticosteroids. As such, BLISS-BELIEVE is the first randomised clinical trial in SLE to investigate disease control and remission off-therapy as stringent study outcomes. Similar proportions of BEL/RTX-treated and BEL/PBO-treated patients achieved disease control; therefore, the study’s primary endpoint was not met. However, the study demonstrated that disease control without immunosuppressants and low-dose corticosteroids can be achieved in 16.7%–19.4% of patients with active SLE.

Belimumab and rituximab have complementary mechanisms of action, providing an immunological rationale for their combined use, 28 as supported by case reports showing improvement with belimumab either preceding rituximab in primary Sjögren’s Syndrome (pSS) or following rituximab in pSS, SLE and LN. 30 33 40–43 While the BEAT-LUPUS trial demonstrated a reduced risk of severe flares among patients receiving belimumab after rituximab compared with placebo after rituximab, this was not observed in the present study of belimumab and subsequent rituximab therapy. The two study designs, sizes and populations differed substantially. For example, BEAT-LUPUS, a small phase 2 trial of 52 patients with refractory SLE, incorporated less stringent corticosteroid tapering and permitted immunosuppression. 32 Furthermore, the risk of severe flares was a secondary endpoint, and a different definition of severe flare was used in BEAT-LUPUS; thus, caution is required in comparing findings across the two trials.

In subgroup analyses, disease control rates at week 52 tended to numerically favour BEL/RTX versus BEL/PBO in patients with low C3/C4 and high anti-dsDNA antibody levels at baseline and in patients with baseline SLEDAI-2K score ≥10. Also, a numerically greater improvement in proteinuria was observed with BEL/RTX versus BEL/PBO in a post hoc analysis; however, these data must be interpreted with caution due to small patient numbers.

In the present study, BEL/RTX led to significant reduction in anti-dsDNA antibody levels at week 52 versus BEL/PBO corroborating the primary outcome results of anti-dsDNA antibody levels from the BEAT-LUPUS trial. 32 Similarly, C3/C4 levels increased from baseline to week 104 in all treatment groups, with a trend for larger increases with BEL/RTX at both week 52 and week 104. With respect to B-cell phenotyping, B-cell subsets (such as naïve B cells) decreased within 16 weeks of belimumab treatment in our study and memory B cells rapidly increased in circulation, consistent with observations made in previous studies. 44–46 More recently, the surge in circulating memory B cells following belimumab initiation has been associated with disrupted lymphocyte trafficking. 34 47 As previously demonstrated, the surge of BLyS levels after rituximab treatment can be targeted by sequentially treating with belimumab and vice versa as the memory B-cell surge following initiation of belimumab can be well targeted by rituximab. It remains, however, to be established whether disrupting lymphocyte trafficking and depriving memory B cells of cell-to-cell interactions can adequately modulate memory B cell-mediated immunological processes driving pathology and/or whether depletion of circulating memory B cells is an absolute requirement to impact the pathological pathways driven by this B-cell subset. We favour the latter, as anti-dsDNA antibodies have been shown to be markedly reduced in all randomised studies of sequential therapy, regardless of the order in which belimumab and rituximab are administered. 31 32 35 Significant decreases in anti-dsDNA antibody levels and increases in complement levels were observed in patients with complete depletion of B cells. 48 Successful depletion of B cells was also shown to predict response to rituximab, whereas repopulation of B cells increased the risk of clinical relapse. 48 Therefore, repopulation of B cells or subsets thereof (such as memory B-cells) could potentially act as an important biomarker for personalised treatment decisions when employing B-cell targeted therapies in active SLE.

Thus, the biomarker investigations as secondary outcomes of this study should prompt further studies to address whether changes seen in serological biomarkers and degree of B-cell depletion can be translated to identify a subgroup of patients with SLE that benefit the most from belimumab/rituximab combination therapy.

Safety findings were consistent with the known safety profiles of belimumab and rituximab, although incidences of AEs and serious infections and infestations, and depression were lower than in the BEAT-LUPUS phase 2 study of rituximab followed by belimumab treatment of patients with SLE. 32 Comparable proportions of patients in all treatment groups experienced ≥1 AE during our study. Although incidence of serious infections and infestations was higher in the BEL/RTX group than in other treatment groups, there was no evidence of new or unexpected safety signals using the combination. Nonetheless, the benefit from sequential belimumab and rituximab treatment in any subgroup of patients will need to be balanced against risk of serious infections and infestations.

In the present study, 25.5% of BEL/ST patients achieved disease control at week 52, which was higher than either BEL/PBO or BEL/RTX patients. One could speculate that a less stringent tapering of immunosuppression in the primary comparator groups BEL/PBO and BEL/RTX could have resulted in better disease control. 49 50 The patients in this study had a median disease duration of 7 years and a baseline mean daily corticosteroid dose of 10 mg/day, perhaps making them better suited to a less stringent tapering regimen, further supporting one of the important learnings of this informative study design.

This study has several limitations. Occurrence of severe SFI flare during the 2-year study period was relatively high, due partly to including the stringent study-specific definition of treatment failure (eg, corticosteroids >5 mg/day rather than 7.5 mg/day, restarting belimumab in year 2 (BEL/PBO or BEL/RTX); see online supplemental materials for full definition). Also, the BEL/ST group was included for descriptive reference only and cannot be directly compared with BEL/RTX; though, in real-world practice, belimumab is administered as an add-on to ST. The study aimed to investigate the hypothesis that combined B-cell targeting therapy would be effective without other ST. As such, the present study was not designed to reflect clinical practice accurately, and the use of less stringent tapering of IS, repetitive treatment cycles of rituximab and a comparison with continued BEL/ST would have been counterproductive to the study’s goal to achieve clinical remission off-therapy. BLISS-BELIEVE used SLEDAI-2K in our stringent efficacy outcomes, which, as a binary assessment, does not measure the improvement in symptoms, nor does it capture incomplete improvement in those symptoms. Furthermore, it is difficult to make direct comparisons between the BLISS-BELIEVE study and previous interventional SLE trials, in which response was determined by the SLE Responder Index 4 or British Isles Lupus Assessment Group-based Composite Lupus Assessment.

Primary and major secondary efficacy endpoints used IBA assessments, while other efficacy endpoints and treatment decisions were based on PI assessments. Some residual bias cannot be ruled out, as PIs were not blinded to the BEL/ST reference group.

The BLISS-BELIEVE study incorporated a unique and stringent efficacy endpoint requiring immunosuppression-free disease remission in patients with active SLE, a concept consistent with treat-to-target criteria. 38 50 Although BEL/RTX treatment was not superior to BEL/PBO and the addition of rituximab to patients’ therapy did not improve disease control using the stringent outcome measures employed by this study, there were significant reductions in circulating B-cells and improvement in serological biomarkers. This warrants further investigation to determine if combination with rituximab provides better disease control for patients. Nonetheless, this large, robust study provides valuable information to clinicians to support their treatment decision-making and informs future studies into combination therapy, perhaps with less rapid immunosuppressant tapering.

Ethics statements

Patient consent for publication.

Consent obtained directly from patient(s).

Ethics approval

This study involves human participants and was approved by "Argentina: 1. Framingham Centro Medico 2. Comite de Etica en Investigacion 3. Comité Independiente de Ética Médica del Noroeste Argentino (CIEM-NOA)""Brazil: 1. CEP do Hospital Universitario Julio Muller / MT 2. Fundação Faculdade Regional de Medicina de são José do Rio Preto 3. Hospital Santa Izabel 4. Comitê de Ética em Pesquisa do Hospital Universitário da Universidade Federal de Juiz de For a""Canada: 1. Advarra Institutional Review Board 2. Hamilton Integrated Research Ethics Board 3. University Health Network, Research Ethics Board""France: 1. Comite de Protection des Personnes Nord-Ouest II - CHU d’Amiens Hôpital Nord ""Germany: 1. Ethik-Kommission des Fachbereichs Medizin der Johann Wolfgang Goethe-Universität 2. Ethik-Kommission bei der Ärztekammer Hamburg 3. Ethik-Kommission der Medizinischen Hochschule Hannover 4. Ethik-Kommission der Med. Fakultaet der Christian-Albrechts-Universitaet zu Kiel""Republic of Korea: 1. IRB of Hanyang University Hospital, College of Medicine 2. IRB of Kyungpook National University Hospital 3. IRB of Chonnam National University Hospital, Clinical trial center 4. IRB of Seoul National University Hospital, Biomedical Research Institute 5. IRB of Seoul Saint Mary’s hospital 6. IRB of Inha University Hospital 7. Ajou University Hospital IRB, 5th Floor Annex building""Mexico: 1. Investigación Biomédica para el Desarrollo de Fárm 2. Hospital Centro de Especialidades Médicas CEM""Netherlands: 1. MEC-U""Russian Federation: 1. Republican Clinical Hospital 2. Local Ethics Committee of The State Educational Institution of the Highest Professional Education 3. University of Roszdrav 4. Institute of Cytology and Genetics 5. BUZ Regional Clinical Hospital 6. I.M. Sechenov First Moscow State Medical University, Local Ethics Committee of Federal State Autonomous Educational Institution of Higher Education 7. Chelyabinsk Regional Clinical Hospital 8. Tver Regional clinical hospital 9. Krasnoyarsk State Medical University 10. Local Ethics Committee at “Clinical Hospital #2, City Hospital #8 11. Kemerovo Regional Clinical Hospital 12. Republican Hospital nom Baranov, Ethics comitee 13. Ulyanovsk Regional Clinical Hospital 14. Local Ethics Committee at LLC Research Medical Complex ""Your Health 15. Local Ethics Committee at State Budgetary Institution of Ryazan Region ‘Regional Clinical Cardiology Dispensary 16. City Rheumatology Center, Hospital #25""Spain1. Comité Etico Hospital U. Germans Trias i Pujol""United States: 1. Advarra Institutional Review Board 2. Biomedical Research Alliance of New York, LLC, Institutional Review Board 3. WCG Institutional Review Board 4. Columbia University Medical Center, Institutional Review Board 5. Ochsner Clinic Foundation Institutional Review Board 6. NYU School of Medicine Institutional Review Board" Participants gave informed consent to participate in the study before taking part.

Acknowledgments

The authors would like to thank the participating patients and their families, clinicians and study investigators. Medical writing support was provided by Olga Conn, PhD, of Fishawack Indicia, UK, part of Avalere Health, and was funded by GSK.

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Supplementary materials

Supplementary data.

