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ORIGINAL ARTICLE
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Year : 2021  |  Volume : 67  |  Issue : 3  |  Page : 139-145  

Association of atopic dermatitis with an increased risk of systemic lupus erythematosus: A systematic review and meta-analysis

B Ponvilawan1, N Charoenngam2, W Wongtrakul3, P Ungprasert4,  
1 Department of Pharmacology, Siriraj Hospital, Mahidol University, Bangkok, Thailand
2 Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
3 Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
4 Department of Rheumatic and Immunologic Diseases, Cleveland Clinic Foundation, Cleveland, OH, USA

Correspondence Address:
B Ponvilawan
Department of Pharmacology, Siriraj Hospital, Mahidol University, Bangkok
Thailand

Abstract

Context: Previous studies on the association between atopic dermatitis (AD) and systemic lupus erythematosus (SLE) have yielded inconsistent results. Aims: To investigate the relationship between atopic dermatitis and systemic lupus erythematosus. Settings and Design: Systematic review and meta-analysis. Materials and Methods: A systematic review was conducted on EMBASE and MEDLINE databases from inception to March 2020 using a search strategy that consisted of terms related to AD and SLE. Eligible study must be either cohort or case-control study. For cohort studies, they must include patients with AD and comparators without AD, then follow them for incident SLE. For case-control studies, they must include cases with SLE and controls without SLE and examine their prior history of AD. Statistical Analysis Used: Meta-analysis of the studies was performed using a random-effect, generic inverse variance method to combine effect estimate and standard error. Funnel plot was used to assess publication bias. Results: A total of 21,486 articles were retrieved. After two rounds of review by three investigators, six case-control studies were qualified for the meta-analysis. The case-control study meta-analysis found a significantly increased odds of SLE among patients with AD with the pooled odds ratio of 1.46 (95% CI, 1.05–2.04). Conclusions: A significant association between AD and increased odds of SLE was observed by this systematic review and meta-analysis.



How to cite this article:
Ponvilawan B, Charoenngam N, Wongtrakul W, Ungprasert P. Association of atopic dermatitis with an increased risk of systemic lupus erythematosus: A systematic review and meta-analysis.J Postgrad Med 2021;67:139-145


How to cite this URL:
Ponvilawan B, Charoenngam N, Wongtrakul W, Ungprasert P. Association of atopic dermatitis with an increased risk of systemic lupus erythematosus: A systematic review and meta-analysis. J Postgrad Med [serial online] 2021 [cited 2022 Jun 25 ];67:139-145
Available from: https://www.jpgmonline.com/text.asp?2021/67/3/139/324236


Full Text



 Introduction



Atopic dermatitis (AD), or atopic eczema, is the most common chronic inflammatory skin disease worldwide which typically develops during childhood. Patients with AD usually present with recurrent eczematous lesions in flexural areas that cause pruritus and can interfere with daily activities.[1],[2] Several epidemiological studies have estimated that around 5–25% of the world population are affected by AD.[3],[4],[5] Family history of atopic diseases and several environmental factors, such as living in urban setting or regions with low ultraviolet light and smoking, are known risk factors for this disease.[1],[6],[7],[8]

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with heterogeneous manifestations involving multiple organs such as joints, kidneys, nervous system, bone marrow, and skin.[9],[10] The incidence rate varies considerably around the world, ranging from 0.3 to 23.2/100,000 person-years with a predilection for women of childbearing age and people of African, Hispanic, or Asian ancestry.[10],[11] Known risk factors include family history, tobacco smoking, obesity, and vitamin D deficiency.[12],[13],[14]

Multiple studies have demonstrated that AD is associated with an increased risk of several chronic diseases such as cardiovascular, neuropsychiatric, and autoimmune disorders.[15],[16],[17],[18] There are also studies to suggest the association between AD and SLE although the results are still conflicting.[19],[20],[21],[22],[23],[24],[25],[26] This systematic review and meta-analysis was performed in order to comprehensively investigate the relationship between AD and SLE by identifying all relevant studies and summarizing their results together.

 Method



Search strategy

Independent search for all relevant publications indexed in EMBASE and MEDLINE from inception to March 2020 was conducted by three investigators (B.P., N.C., and W.W.) using search terms related to AD and SLE. The detailed search strategy is exhibited in the Supplemental Material 1.