This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

• Data supplement 1

Handling editor Josef S Smolen

Contributors Conception or design: INB, RF, JG, RvV, NLF, RBH, AvM, MO, DAR, PPT and YOT. Acquisition of data: CA, CFA, ZA, PCC, WWC and MBU. Data analysis or interpretation: CA, CFA, ZA, INB, PCC, WWC, KLC, RF, JG, MBU, RvV, MD, MO, NLF, YIG, AvM, JCO-A, DAR, DS, PPT and YOT. JCO-A is guarantor for this publication (KLC, JG, MD, NLF, YIG, DS, PPT: at the time of the author’s contribution to this study).

Funding This study (GSK Study 205646) was funded by GSK.

Competing interests CA has received research support from GSK; consulting fees from GSK, AstraZeneca, BMS, Kezar Life Sciences Inc., Merck Sharp & Dohme and Alumis Inc. CFA has received research support from Janssen, AbbVie, and Eli Lilly. ZA has received research support from GSK, Roche, AstraZeneca, and Amgen; and consulting fees from GSK, AstraZeneca, Amgen, Kezar Life Sciences Inc, and Novartis. INB has received research support from Genzyme, Sanofi, and GSK; consulting fees from AstraZeneca, Eli Lilly, Aurinia Pharmaceuticals, GSK, and ILTOO; and has served as an advisory board member for AstraZeneca and Merck Serono. INB is a National Institute for Health Research (NIHR) Senior Investigator Emeritus and is funded by the NIHR Manchester Biomedical Research Centre (NIHR203308). PCC has received consulting and speaker fees from GSK, Aurinia Pharmaceuticals, and Eli Lilly. WWC has received research support from GSK, UCB, Amgen, Pfizer, and BMS; consulting fees from GSK and Aurinia Pharmaceuticals; honoraria from GSK and Aurinia Pharmaceuticals for disease awareness presentations and curricula on achieving disease control and remission in SLE. RF has received research support and consulting fees from GSK. MBU has received research support from GSK; consulting fees from GSK and UCB; and speaker fees from GSK, Eli Lilly, and AstraZeneca. RvV has received research support for educational programmes and institutional grants from AstraZeneca, Pfizer, and UCB; consulting fees from AbbVie, AstraZeneca, Biogen, Biotest, BMS, Galapagos, Gilead, Janssen, Pfizer, Sanofi, Servier, UCB, and Vielabio; speaker fees from AbbVie, Galapagos, GSK, Janssen, Pfizer, and UCB; and research support from BMS, GSK Eli Lilly, and UCB. RBH, AvM, JCO-A, MO and DAR are employees of GSK and hold stocks and shares in the company. RBH is also an inventor for the following patents: US-20220195062-A1, US-11180569-B2, and US-20180265588-A1. KLC, JG, MD, YIG, DS and PPT were employees of GSK at the time of the study and hold stocks and shares in the company. NLF is a former employee and consultant for GSK and holds stocks in the company. YOT has received unrestricted research grants from GSK, Aurinia Pharmaceuticals, and Vifor Pharma; and consulting fees from Aurinia Pharmaceuticals, Novartis, GSK, Kezar Life Sciences Inc, Vifor Pharma, and Otsuka Pharmaceuticals (paid to Leiden University Medical Center).

Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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• Open access
• Published: 26 August 2024

Pregnancy complications and autoimmune diseases in women: systematic review and meta-analysis

• Megha Singh   ORCID: orcid.org/0000-0003-3680-7124 1 ,
• Fathima Fazla Ahamed Fayaz   ORCID: orcid.org/0000-0003-0788-6492 1 ,
• Jingya Wang   ORCID: orcid.org/0000-0003-1498-2693 1 ,
• Steven Wambua   ORCID: orcid.org/0000-0003-2300-7670 1 ,
• Anuradha Subramanian   ORCID: orcid.org/0000-0001-8875-7363 1 ,
• John A. Reynolds   ORCID: orcid.org/0000-0002-8962-4404 2 ,
• Krishnarajah Nirantharakumar   ORCID: orcid.org/0000-0002-6816-1279 1 &
• Francesca Crowe   ORCID: orcid.org/0000-0003-4026-1726 1

on behalf of MuM-PreDiCT

BMC Medicine volume  22 , Article number:  339 ( 2024 ) Cite this article

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Pregnancy complications might lead to the development of autoimmune diseases in women. This review aims to summarise studies evaluating the association between pregnancy complications and the development of autoimmune diseases in women.

Medline, CINAHL, and Cochrane databases were searched up to January 2024. Nineteen pregnancy complications and 15 autoimmune conditions were included. Title, abstract, full-text screening, data extraction, and quality assessment were performed by two reviewers independently. Data were synthesised using narrative and quantitative methods. Results were presented using odds ratios (OR), relative risks (RR), incidence rate ratios (IRR), and 95% confidence intervals (CI).

Thirty studies were included. One study reported composite exposure to pregnancy complications had a risk of any autoimmune disease RR 3.20 (2.90–3.51) compared to women without pregnancy complications. Women with hyperemesis gravidarum had a higher risk of developing coeliac disease ( n  = 1) IRR 1.98 (1.27–2.94), Crohn’s disease ( n  = 1) IRR 1.61 (1.25–2.04), psoriasis ( n  = 1) IRR 1.33 (1.01–1.71), and rheumatoid arthritis ( n  = 2) IRR 1.35 (1.09–1.64). Miscarriage associated with subsequent diagnosis of Sjogren syndrome ( n  = 2) IRR 1.33 (1.06–2.81) and rheumatoid arthritis ( n  = 4) OR 1.11 (1.04–1.20). Gestational hypertension/preeclampsia was linked with the development of systemic sclerosis ( n  = 2) IRR 2.60 (1.10–4.60) and T1DM ( n  = 2) IRR 2.37 (2.09–2.68). Stillbirth associated with composite autoimmune conditions ( n  = 2) RR 5.82 (95% CI 4.87–6.81) and aIRR 1.25 (1.12–1.40). Postpartum psychosis was associated with autoimmune thyroid disease ( n  = 1) aIRR2.26 (1.61–2.90).

Conclusions

Women with pregnancy complications subsequently had a higher risk of being diagnosed with autoimmune conditions. Whether this is due to pre-existing undiagnosed health conditions or being causally linked to pregnancy complications is not known.

Peer Review reports

What is already known about this subject?

The prevalence of autoimmune conditions and pregnancy complications has increased globally.

Women with pregnancy complications are at higher risk of cardiometabolic conditions in later life.

What does this study add?

This systematic review consolidates evidence from studies which have studied the association of pregnancy complications and the later development of autoimmune diseases in women.

This review provides new knowledge to help establish the association of pregnancy complications and autoimmune diseases and identifies the need for further research to establish the true association between few conditions like the development of SLE or rheumatoid arthritis followed by miscarriage.

How might this impact on clinical practice?

This study will be useful for health professionals and policymakers to navigate the research findings and identify the need for clinical guidelines beyond postnatal care for women with pregnancy complications.

The prevalence of autoimmune diseases has been increasing globally over the last decade [ 1 ], and in the UK, 1 in 10 people have an autoimmune disease [ 1 , 2 , 3 ]. The majority of autoimmune diseases are more common in women than men [ 4 ] and are a leading cause of death in women between the age of 65 and 75 in the US and UK [ 5 , 6 ]. Although the aetiology of autoimmunity is still not fully understood, the increased prevalence of autoimmune disease has been linked to defective X chromosome inactivation [ 7 , 8 ] and the effects of female hormones [ 9 ].

During pregnancy, there are significant fluctuations in hormone levels and increased physiological stress. Women with pre-existing autoimmune diseases may experience flare-ups or a decrease in their symptoms. For example, rheumatoid arthritis, Grave’s disease, or psoriasis may improve during pregnancy [ 10 , 11 , 12 ], whilst patients with systemic lupus erythematosus (SLE) or multiple sclerosis are at an increased risk of disease exacerbations [ 13 , 14 ]. With an increasing trend in pregnancy complications due to factors such as older age at pregnancy and women entering pregnancy with pre-existing long-term health conditions [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ], it is important to study the role of pregnancy complications in the development of autoimmune diseases. Whilst it is well-established that women with autoimmune diseases have an increased risk of fertility problems and adverse pregnancy outcomes such as miscarriage and foetal growth restriction [ 24 , 25 , 26 , 27 , 28 , 29 , 30 ], less is known about the risk of developing autoimmunity in women who experience pregnancy complications [ 31 ]. Some studies have shown an association between parity and increased risk of Hashimoto thyroiditis, Sjögren’s syndrome, Graves’ disease, and rheumatoid arthritis [ 32 , 33 ]. Moreover, the association between gestational diabetes mellitus (GDM) and the development of type 1 diabetes (T1DM) is well established [ 34 ]. Some pregnancy complications such as hyperemesis gravidarum and gestational hypertension have been associated with the development of rheumatoid arthritis [ 35 , 36 ], whilst other studies have reported that pregnancy loss and gestational hypertension are associated with the development of SLE and systemic sclerosis [ 37 , 38 ]. But other studies conducted on these associations have reported contradictory/inconsistent findings [ 39 , 40 ].

This systematic review aims to determine the association between a wide range of pregnancy complications and the development of autoimmune diseases in women.

This systematic review and meta-analysis have been conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and Reporting Guidelines for Meta-analyses of Observational Studies (MOOSE) (Additional file 1 table 2 and Additional file 2 table 1) [ 41 ]. The protocol for this review was registered with Prospero CRD42023412549.

Inclusion and exclusion criteria

Cohort, cross-sectional, or case-control studies reporting on the associations between pregnancy complications and the risk of autoimmune diseases were included. No language restrictions were applied. The population considered were pregnant women without any age restriction. The pregnancy complications (19) and autoimmune diseases (15) selected for inclusion were those that were more common in women, after consultation with experts in the subject (obstetricians, obstetric physicians, rheumatologists, and epidemiologists), and after input from patient and public involvement and engagement (PPIE) group members.

The pregnancy complications included are listed in Table  1  and autoimmune disease in Table 2 .

Search strategy

Medline, CINAHL, and Cochrane Library were searched for studies from 2010 till January 2024.

The search strategies used pre-defined keywords of the exposures (pregnancy complications) and outcomes (autoimmune disease). Terms/keywords for each of the pregnancy complications (early adj3 pregnancy loss*, mp.miscarriage.mp, GDM) and autoimmune diseases (for example arthritis, rheumatoid systemic lupus, or SLE) were used in the search strategy. Google Scholar was searched to identify other grey literature. In addition, the reference list of the included studies, systematic reviews, and scoping reviews were searched manually to minimise the possibility of missing any relevant studies. Letters, commentaries, or editorials were excluded and studies that did not involve humans were also excluded. The searches were repeated periodically to identify newly published studies. The detailed search strategy for Medline is presented in the Additional file 1 table 1 (Table  1 ). This search strategy was adapted for use in other databases (CINAHL and Cochrane library). Pragmatic approach was taken given there was a substantial number of studies that needed screening ( n  = 24,340) and the study period was limited from 2010 to 2023 ( n  = 13,234). But this was complimented by a secondary search strategy looking at references of included studies, systematic reviews, scoping reviews, and by discussing with topic experts (KN, FC) to minimise the possibility of missing any study before 2010.

Study selection

EndNote reference manager [ 42 ] was used for the title and abstract screening by two researchers independently (MS, JW). Full text of the eligible reviews was screened by two researchers independently (MS, FF). Covidence software [ 43 ] was used for full-text screening and data extraction. A third senior researcher was consulted to resolve any discrepancies in the selection of the studies (FC, KN).

Data extraction

Two reviewers extracted data from the included studies. The data extraction form was adapted from JBI (Joanna Briggs Institute) data extraction form [ 44 ]. A standardised data extraction form was used and was piloted before use. The data were extracted for the following fields: author/s, year of publication, geographical area, aim of the study, population, exposures, comparator, outcomes, covariates, study design, definition of exposure, risk of bias assessment tool and result, number of participants included in the study, summary estimates, authors’ conclusion, and study limitations. The data extraction form is enclosed in Additional file Table 6.

Quality assessment

The quality of included cohort, cross-sectional, and case-control studies was assessed using the Newcastle–Ottawa scale that measures study quality based on selection, comparability of the exposure and comparator groups, and the ascertainment of outcomes and exposures [ 45 ]. The scale has an overall score of 8 points for cohort or case–control studies, and 7 for cross-sectional studies with a maximum of 1 point for each numbered item within the selection and outcome/exposure categories and a maximum of 2 points for the comparability category. We defined studies with a score of ≥ 7 points as low-risk of bias studies (very good), studies with a score of 6 points as moderate-risk of bias studies (good), and those with a score of ≤ 5 points as high-risk of bias studies (satisfactory).

Data synthesis

The effect estimates were reported as adjusted incidence rate ratios (aIRR), adjusted hazards ratios (aHR), adjusted odds ratios (aOR), or adjusted relative risks (aRR) and 95% confidence intervals (CI). We converted these effect estimates using appropriate methods (where possible) to maintain uniformity across studies [ 46 ]. Where more than one study reported the same exposure and outcome, a meta-analysis was conducted using a random effects model to generate a summary estimate. Statistical heterogeneity was estimated using the I 2 statistic. To deal with potentially missing data (sample size, number exposed and unexposed), Additional file 1 of each included study was checked thoroughly, and the authors of the studies were contacted to request the data. If the data was not available and a meta-analysis could not be conducted, then effect estimates were reported as they were published. Where statistical pooling was not possible, the findings were presented in a narrative form including tables and figures to aid data presentation. R (3.3.0) and R Studio (12.1) were used to conduct statistical analysis [ 47 , 48 , 49 ].

Patient and public involvement

Patient and public involvement and engagement (PPIE) representatives (RP and NM) participated in formulating the research question. They have also played key role in collaboration with clinicians and researchers to identify and consider the list of pregnancy complications and autoimmune diseases in the study. They will play a key role in disseminating the results.

Out of the 13,234 records identified from the search and after full-text screening of 85 studies, 30 studies were included [ 31 , 34 , 35 , 36 , 39 , 40 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 ]. Studies were excluded if they did not qualify in the study inclusion criteria based on the study design ( n  = 22), population ( n  = 5), intervention (2), outcome (23), and comparator(3). The selection process is shown in the PRISMA diagram (Fig.  1 ) [ 41 ]. The list of excluded studies is provided in Additional file 1 table 3.

Preferred reporting items for systematic review and meta-analysis (PRISMA) flow diagram

Characteristics of the included studies are reported in Table 3 . Out of the 30 studies, the majority were prospective cohort studies ( n  = 21), 8 were retrospective case–control studies, and 1 was a cross-sectional study. There were 23 studies conducted in Europe, the remainder were in Taiwan (2), China (2), South Korea (1), and the United States (2). In most cohort studies ( n  = 14), information about the pregnancy complications and autoimmune diseases was collected through medical records. Medical records were used to establish the autoimmune diseases in case–control studies, and questionnaires were used to determine the pregnancy complications. The follow-up period of the cohort studies varied from 9 months to 26 years with a median of 12 years. Out of the 21 cohort studies, 9 used the data from the same cohort (Danish national registry) [ 31 , 36 , 39 , 53 , 54 , 63 , 64 , 69 ]. In the instance of two studies reporting the same exposure and outcome, the most recent study was used to avoid duplication. We have done this in accordance with the Cochrane handbook for systematic reviews [ 74 ]. For instance, two studies, Mikkelsen et al. [ 63 ] and Nielsen et al. [ 64 ], were both reporting the association of pregnancy complications and the future development of multiple sclerosis in women using Danish Civil Registration System. Mikkelsen et al.’s study was used to report the findings in this review. Details have been added in Additional file tables 1 and 5 [ 75 , 76 ]. A total of 18 different pregnancy complications and 12 autoimmune diseases (including an overall “all autoimmune diseases”) were investigated across the studies. Rheumatoid arthritis (8 studies) and SLE (5 studies) were two of the most included outcomes. The meta-analysis performed in this systematic review is included in Additional file 1 figure 1.1–1.11.

Results of the quality assessment of the studies using the Newcastle–Ottawa scale are shown in Fig.  2 and Additional file 1 Table 4.1–4.3 [ 77 ]. Eighteen out of 30 studies had a low risk of bias with an overall “very good” rating. The principal areas of concern were the comparability of cohorts and the adequacy of follow-up.

Quality assessment of included studies (Newcastle–Ottawa scale). A Cohort studies (21). B Case–control studies (8). C Cross-sectional study (1)

All autoimmune diseases

There was more than a threefold higher risk of developing autoimmune diseases ( n  = 7) in women with pregnancy complications ( n  = 6) RR 3.20 (95% CI 2.90–3.51) when compared with women without pregnancy complications [ 58 ]. Out of the pregnancy complications studied individually, two studies reported, women with previous miscarriage RR 3.41 (3.03–3.85) and aIRR 1.10 (1.07–1.14) was reported to have higher risk [ 58 ]. One cohort and one case–control study reported a higher risk of autoimmune diseases in women with gestational hypertension or pre-eclampsia; RR 2.05 (1.70–2.48) and aIRR 1.21 (1.16–1.26) [ 54 , 58 ], respectively. Women with stillbirth were reported to have higher chances to have autoimmune disease in later life reported by two studies RR 5.82 (4.97–6.81) [ 58 ] and aIRR 1.25 (1.12–1.40) [ 54 ]. There was a significantly higher risk of developing autoimmune diseases for women with preterm birth RR 2.35 (1.89–2.92) [ 58 ]. There was little association reported with caesarean section, induced abortion, or postpartum depression with the development of autoimmune diseases [ 31 , 54 , 61 ]. However, a study reported a higher risk of developing autoimmune diseases in women with perinatal depression aHR 1.52 (1.46–1.58), with antenatal depression aHR 1.50 (1.43–1.58), and postpartum depression aHR 1.55 (1.45–1.65) [ 73 ].

Autoimmune thyroid diseases

Hyperemesis gravidarum aIRR 1.49 (1.28–1.72), gestational hypertension or pre-eclampsia aIRR 1.20 (1.10–1.30), and postpartum depression aHR 1.57 (1.05–2.33) [ 54 , 60 ] were all associated with a higher risk of Grave’s disease but there was no significant association between ectopic pregnancy and Grave’s disease aIRR 1.04 (0.93–1.17) [ 54 ]. Gestational hypertension/pre-eclampsia aIRR 1.41 (1.17–1.68) was associated with a higher risk of Hashimoto’s thyroiditis but there was little association of hyperemesis gravidarum or ectopic pregnancy with Hashimoto’s thyroiditis; aIRR 1.38 (0.95–1.92) and aIRR 0.92 (0.68–1.21), respectively [ 54 ]. Two cohort studies reported a greater risk of autoimmune thyroid disease in women with postpartum psychosis aOR 2.78 (1.08–7.17) at 9 months and aIRR 2.26 (1.61–2.90) with 2 years follow-up postpartum when compared with women without postpartum psychosis [ 50 , 51 ].

Coeliac disease

Women who experienced hyperemesis gravidarum had almost a twofold risk of coeliac disease compared to women without; aIRR 1.98 (1.27–2.94) [ 54 ]. None of the other pregnancy complications were significantly associated with coeliac disease; ectopic pregnancy aIRR 1.12 (0.75–1.61), gestational hypertension, pre-eclampsia aIRR 1.19 (0.89–1.56), and intrahepatic cholestasis of pregnancy aHR 1.20 (0.82–1.74) [ 54 , 72 ].

Inflammatory bowel disease (Crohn’s disease and ulcerative colitis)

Out of the five pregnancy complications reported for IBD (hyperemesis gravidarum, missed abortion, gestational hypertension, pre-eclampsia, and Caesarean section), none of these associations were statistically significant. However, studies reporting ulcerative colitis and Crohn’s disease separately found significant associations. Hyperemesis was significantly associated with the development of both ulcerative colitis and Crohn’s disease, aIRR 1.34 (1.09–1.62) and aIRR 1.61 (1.25–2.04), respectively [ 54 ]. Furthermore, a higher risk of Crohn’s disease was also observed in women with intrahepatic cholestasis of pregnancy, HR 1.55 (1.14–2.10) [ 72 ]. No other pregnancy complications were associated with the development of IBD as reported in Fig.  4 .

Ankylosing spondylitis

Out of the three pregnancy complications studied with the development of ankylosing spondylitis in women, there was no significant association for hyperemesis gravidarum IRR 1.63 (0.96–2.25) or ectopic pregnancy IRR 1.02 (0.66–1.50); a significant association was noted with gestational hypertension and pre-eclampsia IRR 1.40 (1.06–1.82) [ 54 ] (Fig.  5 ).