Inclusion criteria

Eligible study must be either cohort or case-control study. For cohort studies, they must include patients with AD and comparators without AD, then follow them for incident SLE. Relative risk (RR), incidence rate ratio (IRR), hazard risk ratio (HR), or standardized incidence ratio (SIR) with associated 95% confidence interval (95% CI) that compare the incidence of SLE between the two groups must be reported. For case-control studies, they must include cases with SLE and controls without SLE and examine their prior history of AD. Odds ratio (OR) with 95% CI of the association between AD and SLE must be reported.

Study eligibility was independently determined by three investigators (B.P., N.C., and W.W.). The senior investigator (P.U.) provided the final determination after discussions with all investigators if different conclusions were made by the three investigators. The Newcastle-Ottawa quality assessment scale for cohort study and case-control study was used for determination of the quality of each study.[27] This quality assessment was performed by two investigators (B.P. and P.U.).

Data extraction

Data extraction was performed using a standardized collection form which contains the following information: the first author's surname, country where the study was conducted, study design (case-control versus cohort study), year of publication, number of participants, recruitment of participants, diagnosis of SLE, diagnosis of AD, follow-up duration (for cohort studies only), average age of participants, percentage of female participants, comorbidities of participants, variables adjusted in multivariate analysis, and adjusted effect estimates along with their 95% CI.

Statistical analysis

Review Manager 5.3 software (The Cochrane Collaboration, London, United Kingdom) was used for analysis of data. Point estimates along with their standard errors were extracted from each study and were combined together to calculate pooled effect estimates using the generic inverse variance method of DerSimonian and Laird which assigns weight for each study based on its variance.[28] Two meta-analyses of cohort studies and case-control studies were performed separately if there are enough number for each type of studies. IRR, HR, and SIR of cohort study was used as an approximation of RR to calculate pooled risk ratio for cohort studies. Random-effect model was used instead of fixed-effect model because of the difference in study design, protocols, and background populations of the included studies. Statistical heterogeneity was evaluated using Cochran's Q test along with I2 statistic which quantifies the proportion of the total variation across studies that is from heterogeneity instead of coincidence. A value of I2 of 0–25% implies insignificant heterogeneity, 26–50% low heterogeneity, 51–75% moderate heterogeneity, and >75% high heterogeneity.[29] The presence of publication bias was investigated by visualization of funnel plot to look for evidence of asymmetry.

 Results



Search results

A comprehensive systematic review of EMBASE and MEDLINE database yielded 21,486 articles in which 2372 articles were duplication and were removed, resulting in 19,114 articles for title and abstract review. A total of 19,051 articles were then eliminated as they obviously did not meet the eligibility criteria based on study design, type of article, and participants, leaving 63 articles for full-length article review. A total of 55 articles were eliminated at this stage as they did not report the outcome of interest. Ultimately, two cohort studies[19],[20] with 4,525,973 participants and six case-control studies[21],[22],[23],[24],[25],[26] with 19,713 participants met all of the eligibility criteria. Due to the limited number of cohort studies, only case-control studies were included into the meta-analysis. [Figure 1] illustrates the search methodology and selection process of this study. [Table 1] and [Table 2] provide information on design and baseline characteristics of participants of the included cohort studies and case-control studies, respectively.{Table 1}{Table 2}{Figure 1}

Association between atopic dermatitis and systemic lupus erythematosus

The meta-analysis of case-control studies also showed a significantly elevated odds of SLE among patients with AD compared with individuals without AD with the pooled odds ratio of 1.46 (95% CI, 1.05–2.04). Statistical heterogeneity of this meta-analysis was moderate with I2 of 63% [Figure 2].{Figure 2}

Evaluation for publication bias

Presence of publication bias was assessed by visualization of funnel plot. The plot for case-control studies was asymmetrical, which was suggestive of the presence of publication bias [Figure 3].{Figure 3}

To assess the effect of this publication bias on the pooled result, trim-and-fill sensitivity analysis as described by Duval et al.[30] was performed using Comprehensive Meta-analysis Program (Biostat, Englewood, New Jersey, USA). Using this technique, one hypothetical missing study was identified [Figure 4]. Inclusion of this hypothetical missing study into the meta-analysis did not significantly alter the pooled result with the new pooled OR of 1.56 (95% CI, 1.09–2.23).{Figure 4}

 Discussion



This systematic review and meta-analysis included data from 19,713 participants and found that patients with AD had 1.46-fold increased odds of developing SLE compared with individuals without AD. The results of two cohort studies further supported the result of our meta-analysis as they also reported the significantly increased risk of developing SLE in patients with AD.[19],[20] The exact mechanisms responsible for this association are still not known with certainty. Some possible explanations are discussed below.