Rheumatoid arthritis

Out of the five studies reporting the association of miscarriage and rheumatoid arthritis, four were meta-analysed to estimate 11% higher odds: pooled OR 1.11 (1.04–1.20) with the other study showing a slightly elevated risk that was not statistically significant aIRR 1.06 (0.97–1.15) [ 35 , 36 , 54 , 57 , 66 , 67 ]. A significant association was also reported with hyperemesis, gestational hypertension, and pre-eclampsia with aIRR 1.35 (1.09–1.64), aIRR 1.18 (1.05–1.31), respectively [ 54 ]. [ 35 , 36 , 54 , 57 , 66 , 67 ]. Whilst three studies were pooled to derive a significant association between rheumatoid arthritis and induced abortion 1.46 OR (1.01–2.12). Women with any pregnancy loss were reported to be at higher risk of developing the disease in one study aIRR 1.12 (1.06–1.12) and others reported no association aIRR 1.01 (0.67–1.44), and this will require further research to establish the true association. The association for induced abortion or any pregnancy loss with rheumatoid arthritis reported mixed findings with significant association reported by few studies and insignificant by others as shown in Fig.  5 [ 31 , 35 , 36 , 54 , 57 , 66 , 67 ]. A higher risk of developing rheumatoid arthritis was observed in women who delivered “extremely low birth weight” babies (< 1000 g) with RR 3.70 (1.00–13.20) or “low birth weight” babies (< 2500 g) with RR 1.40 (1.00–2.10) when compared to women who delivered normal birth weight babies [ 40 ]. An increased risk of rheumatoid arthritis was also reported for women with postpartum depression with aHR 2.62 (1.28–5.39) [ 60 ]. No other pregnancy complications studied in relation with the development of rheumatoid arthritis were statistically significant (Fig.  5 ). There was also no significant association with the development of rheumatoid arthritis as reported in women who delivered very low birth weight babies (< 1500 g) in a study with a small sample size ( n  = 20) [ 40 ].

Rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis (composite outcome)

There were no other significant associations with rheumatoid arthritis or the composite outcome with other pregnancy complications studied (gestational hypertension or pre-eclampsia, caesarean section, postpartum haemorrhage, or mothers delivering preterm births or low birth weight babies) (Fig.  5 ) [ 71 ]. Women who delivered small for gestational age babies were more likely to have the composite outcome of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis aOR 1.60 (1.00–2.56) when compared to women with normal for gestational age babies.

Connective tissue diseases (systemic lupus erythematosus, Sjogren syndrome, systemic sclerosis)

Connective tissue disease.

Seven pregnancy complications were reported in association with connective tissue disease (CTD). Women with placental abruption or preterm birth had significantly higher risk of CTD; RR 3.39 (1.96–5.89) and RR 1.78 (1.12–2.82), respectively, [ 58 ] in Fig.  6 . The associations of gestational hypertension, intrauterine growth restriction (IUGR), miscarriage, stillbirth, and composite pregnancy complications with CTD were not statistically significant [ 58 ].

Systemic lupus erythematosus (SLE)

Results for an association between miscarriage and SLE were mixed with one study reporting aIRR of 1.43 (1.08–1.88), and a pooled RR for two smaller studies showing no significant association 0.94 (0.37–2.40) [ 54 , 58 , 66 , 69 ]. However, there was a significant association reported with any pregnancy loss and future development of the disease with OR 1.87 (1.31–2.67) [ 52 , 55 ]. Missed abortions were associated with a higher risk of SLE; IRR 2.13 (1.48–2.98) [ 54 , 69 ]. Women with history of IUGR had almost a fivefold higher risk of SLE; RR 4.80 (1.60–14.50) when compared with women with no IUGR [ 55 ]. Results from three studies showed that a history of stillbirth was associated with a four times higher risk of SLE, pooled RR 4.01 (3.11–5.17) and pooled IRR 3.29 (3.22–4.88) [ 54 , 58 , 66 , 69 ].

Systemic sclerosis

There was an association between gestational hypertension or pre-eclampsia and systemic sclerosis in two studies: OR 2.60 (1.10–4.60). Kamper et al. [ 56 ] reported a significant association with the development of localised scleroderma in women with pre-eclampsia with IRR 1.69 (1.02–2.80) but a nonsignificant association with subset of systemic disease aIRR 1.46 (0.75–2.80) [ 56 , 70 ]. There was a three- to fourfold higher risk of systemic sclerosis for women with IUGR compared with women with normal foetal growth OR 3.90 (1.20–12.30) [ 70 ] and caesarean birth compared to vaginal birth RR 3.09 (1.96–4.63) [ 59 ].

Sjögren’s syndrome

There were seven pregnancy complications examined in relation to Sjögren’s syndrome with results showing a greater risk with hyperemesis gravidarum, aIRR 1.79 (1.06–2.81); miscarriage, aIRR 1.33 (1.08–1.63); induced abortion, aIRR 1.18 (1.01–1.38); and gestational hypertension or pre-eclampsia, aIRR 1.43 (1.09–1.85) [ 54 ]. The associations for ectopic pregnancy, missed abortion, or preterm birth, aIRR 1.18 (0.79–1.68), aIRR 1.12 (0.80–1.51), and RR 0.09 (0.04–18.09), respectively [ 54 , 58 , 66 ], were not statistically significant.

Type 1 diabetes mellitus (T1DM)

Hyperemesis gravidarum aIRR 1.05 (0.74–1.45) and ectopic pregnancy aIRR 1.06 (0.58–1.77) were not significantly associated with T1DM [ 34 , 54 , 65 , 68 ] in Fig.  7 . Results from one cohort study showed that gestational hypertension or pre-eclampsia was associated with a twofold higher risk of T1DM; aIRR 2.37 (2.09–2.68) [ 68 ], whereas in the other study, the association was higher but not statistically significant; OR 1.80 (0.80–3.80) [ 65 ]. Results from two studies showed that the risk of T1DM for women with gestational diabetes was considerably higher; pooled OR 40.89 (24.31–68.78) [ 34 , 65 ]. There was almost a fourfold higher risk of T1DM in women who delivered large for gestational age babies compared to women delivering normal weight for gestational age babies aHR 3.60 (3.23–4.01) [ 68 ]. There was no significant association for women who delivered small for gestational age babies and T1DM; aHR 1.11 (0.94–1.30) [ 62 , 71 ].

Out of the seven pregnancy complications, five complications were associated with a higher risk of psoriasis: hyperemesis gravidarum HR 1.33 (1.01–1.71), ectopic pregnancy aIRR 1.28 (1.07–1.53), induced abortions aIRR 1.33 (1.24–1.42), gestational hypertension or pre-eclampsia aIRR 1.22 (1.06–1.40), and intrahepatic cholestasis of pregnancy aIRR 1.27 (1.07–1.51) [ 54 , 61 , 72 ]. Missed abortion and postpartum depression were not significantly associated with the risk of psoriasis (Fig.  7 ) [ 54 , 61 ].

Associations of pregnancy complications with other miscellaneous autoimmune conditions

No significant association was reported with pregnancy complications studied (hyperemesis, ectopic pregnancy, miscarriage, or gestational hypertension) and the development of multiple sclerosis as mentioned in Fig.  7 [ 64 ]. The association of postpartum depression and alopecia areata (HR 1.97, 0.72–5.37) [ 60 ], and recurrent pregnancy loss and myasthenia gravis (RR 0.85, 0.54–1.31) were not statistically significant [ 63 ].

Timing of developing autoimmune diseases following pregnancy/pregnancy complications

Four studies reported the occurrence of autoimmune diseases following pregnancy over different follow-up times [ 31 , 51 , 54 , 69 ]. Following a pregnancy complication, a woman’s risk of developing Grave’s disease or SLE was higher in the early years after childbirth in comparison to later in life [ 35 , 39 , 54 , 63 , 69 ]. For instance, there was a higher risk of SLE in women with pregnancy loss in the first year postpartum IRR 2.64 (1.18–6.29), whereas there was no significant association noted after two or more years postpartum IRR 1.90 (0.87–4.48) [ 69 ]. Conversely, the risk of developing rheumatoid arthritis (RR 1.05; 0.98–1.13, 5+ years: RR 2.24; 1.58–3.05, and multiple sclerosis) (RR 1.00; 0.91–1.09, 5+ years: RR 2.20; 1.72–2.77) was greater after 5 or more years postpartum. Also, women with hyperemesis gravidarum were at a greater risk of developing rheumatoid arthritis in the first 4 years post birth; this reduced after 5 years, IRR 1.40 (1.09–1.76) and IRR 1.02 (0.59–1.11), respectively [ 54 , 69 ]

This systematic review provides an overview of the associations of 18 pregnancy complications with the risk of developing 15 autoimmune diseases. This review compiles all the available evidence on pregnancy complications linked to the development of autoimmune diseases in women in later life (Figs. 2 , 3 , 4 , 5 , 6 and 7 ) and generates new evidence by quantitative or qualitative analysis of the studies studying the same exposure and outcomes (Additional file 1 figure 1.10). This also further points out the differences in the results observed in two or more studies analysing the association of the same pregnancy complication and autoimmune disease (Additional file 1 fig. 1.11).

Forest plot association of pregnancy complications and autoimmune diseases (overall) and autoimmune thyroid diseases

Forest plot-association of pregnancy complications and coeliac disease or inflammatory bowel disease (Crohn’s disease and ulcerative colitis)

Forest plot- association of pregnancy complications and Ankylosing spondylitis, rheumatoid arthritis, or RA/PSA/ANK S

Forest plot showing the association of pregnancy complications and connective tissue diseases

Forest plot showing the association of pregnancy complications and alopecia areata, multiple sclerosis, myasthenia gravis, psoriasis, or T1DM

Studies reported associations for gestational hypertension/preeclampsia followed by preterm birth, hyperemesis gravidarum and ectopic pregnancy, and future autoimmunity. However, there was little or no research on some complications such as molar pregnancy or placental disorders. From the perspective of autoimmune disease outcomes, most studies examined the associations with rheumatoid arthritis followed by autoimmune thyroid diseases, Sjögren’s syndrome, and psoriasis. In contrast, there were very few studies that included vitiligo or myasthenia gravis.

Many of the pregnancy complications increased the risk of overall autoimmune diseases almost threefold, particularly hyperemesis gravidarum, miscarriage, gestational hypertension, stillbirth, and antenatal/postpartum depression. Apart from the known association of gestational diabetes and T1DM, results from this review showed that IUGR or stillbirth were associated with almost three- to fourfold increased risk of systemic sclerosis or systemic lupus erythematosus. There was a higher risk of rheumatoid arthritis with preterm birth and low birth weight babies.

There are findings which require further research, for example, the association of miscarriage and development of SLE [ 58 , 65 , 69 ] and the association of gestational hypertension with T1DM [ 54 , 65 ]. The difference in the findings could possibly be due to the varying study designs or difference in the sample size of the studies. There had been mixed findings amongst the studies included and these may be due to the varying sample size or the study designs.

Earlier studies focused on the association of pregnancy complications with child outcomes such as caesarean birth or pre-eclampsia and the association with long-term health conditions in babies [ 78 , 79 , 80 , 81 , 82 , 83 , 84 ]. However, more recently, studies have reported the association of pregnancy complications and the development of long-term conditions in the mother [ 31 , 85 ]. Reproductive factors and pregnancy complications were found to be associated with later development of metabolic conditions [ 86 , 87 , 88 ]. An association between pregnancy itself, irrespective of pregnancy complications, and the development of autoimmune diseases has been reported [ 31 ]. Some studies identified the association between parity and the development of systemic sclerosis; however, the findings have been conflicting [ 89 , 90 , 91 , 92 ].

It is not clear whether the observed pregnancy complications occur in women with preclinical autoimmune disease or whether these events directly pre-dispose to the development of autoimmune disease [ 93 ]. In terms of the former, women with undifferentiated connective tissue disease (UCTD), who have features compatible with a CTD but do not have a defined CTD [ 94 ], have an increased risk of pregnancy complications including premature delivery, pre-eclampsia, and stillbirth [ 95 ]. As approximately 30% of UCTD may progress to CTD, typically SLE, it is possible that some of the pregnancy complications occurred in women who were in the initial stages of UCTD, i.e. the pregnancy complications were due to a subclinical autoimmune disease.

On the other hand, pregnancy/pregnancy complications bring about fluctuations in female sex hormones accompanied by physiological stress [ 96 ]. The blood levels of both oestrogen and progesterone increase rapidly from the middle of the second trimester, peaking at term. Oestrogen and progesterone have broad effects on the function of both innate and adaptive immune cells (including monocytes/macrophages, neutrophils, dendritic cells, and T and B lymphocytes) [ 97 ]. In pregnancy, placental production of oestriol (E3) increases dramatically. Oestriol has potent anti-inflammatory effects including reducing pro-inflammatory cytokine production, increasing anti-inflammatory cytokines, and reducing CD4+ and CD8+ T cells [ 98 ]. Similarly, progesterone increases regulatory T cells and reduces natural killer cell function systemically and within the placenta [ 98 ]. It is possible, therefore, that hormonal fluctuations and the loss of this anti-inflammatory state postpartum could accelerate the development of autoimmune disease. Furthermore, oestrogens reduce B cell apoptosis which, whilst contributing to maternal humoral immunity, may promote autoreactive B cell survival and drive the immune system toward autoimmunity [ 99 ].

A key driver of future autoimmune disease may be foetal microchimerism [ 100 ]. Foetal cells are present at a low frequency in the maternal circulation postpartum and may persist for decades [ 57 , 101 , 102 , 103 ]. Foetal origin microchimerism is observed at increased rates during pregnancy complications such as miscarriage, pre-eclampsia, foetal growth restriction [ 104 ], or premature labour [ 102 , 105 ]. The mechanisms by which foetal microchimeric cells mediate an increased risk of autoimmunity is not understood although an increased number of these cells is observed in the thyroid gland of women with autoimmune thyroid disease [ 106 ]. To date, a pathogenic role for foetal microchimeric cells has not been demonstrated, and these cells may induce maternal tolerance to foetal antigens and via a bystander effect reduce the severity of some autoimmune diseases such as RA during pregnancy [ 106 ].

Our study has several strengths. The scope of our review was broad and summarises the association of pregnancy complications and the subsequent development of a wide range of autoimmune diseases, and we were able to perform a meta-analysis of studies reporting the same exposure and outcome where possible. We employed rigorous methodology with a pre-specified protocol, and our systematic search was conducted without language restriction and two reviewers screened, extracted data, and appraised the quality of the studies.

There are, however, some limitations. A meta-analysis could not be performed for some of the studies due to missing data such as the sample size or number of exposed/unexposed. Some of the results reported therefore are as reported in one study. Also, nine studies were conducted using the same cohort (Danish birth cohort); this may have a disproportionate effect on our findings. However, efforts were made to avoid duplication in the reporting of results. This study is not able to determine causality and there is a possibility that the women already have undiagnosed preclinical autoimmune diseases, which increased their risk of pregnancy complications in studies, especially those with shorter follow-up time.

Additional research is required that incorporates a comprehensive analysis of pregnancy complications and characterise the phenotype and functionality of persistent foetal origin cells in women with autoimmune diseases compared with healthy women. The exact pathophysiology behind the development of these conditions remains unclear and we do not know why some pregnancy complications have a larger effect than others. To address these questions, prospective longitudinal studies following up on women who experienced pregnancy complications are needed, observing when autoantibodies are first detected [ 107 ]. Furthermore, larger epidemiological studies would be required to define whether autoimmune disease is more prevalent in women who have experienced pregnancy complications and if there is a clear underlying association.

This review has reported that there is an association between pregnancy complications and the subsequent development of autoimmune diseases in women. To further address this question, prospective longitudinal studies following up on women who experienced pregnancy complications are needed, observing when autoantibodies are first detected. Meanwhile, clinicians should be vigilant and detect autoimmune conditions early in women with a history of pregnancy complications.

Availability of data and materials

No datasets were generated or analysed during the current study.

Abbreviations

95% Confidence intervals

Adjusted hazard ratio

Adjusted incidence risk ratio

Adjusted odds ratio

Adjusted risk ratio

Axial spondyloarthropathy

Clusters of differentiation

Caesarean section

Connective tissue diseases

Gestational diabetes mellitus

Gestational hypertension or pre-eclampsia

Haemolysis, elevated liver enzymes, and low platelet syndrome

Inflammatory bowel disease

Intrauterine growth retardation

Low birth weight

Medical subject headings

Meta-analyses of observational studies

Multiple sclerosis

Not applicable

Newcastle–Ottawa scale

Patient and public involvement and engagement

Preferred reporting items for systematic review and meta-analysis

Rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis

Small for gestational age

Systemic lupus erythematosus

Type 1 diabetes mellitus

Undifferentiated connective tissue disease

United Kingdom

United States

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MS was responsible for the analysis and drafting of the manuscript. FF/JW were the second reviewers for the study selection, data extraction check, and quality appraisal. FC and KN were the third reviewers and provided their inputs and guidance at each step of the review. KN, JR, AS, FC, and SW were responsible for revising the manuscript critically and for important intellectual content. All authors read and approved the final manuscript.

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12916_2024_3550_moesm1_esm.docx.

Additional file 1: Table 1. Search Strategy MEDLINE. Table 2. The Preferred Reporting Items for Systematic reviews and Meta-Analyseschecklist. Table 3. List of excluded studies. Table 4.1. Quality assessment of the Cohort studies using NOS. Table 4.2. Quality assessment of the case control studies using NOS. Table 4.3. Quality assessment of the cross-sectional studies using NOS. Figure 1.1. Meta-analysis of two studies reporting association of miscarriage and future development of SLE. Figure 1.2. Meta-analysis of two studies reporting association of miscarriage and future development of rheumatoid arthritis. Figure 1.5. Meta-analysis of two studies reporting association of stillbirth and future development of SLE. Figure 1.6. Meta-analysis of two studies reporting association of gestational hypertension or pre-eclampsia and future development of SLE. Figure 1.7. Meta-analysis of two studies reporting association of preterm birth and future development of SLE. Figure 1.8. Meta-analysis of two studies reporting association of preterm birth and future development of rheumatoid arthritis. Figure 1.9. Meta-analysis of two studies reporting association of gestational diabetes and future development of T1DM. Figure 1.10. The new findings from this review. Figure 1.11. The mixed findings of this review. Table 5. Cohort studies with same or overlapping cohorts. Table 6. Data Extraction form.

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Singh, M., Fayaz, F.F.A., Wang, J. et al. Pregnancy complications and autoimmune diseases in women: systematic review and meta-analysis. BMC Med 22 , 339 (2024). https://doi.org/10.1186/s12916-024-03550-5

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Mind Over Matter: Unraveling the Cognitive Gains in Anxiety and Depression with the Cognitome Program

Integrating Mind and Brain: A Comprehensive Analysis of the Cognitome Program’s Impact on Cognitive Abilities in Chronic Anxiety and Depression

In the ever-evolving field of mental health treatment, innovative approaches are continuously being explored to address complex and chronic conditions. One such approach is the Cognitome Program, a novel, integrated treatment designed to enhance cognitive abilities in patients with chronic generalized anxiety disorder (GAD) and moderate depression. The article “Improvement of the Cognitive Abilities in a Chronic Generalized Anxiety Disorder and Moderate Depression Case using a Novel Integrated Approach: The Cognitome Program” presents a detailed case study of how this program was implemented and the resulting outcomes. This blog post will analyze the article, discussing the significance of its findings, the methodology used, and the broader implications for mental health treatment.

Overview of the Cognitome Program: A Novel Integrated Approach

The Cognitome Program, as described in the article, is a multi-faceted treatment protocol that combines cognitive training, psychotherapeutic interventions, and neurobiological techniques to target both the psychological and cognitive deficits associated with chronic anxiety and depression. The program’s primary objective is to improve cognitive functions such as memory, attention, and executive function, which are often impaired in individuals suffering from these conditions.

• Cognitive Training : The program includes structured cognitive exercises aimed at enhancing specific cognitive domains. These exercises are designed to be adaptive, gradually increasing in difficulty as the patient’s abilities improve. This personalized approach ensures that the training remains challenging yet achievable, promoting continuous cognitive growth.
• Psychotherapeutic Interventions : In addition to cognitive training, the Cognitome Program integrates psychotherapeutic techniques such as cognitive-behavioral therapy (CBT). CBT is well-established for its efficacy in treating anxiety and depression by helping patients identify and modify maladaptive thought patterns. The integration of CBT into the Cognitome Program provides a dual benefit—addressing both the cognitive deficits and the psychological symptoms of the disorders.
• Neurobiological Techniques : The program also incorporates neurobiological methods, such as neurofeedback and transcranial magnetic stimulation (TMS), to directly influence brain activity. These techniques aim to modulate neural circuits that are dysregulated in anxiety and depression, potentially enhancing the effectiveness of the cognitive and psychotherapeutic components.

The Case Study: A Detailed Examination

The article presents a detailed case study of a patient with chronic generalized anxiety disorder and moderate depression who underwent the Cognitome Program. The patient’s history, treatment course, and outcomes are meticulously documented, providing valuable insights into the program’s efficacy.