First, immunologic pathways involving Th1, Th2, and Th17 cells might be responsible for both AD and SLE. A considerable amount of evidence shows that both patients with AD and SLE have an upregulation of Th2 cytokines, such as IL-5 and IL-13, and Th17 cytokines, such as IL-17 and IL-22. On the other hand, they had a downregulation of IL-2, one of the major cytokines of Th1 cells.[31],[32],[33],[34],[35],[36],[37],[38] Moreover, recent studies have demonstrated an increased level of IgE among patients with SLE, particularly among those with active disease, similar to patients with AD.[39],[40],[41] Thus, it is possible that dysregulation of Th1, Th2, and Th17 activities in AD could give rise to evolution of SLE in the same patients later in life.

Second, genetic factor might also play a role in the association between AD and SLE as family history is a known predisposing factor for both diseases.[7],[12] In fact, individuals with certain human leukocyte antigen (HLA) genotypes, such as HLA-B and HLA-DRB1, are found to have an increased tendency to develop both diseases.[42],[43],[44],[45] Nonetheless, common susceptibility locus and single nucleotide polymorphisms (SNPs) in HLA genes are yet to be found.

Apart from genetic risk factor, AD and SLE also share some environmental risk factors. Tobacco smoking and obesity are reported to be associated with an increased risk of both AD and SLE.[6],[13],[14] Tobacco smoking could promote elevation of serum IgE level and inflammatory response which, in turn, generate dysregulation of T and NK cells, DNA damage, and epigenetic changes. Obesity could create proinflammatory effect via adipokines secreted from dysfunctional adipocytes.[46],[47],[48],[49],[50],[51],[52],[53],[54]

Last, surveillance bias could also partially be responsible for an increased risk of SLE as patients with AD tend to have a more frequent exposure to healthcare providers due to the chronic nature of AD. However, SLE is a disease which would generally cause noticeable symptoms that patients usually seek for medical attention. Therefore, surveillance bias is probably not the only reason for the observed relationship.

Nonetheless, this systematic review and meta-analysis carries some limitations and the pooled results should be interpreted with caution. First, statistical heterogeneity of the meta-analysis was not low. We believe that difference in study design, protocols, and characteristics of the participants across the studies was responsible for the inter-study variation. Second, the accuracy of case identification of AD and SLE could be limited as about half of the included studies used diagnostic codes from administrative databases[19],[20],[25],[26] to identify and confirm the diagnosis. Finally, publication bias may have been present as evident by the asymmetrical funnel plot.

 Conclusion



This systematic review and meta-analysis observed an elevated odds of incident SLE among patients with AD compared with individuals without AD. Limitations included between-study heterogeneity, limited accuracy of case identification in the primary studies, and publication bias. Clinicians who take care of patients with AD should be aware of the higher risk and further evaluation is warranted when they develop new systemic symptoms.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 Supplemental Material 1 – Searching Strategy



EMBASE Database

'asthma'/exp OR 'asthma''reactive airway disease'/exp OR 'reactive airway disease''bronchus hyperreactivity'/exp OR 'bronchus hyperreactivity''bronchial hyperresponsiveness'/exp OR 'bronchial hyperresponsiveness''atopic dermatitis'/exp OR 'atopic dermatitis''eczema'/exp OR 'eczema''allergic rhinitis'/exp OR 'allergic rhinitis''atopy'/exp OR 'atopy'atopic'autoimmune disease'/exp OR 'autoimmune disease''rheumatic disease'/exp OR 'rheumatic disease''lupus'/exp OR 'lupus''systemic lupus erythematosus'/exp OR 'systemic lupus erythematosus''lupus erythematosus'/exp OR 'lupus erythematosus''sle'/exp OR 'sle'#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9#10 OR #11 OR #12 OR #13 OR #14 OR #15#16 AND #17

Ovid MEDLINE Database

asthma.mp. or exp asthma/exp bronchial hyperreactivity/or reactive airway disease.mp.reactive airway disease.mpatopic dermatitis.mp. or exp dermatitis, atopic/eczema.mp. or exp eczema/allergic rhinitis.mp. or exp rhinitis, allergic/atopic.mp.atopy.mp.rheumatic disease.mp. or exp rheumatic diseases/autoimmune disease.mp. or exp autoimmune diseases/systemic lupus erythematosus.mp or exp lupus erythematosus, systemic/sle.mp1 or 2 or 3 or 4 or 5 or 6 or 78 or 9 or 10 or 11 or 1213 and 14

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