• Baseline Assessment : At the start of the program, the patient underwent a comprehensive assessment, including neuropsychological tests, clinical interviews, and brain imaging. This baseline evaluation revealed significant impairments in cognitive functions such as working memory, attention, and executive functioning, alongside the clinical symptoms of anxiety and depression.
• Treatment Course : The patient participated in the Cognitome Program over several months, with regular sessions that combined cognitive training, CBT, and neurobiological techniques. The program was tailored to the patient’s specific needs, with adjustments made based on ongoing assessments of cognitive progress and symptom reduction.
• Outcomes : The results were promising. The patient demonstrated significant improvements in cognitive abilities, particularly in areas such as working memory, attention, and problem-solving. Additionally, there was a marked reduction in anxiety and depressive symptoms, as measured by standardized clinical scales. These improvements were sustained over time, indicating the potential for long-term benefits.

Analyzing the Significance of the Findings

The case study’s findings are significant for several reasons, offering valuable insights into the potential of integrated treatment approaches for chronic mental health conditions.

• Holistic Treatment : The Cognitome Program’s holistic approach, which addresses both cognitive and psychological aspects of anxiety and depression, is a key factor in its success. Traditional treatments often focus on alleviating symptoms without directly targeting the cognitive deficits that contribute to the persistence of these disorders. By integrating cognitive training with psychotherapeutic and neurobiological interventions, the Cognitome Program offers a more comprehensive treatment option.
• Personalization and Adaptation : The program’s personalized nature is another important aspect. The ability to tailor the treatment to the patient’s specific cognitive profile ensures that the interventions are both relevant and effective. This adaptive approach contrasts with more standardized treatments, which may not fully address individual differences in cognitive function and symptomatology.
• Sustainability of Results : The sustained improvement in both cognitive abilities and psychological symptoms observed in the case study is particularly noteworthy. Chronic anxiety and depression are often resistant to treatment, with high rates of relapse even after successful intervention. The Cognitome Program’s ability to produce long-lasting benefits suggests that it may offer a more durable solution for these challenging conditions.

Broader Implications for Mental Health Treatment

The success of the Cognitome Program in this case study has broader implications for the treatment of chronic anxiety and depression, as well as for the field of mental health more generally.

• Integration of Cognitive and Psychological Interventions : The findings support the growing recognition of the importance of integrating cognitive and psychological interventions in the treatment of mental health disorders. Cognitive impairments are increasingly acknowledged as a core feature of many psychiatric conditions, and their treatment should be considered alongside traditional symptom-focused therapies.
• Potential for Broader Application : While the article focuses on a single case, the principles underlying the Cognitome Program could potentially be applied to a wider range of mental health conditions. Disorders such as bipolar disorder, schizophrenia, and PTSD also involve cognitive deficits that contribute to their severity and chronicity. An integrated approach similar to the Cognitome Program could be beneficial for these conditions as well.
• Future Research Directions : The article also highlights the need for further research to validate and refine the Cognitome Program. Larger studies involving more diverse patient populations are necessary to confirm its efficacy and to identify the specific components that contribute most to its success. Additionally, research into the underlying neural mechanisms of the program could provide valuable insights into how cognitive and psychological interventions can be most effectively combined.

Conclusion: A Promising Path Forward in Mental Health Treatment

The article “Improvement of the Cognitive Abilities in a Chronic Generalized Anxiety Disorder and Moderate Depression Case using a Novel Integrated Approach: The Cognitome Program” offers a compelling case for the efficacy of integrated treatment approaches in mental health care. (Link below) The Cognitome Program, with its combination of cognitive training, psychotherapeutic interventions, and neurobiological techniques, represents a promising path forward for the treatment of chronic anxiety and depression.

By addressing both the cognitive and psychological aspects of these conditions, the Cognitome Program provides a more comprehensive and potentially more effective treatment option. The sustained improvements observed in the case study suggest that this approach may offer long-term benefits, reducing the risk of relapse and improving overall quality of life.

As mental health treatment continues to evolve, integrated programs like the Cognitome Program could play a crucial role in addressing the complex and multifaceted nature of psychiatric disorders. With further research and refinement, this approach has the potential to significantly enhance the effectiveness of mental health care, offering new hope to those struggling with chronic anxiety, depression, and other mental health conditions.

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The International Journal of Indian Psychȯlogy

Cognitive Behavioral Therapy for Depression in an Adult: A Clinical Case Study

| Published: August 26, 2024

World Health Organization (WHO) reported, depression is the most common psychiatric disorder in the mental health field. Depression is various from habitual mood swings and short lived emotional responses to challenges in day to day life. Although strong evidence of supports that cognitive behavioral therapy for depression. The patient is a 22-year elderly a male which pre-treatment give a diagnosis of severe depressive symptoms without psychotic (based on case history + MSE + ICD-10 + BDI-II), low mood, frequently crying spell and suicidal ideation, highly dysfunctional attitudes and also decreased sleep and appetite. The CBT Treatment consisted of 12 standard individual therapy sessions. In this study used a case study method and also used the qualitative as well as quantitative data for the case is presented using self-report instruments or clinical case notes. Treatment effects such as his mood over the course of treatment was assessed using Beck Depression Inventory and after 6 months of follow up. Also enhancing his mood was accompanied by a reduction in dysfunctional beliefs and attitudes about self and relationship. Additionally, the patient was reported an improvement in his mood, Activity of Daily Living (ADL) functioning as well as socialization.

Depression , Cognitive Behaviour Therapy , Treatment Outcome , Case Report

This is an Open Access Research distributed under the terms of the Creative Commons Attribution License (www.creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any Medium, provided the original work is properly cited.

© 2024, Chaudhary, N.

Received: April 15, 2024; Revision Received: August 23, 2024; Accepted: August 26, 2024

Mr. Narsinh Chaudhary @ [email protected]

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Persistence of Depression and Anxiety despite Short-Term Disease Activity Improvement in Patients with Systemic Lupus Erythematosus: A Single-Centre, Prospective Study

Myrto nikoloudaki.

1 Department of Rheumatology and Clinical Immunology, University Hospital of Heraklion and Medical School, University of Crete, 71110 Heraklion, Greece; [email protected] (M.N.); rg.oohay@2002aperra (A.R.); moc.evilswodniw@demaifos (S.P.); moc.nsm@hilasrunya (A.M.I.S.); rg.cou@pporidis (P.S.)

Argyro Repa

Sofia pitsigavdaki, ainour molla ismail sali, prodromos sidiropoulos.

2 Institute of Molecular Biology and Biotechnology—FORTH, 71110 Heraklion, Greece

Christos Lionis

3 Clinic of Social and Family Medicine, University of Crete Medical School, 71110 Heraklion, Greece; rg.cou.dem.sonilag@sinoil

George Bertsias

Associated data.

Data are available upon request.

Mental disorders such as anxiety and depression are prevalent in systemic lupus erythematosus (SLE) patients, yet their association with the underlying disease activity remains uncertain and has been mostly evaluated at a cross-sectional level. To examine longitudinal trends in anxiety, depression, and lupus activity, a prospective observational study was performed on 40 adult SLE outpatients with active disease (SLE Disease Activity Index [SLEDAI]-2K ≥ 3 [excluding serology]) who received standard-of-care. Anxiety and depression were determined at baseline and 6 months by the Hospital Anxiety and Depression Scale. Treatment adherence was assessed with a self-reported patient survey. Increased anxiety (median [interquartile range] HADS-A: 11.0 [7.8]) and depression (HADS-D: 8.0 [4.8]) were found at inclusion, which remained stable and non-improving during follow-up (difference: 0.0 [4.8] and −0.5 [4.0], respectively) despite reduced SLEDAI-2K by 2.0 (4.0) ( p < 0.001). Among possible baseline predictors, paid employment—but not disease activity—correlated with reduced HADS-A and HADS-D with corresponding standardized beta-coefficients of −0.35 ( p = 0.017) and −0.27 ( p = 0.093). Higher anxiety and depression correlated with lower treatment adherence ( p = 0.041 and p = 0.088, respectively). These results indicate a high-mental disease burden in active SLE that persists despite disease control and emphasize the need to consider socioeconomic factors as part of comprehensive patient assessment.

1. Introduction

Patients with Systemic Lupus Erythematosus (SLE) tend to suffer from a variety of physical and mental comorbidities [ 1 , 2 ]. The latter comprise predominantly depression and anxiety disorders with point prevalence rates of 35.0% (95% confidence interval [CI] 29.9–40.3%) and 25.8% (95% CI 19.2–32.9%), respectively [ 3 ], although estimations vary according to the metrics and definitions used [ 3 , 4 ]. In the University of California San Francisco Lupus Outcomes Study, depression (defined by the Center for Epidemiologic Studies depression scale) incidence rate was 8.8 per 100 person-years [ 5 ] and in another multi-ethnic and racial cohort from the same region, 16% of SLE patients developed depression (based on the Patient Health Questionnaire-8) over an average observation period of 26 months [ 6 ]. Anxiety disorder has been less extensively evaluated, nevertheless a small case-control study found increased prevalence in SLE patients when compared to counterparts with rheumatoid arthritis and healthy individuals [ 7 ].

Accruing evidence suggests that mental disorders, especially depression, in patients with SLE are associated with multiple adverse outcomes such as fatigue [ 8 ], cognitive difficulties [ 9 , 10 ], subclinical atherosclerosis [ 11 ], work [ 12 ] or functional [ 13 ] disability, and reduced health-related quality of life [ 14 , 15 ]. Indeed, severe forms of these disorders can have detrimental effects on daily-life activities and social roles. In a cross-sectional analysis of 80 SLE patients, Nowicka-Sauer et al. [ 16 ] found that anxiety and depression collectively explained 43% of illness perception variance. Accordingly, identifying factors contributing to these comorbidities can advance our understanding of their etiology and also rationalize their possible modification towards the improvement of patient well-being.

In this regard, controversy exists over the relationship between anxiety and depression and SLE disease activity. Thus, active lupus (quantified for example, with the SLE Disease Activity Index [SLEDAI]), especially from the mucocutaneous and musculoskeletal domains, has been correlated with increased depression and anxiety symptoms in some [ 14 , 17 , 18 , 19 ]—but not all [ 15 , 20 , 21 , 22 , 23 ]—studies. Likewise, a connection between inflammatory mediators such as lupus autoantibodies and mood disorders has not been consistently shown (reviewed in [ 24 ]). Of potential relevance is the association between depression and lower treatment adherence [ 25 , 26 , 27 , 28 ], a known driver for lupus flare and activity. This finding, however, lacks extensive confirmation or may be influenced by other factors such as ethnicity [ 29 , 30 , 31 , 32 ]. Therefore, evaluation of the frequency and determinants of mental disorders in different regions and clinical settings is important. Importantly, the majority of aforementioned studies had a cross-sectional design or included patients with no prespecified activity level at entry.

To this end, we carried out a prospective observational study in active and flaring SLE patients who were treated according to standard-of-care, in order to monitor longitudinal changes in depression and anxiety in relation to disease activity. The main hypothesis we sought to test was whether treatment-induced amelioration of the disease would result in the improvement of the aforementioned mental disorders. Taking advantage of our study context of active SLE, we also examined for the possible relationship between anxiety and depressive symptoms with reduced adherence to treatment.

2. Materials and Methods

2.1. study population.

A prospective observational (non-interventional) study was performed at the outpatient clinics of the Department of Rheumatology and Clinical Immunology, University Hospital of Heraklion (Crete, Greece), covering from primary to tertiary care [ 33 , 34 ]. Patients were enrolled by consecutive sampling techniques between May 2021 and September 2021. Inclusion criteria were: (a) SLE diagnosis according to physician assessment and ascertained by the 2019 European Alliance of Associations for Rheumatology (EULAR) and American College of Rheumatology (ACR) classification criteria [ 35 ]; (b) age 18–65 years; (c) active disease defined by a clinical (excluding serology) SLEDAI-2K ≥ 3 [ 36 ] not present in the previous visit; (d) permanent residence in Crete; and (e) comprehension of Greek language. Patients with other coexisting rheumatic diseases, active neuropsychiatric lupus (diagnosed according to multidisciplinary approach as described elsewhere [ 37 ]), dementia, malignancy (past or present), and ongoing pregnancy were excluded. A total of 117 patients visited the outpatient clinics during the enrolment period, 50 of whom met the inclusion criteria. Ten participants did not attend their scheduled follow-up visit, thus data from 40 participants were analyzed.

2.2. Monitoring Protocol, Disease Evaluation, and Data Collection

Patients were monitored at two to four-month intervals over a period of six months as part of routine clinical practice and according to disease severity (based on physician judgment). Disease assessment at baseline and during follow-up included: (a) laboratory (complete blood count, liver and renal function, urinalysis) and immunological [serum anti-dsDNA, C3, C4, antiphospholipid antibodies] tests, (b) disease activity (quantified by the SLEDAI-2K [ 38 ] and the Safety of Estrogens in Lupus Erythematosus, National Assessment (SELENA)-SLEDAI Physician Global Assessment [PGA] [ 39 ]), (c) organ damage (quantified by the Systemic Lupus International Collaborating Clinics (SLICC) and ACR damage index [SDI] [ 40 ]), (d) comorbid diseases (ascertained by medical history, chart review and electronic prescription data) and, (e) use of medications, including the route of administration and dosage of glucocorticoids. Data on sociodemographic factors (age, disease duration, education level, marital status) were retrieved from medical charts and verified by patient interviews. Working status was assessed as described elsewhere [ 41 ] and included past (never or ever had paid employment) and current working status (having paid employment or not). Data were entered into a secure electronic database installed on the Department of Rheumatology and Clinical Immunology (University Hospital of Heraklion) protected server and network. The operation and maintenance of the database were strictly supervised by the scientifically accountable protocol and access was granted only to authorized users and researchers. All principles of anonymity, confidentiality, and non-traceability of data were adhered to.

2.3. Assessment of Anxiety, Depression, and Treatment Adherence

Anxiety and depression levels were determined at baseline and during follow-up by the Hospital Anxiety and Depression Scale (HADS), a self-rating psychometric instrument widely used in SLE [ 4 , 24 , 42 ] and validated in Greek patients [ 43 ] (including patients with chronic rheumatic diseases [ 44 ]). Briefly, HADS includes seven questions for each disorder (anxiety, depression), with a score ranging from 0–21. Scores ≤ 7 correspond to normal levels of anxiety or depression, 8–10 to borderline pathological levels, and 11–21 to pathological levels. Patients with a diagnosis of anxiety disorder or depression were identified by reviewing the medical history, formal psychiatric evaluations, use, and indications for anxiolytic or antidepressant treatments (i.e., prescribed for underlying mental disorder as opposed to other conditions such as fibromyalgia). Treatment adherence was estimated with a methodology based on self-reported patient survey (modified from [ 45 ]). The scale is calculated by assigning one point for each positive answer, thus ranging from 0 (highest adherence) to 4 (lowest adherence).

2.4. Statistical Analysis

Categorical data are presented as numbers with percentages and continuous data as mean with standard deviation (continuous variables) or median with interquartile range (ordinal variables). Linear regression was used to identify factors associated with anxiety and depression. Possible predictors were first assessed by univariate analysis and variables associated with p -Value < 0.100 were considered for multivariate-adjusted analysis (stepwise backward selection method). To determine longitudinal changes (follow-up vs. baseline) in disease activity (SLEDAI-2K), anxiety (HADS-A), and depression (HADS-D), we applied the Wilcoxon Signed Rank test. In addition, absolute differences (Δ( delta ) = follow-up minus baseline scores) were calculated for SLEDAI-2K, HADS-A, and HADS-D. Patients were grouped as having stable or worsening, or improving anxiety and depression (ΔHADS-A/D ≥ 0 vs. < 0, respectively) and independent samples Mann–Whitney test was used to examine for between-group differences in ΔSLEDAI-2K. We also used the Spearman correlation test for the correlation of longitudinal changes in anxiety and depression. The association between treatment adherence and baseline anxiety or depression levels was evaluated by a chi-squared test. Statistical significance was indicated as a two-tailed p -Value < 0.05. All statistical analyses were performed using SPSS V25.0.

2.5. Ethical Aspects

The study was approved by the Research Ethics Committee of the University of Crete and by the Ethics Committee of the University General Hospital of Heraklion, Crete. Written informed consent was obtained from all patients. All conditions for the protection of personal data and medical confidentiality were met.

3.1. Patients with Active SLE Manifest Increased Anxiety and Depression Levels That Persist over Time

We evaluated 40 SLE patients (39 women) with an average (SD) age and disease duration of 50.5 (10.3) and 10.3 (7.0) years, respectively ( Table 1 and Supplementary Table S1 ).

Demographic and clinical characteristics of SLE patients ( n = 40).

1 SD, standard deviation; 2 COPD, chronic obstructive pulmonary disease; 3 SDI, SLICC/ACR damage index.

Fourteen patients (35.0%) had high- or tertiary-level education and the majority (52.5%) were engaged in paid employment. A variety of comorbid conditions were present in our study sample, including mental disorders previously diagnosed by a specialist (depression in n = 13 patients). Organ damage (defined as SDI 0) had accrued in 18 (45.0%) patients ( Table 1 ).

At inclusion, all patients had active disease with a median (IQR) SLEDAI-2K of 6.0 (4.0) ( Table 2 ). Assessment of mental status by the HADS index indicated an increased burden of both anxiety (HADS-A) and depression (HADS-D) with corresponding median (IQR) scores of 11.0 (7.8) and 8.0 (4.8). Accordingly, anxiety and depression of even a mild degree were detected in 70.0% and 52.5% of our patient cohort, respectively.

Disease activity, anxiety, and depression levels in SLE patients at inclusion and follow-up visits.

1 Data are presented as median (interquartile range) or no. (%). 2 Wilcoxon Signed Rank Test. 3 SLE Disease Activity Index-2K.

According to physician judgment and in line with standard clinical practice, patients were offered with treatment modifications due to active disease including initiation or dosage increase of hydroxychloroquine (n = 1), methotrexate (n = 8), azathioprine (n = 3), mycophenolate (n = 3), cyclophosphamide (n = 1), biological agent (n = 6), and glucocorticoids (n = 14). At the follow-up assessment, a significant reduction was noted in SLEDAI-2K, which reached a median of 4.0 (2.0) ( Table 2 ). Conversely, neither anxiety (HADS-A) nor depression (HADS-D) showed significant trends. Thus, average changes in anxiety and depression scores were minimal (median [IQR]: 0.0 [4.8] and −0.5 [4.0], respectively). These results indicate that despite a short-term lowering of disease activity, the burden of mental disorders tends to remain stable and non-improving in patients with SLE.

3.2. Lack of Correlation between Longitudinal Changes in Disease Activity and Mental Disorders in SLE Patients

We sought to gain additional insights into the relationship between anxiety, depression, and disease activity in patients with SLE. Further to examining average trends, we grouped our study sample according to whether SLEDAI-2K was improved (by at least one unit; n = 24) or not (n = 16) during follow-up. We then compared the longitudinal changes in anxiety and depression levels (HADS-A and -D at follow-up minus HADS-A and -D at inclusion visit) between the two aforementioned patient subsets. Comparable changes in HADS-A and HADS-D scores were noted in SLE patients with improved vs. non-improved disease activity ( Figure 1 A).

Longitudinal changes in anxiety and depression in association with improvement or not in disease activity. ( A ) Dot plots demonstrate changes (follow-up minus baseline) in HADS-A (left panel) and HADS-D (right panel) in SLE patients with improving vs. stable or worsening disease activity (SLEDAI-2K). Independent samples Mann–Whitney test was performed between the two patient groups. Blue lines represent medians (interquartile range). ( B ) Correlation of longitudinal changes (follow-up minus baseline) in HADS-A (Δ HADS-A) and HADS-D (Δ HADS-D) values in the SLE sample (each patient is represented by a separate black circles). The Spearman’s correlation coefficient rho = 0.457 ( p -Value = 0.003).

In addition, we identified patients who attained a low-disease activity state according to the definitions proposed by Franklyn et al. [ 46 ] and Polachek et al. [ 36 ]. Again, HADS-A and HADS-D temporal trends did not differ significantly in patients who achieved or did not achieve low-disease activity ( Supplementary Table S2 ). To address any confounding effects of administered treatments, the previous analyses were repeated separately in patients who were started on or received an increased dose of glucocorticoids due to active disease. In an ancillary analysis, we classified patients according to whether their level of anxiety or depression (as defined in Table 2 ) improved (for instance, from “severe” to “moderate”), remain stable, or worsened (for instance, from “mild” to “moderate”). By comparing the three aforementioned groups for corresponding changes in SLEDAI-2K, we found no significant trends ( Supplementary Table S3 ).

Notwithstanding the small sample size, results were similar to the whole patient cohort (data not shown). Notably, longitudinal changes in anxiety showed a strong correlation (rho = 0.457, p = 0.003) with corresponding changes in depression levels ( Figure 1 B). Altogether, these data reiterate that SLE patients whose disease improved and even reached a low-activity state, are still burdened with mental disorders.

3.3. Association of Mental Disorders with Sociodemographic Characteristics in SLE Patients

The previous findings prompted us to search for other possible predictors of mental disorders in our study sample. To this end, we examined the baseline (i.e., registered at inclusion visit) scores of HADS-A and HADS-D in relationship with standard sociodemographic and clinical parameters. Using previously recommended cut-offs, we found no significant differences in average age, SLE duration, disease activity or severity (SLEDAI-2K), organ damage, presence of comorbidities, and education level in patients with high anxiety (HADS-A ≥ 11) or depression (HADS-D ≥ 8) levels as compared to their counterparts with lower scores ( Supplementary Table S4 ). Conversely, patients with lower levels of anxiety reported paid employment at a significantly higher frequency than those with high anxiety (73.7% vs. 33.3%, respectively, p = 0.011). A similar trend in active employment status was observed in SLE patients with low when compared to high-depressive symptoms (68.2% vs. 33.3%, respectively, p = 0.028) ( Supplementary Table S4 ). Next, the same parameters were analyzed by linear regression resulting in comparable findings although the association between employment status and HADS-D scores did not reach statistical significance ( Table 3 ).

Anxiety and depression in association with sociodemographic and clinical characteristics of SLE patients.

1 Linear regression analysis. 95% CI (95% confidence interval); 2 Treated as ordinal variable (0 = primary level; 1 = secondary levels; 3 = tertiary level); 3 Treated as dummy variable (1 = paid employment; 0 = not paid employment); 4 Treated as dummy variable (1 = use; 0 = no use); 5 Backwards elimination model (variables with univariate p -Value 0.100 were entered); HCQ, hydroxychloroquine.

Coupled with our aforementioned results, this analysis suggests that socioeconomic factors (employment)—rather than disease activity—may be linked to the excessive burden of mental disorders in patients with SLE.

3.4. Increased Anxiety and Depression Levels Are Associated with Lower Adherence to Treatment

Our study focused on trends of anxiety and depression in the context of active lupus. Notably, previous studies have associated mental disorders with poor treatment compliance in patients with SLE [ 25 , 26 , 27 , 28 ]. Using a self-reported measure, we found that 19 out of 40 patients (47.5%) had low or very low adherence to treatment. We then investigated whether the severity of mental disorders (assessed at the inclusion visit) correlated with treatment adherence. Within patients with low-anxiety levels (HADS-A < 11), the majority (68.4%) had high compliance; in contrast, among patients with high anxiety (HADS-A ≥ 11), only 38.1% had high compliance and 23.8% exhibited very low or no adherence to treatment ( p = 0.041; Table 4 ).

Association of anxiety and depression with treatment adherence in SLE patients.

1 Chi-squared test. 2 HADS-A ≥ 11. 3 HADS-D ≥ 8.

This relationship was confirmed by a statistically significant positive correlation between HADS-A and adherence scores treated as continuous variables (Spearman’s rho = 0.324, p = 0.041) (data not shown). Likewise, SLE patients with lower severity of depressive symptoms (HADS-D < 8) had better treatment compliance (58.1% with high compliance) when compared to those with HADS-D ≥ 8 (33.3%), however, this association was not statistically significant ( p = 0.088) probably due to the small sample size. Altogether, active SLE patients with a high burden of mental disorders are less likely to adhere to treatment of their disease.

4. Discussion

Mental comorbidities such as anxiety and depression are common in patients with SLE, however their association with underlying activity and likewise, their responsiveness to disease improvement remains inconclusive [ 24 ]. Our longitudinal analysis of 40 active lupus patients who received standard-of-care treatment to control their disease, demonstrated a high burden of anxiety and depression that remains unchanged at least over a short-term follow-up period and may be determined by socioeconomic factors such as employment status rather than by clinical parameters. Notably, increased levels of anxiety and depression tended to correlate with lower treatment adherence, an established determinant for disease flares [ 47 , 48 ], thus further emphasizing the importance of assessing mental disorders and associated risk factors as part of a comprehensive management plan in patients with SLE.

In our sample comprising of active SLE patients with an average age and disease duration of 50.5 and 10.3 years, respectively, significant anxiety (HADS-A ≥ 11) and depression (HADS-D ≥ 8) was each noted in 52.5%. This is in line with the results from previous cross-sectional observational studies [ 7 , 11 , 18 , 23 , 49 , 50 , 51 , 52 ] and meta-analyses of published data [ 3 , 4 ], although reported rates may vary according to the study design, population characteristics, and diagnostic instruments used. In the same context, a large Danish cohort study found that compared with the general population, the adjusted hazard ratio of depression was 2.22 (95% CI 1.77–2.77) for SLE patients [ 53 ]. Intriguingly, Roberts et al. [ 54 ] analyzed data from 194,483 women and found that a history of depression was linked to increased risk (adjusted hazard ratio 2.45; 95% CI 1.74–3.45) for subsequent development of SLE, irrespective of the effect of other confounding factors, thus suggesting a possible cross-interaction between the two conditions.

Although it is plausible to consider inflammation as a determining factor for mental disorders in SLE [ 55 ], there are conflicting reports regarding the relationship of disease activity with anxiety and depression [ 14 , 15 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. To overcome the cross-sectional design limitations of most aforementioned studies, we enrolled active SLE individuals according to predetermined criteria and monitored them at two consecutive time points, i.e., at inclusion and six months post-treatment modification. Contrary to SLEDAI which was significantly improved over time, HADS-A and -D scores remained unchanged. Additionally, we found no reduction in mental disorders within patients who attained a state of low-lupus activity. Subgroup analysis according to intake or not of glucocorticoids yielded similar findings, thus reducing the possibility for a treatment confounding effect [ 56 ]. Our results are in agreement with a longitudinal study of 139 SLE patients which revealed four distinct anxiety trajectories that remained stable and not affected by disease activity over an average period of 30.9 months [ 57 ]. A similar analysis focusing on depression also showed persistence over time and a lack of association with temporal trends in SLEDAI-2K (average follow-up of 30.2 months) [ 58 ]. Collectively, and in line with a previous cohort study indicating that depression might be a long-term outcome of SLE [ 53 ], these data suggest that fluctuations of disease activity might not be major drivers of anxiety and depression, especially in the context of long-standing disease, although it has been argued that prolonged remission (i.e., lasting at least 5 years) might have a positive impact on depression [ 59 ].

Our previous finding coupled with the lack of association between other clinical characteristics and mental disorders prompted us to explore the possible role of sociodemographic factors. We found paid employment status to be protective against both anxiety and depression with corresponding odds ratios of 0.18 and 0.23, independent of SLE severity measures such as SLEDAI and organ damage. This is in agreement with other studies that have identified socioeconomic factors, in particular unemployment, financial strain, or low-social support, as significant correlates of depression in SLE [ 5 , 14 , 19 , 23 , 60 ]. Indeed, mediation modeling has suggested that low-socioeconomic status may impact negatively on the psychosocial resilience [ 60 ] and perceived stress [ 13 ] of lupus patients, thus contributing to higher anxiety, depression, and subsequent disability. It might be also that some SLE individuals are unable to (find) work due to the severity of the underlying disease or the concomitant anxiety or depressive symptoms [ 19 ]. These data underscore the importance of considering relevant socioeconomic factors when assessing the mental status of patients with SLE.

To our knowledge, our study is the first to evaluate medication adherence in Greek individuals with SLE. Using a self-reported survey, we found that 47.5% of patients with active lupus had low or very low compliance to treatment, a percentage that falls within the range (typically, 43–75%) of previously reported adherence rates [ 61 ]. Notably, increased levels of mental disorders tended to correlate with non-adherence, an association that has been previously shown especially for depression in several observational studies [ 25 , 26 , 27 , 28 , 62 , 63 ]. In this regard, anxiety and depression have been recognized as major determinants of the resilience [ 29 ] and illness perception [ 16 ] of lupus patients, which can both impact on compliance. Considering the prognostic implications of treatment adherence in terms of flares prevention and improved patient outcomes [ 64 ], these findings underline the importance of identifying and managing mental disorders in patients with SLE.

Several study limitations should be discussed such as that our results were derived from patients with distinct ethnic, demographic, and clinical characteristics, thus may not be generalizable to the whole SLE spectrum. Nevertheless, we applied specific inclusion criteria for active disease evaluated before and after treatment modifications, which facilitates the homogeneity of our data. Although the sample size can be considered relatively small to detect modest effect sizes, our prospective design enabled the generation of robust data regarding intra-individual temporal changes in SLE activity and mental disorders. Because our cohort was followed for six months, we were not able to examine the possible effect of sustained disease control on anxiety and depression. Additionally, the levels of mood disorders prior to study enrolment and how this might have affected the study findings was not available. Finally, the association between mental disorders and employment might be confounded by other parameters not captured in our analysis, still, the validity of our findings has been confirmed by other studies [ 5 , 14 , 19 , 23 , 60 ].

5. Conclusions

Active SLE patients exhibit a significant burden of anxiety and depressive symptoms, which remain unchanged despite treatment-induced short-term improvement in disease activity. This concurs with the fact that socioeconomic factors such as employment status, rather than clinical parameters, are significant predictors of the mental status of these patients. Despite the lack of association with disease activity, higher levels of anxiety and depression tend to coincide with lower treatment adherence, which is an established driver of adverse disease outcomes and flares. Together, our findings reiterate the importance of a comprehensive risk assessment for mental disorders in patients with SLE towards the improvement of their overall health status and prognosis.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/2077-0383/11/15/4316/s1 , Table S1: Treatment of SLE patients included in the study; Table S2. Longitudinal changes in anxiety and depression in SLE patients who achieved or did not achieve a state of low-disease activity; Table S3: Reclassification of the anxiety and depression level in association with longitudinal change in disease activity in SLE patients; Table S4: Anxiety and depression in association with sociodemographic and clinical characteristics of SLE patients.

Funding Statement

This research was funded by the Special Account for Research Funds (ELKE) of the University of Crete (grant number KA10210).

Author Contributions

Conceptualization, G.B. and C.L.; methodology, M.N.; formal analysis, G.B. and M.N.; investigation, A.R., S.P., A.M.I.S. and P.S.; data curation, M.N. and G.B.; writing—original draft preparation, M.N.; writing—review and editing, G.B. and P.S.; supervision, G.B. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the University Hospital of Heraklion (protocol code 38/14-11-2018).

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

Conflicts of interest.

The authors declare no conflict of interest.

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