How do autoimmune diseases cluster in families? A systematic review and meta-analysis

Abstract

Background: A primary characteristic of complex genetic diseases is that affected individuals tend to cluster in families (that is, familial aggregation). Aggregation of the same autoimmune condition, also referred to as familial autoimmune disease, has been extensively evaluated. However, aggregation of diverse autoimmune diseases, also known as familial autoimmunity, has been overlooked. Therefore, a systematic review and meta-analysis were performed aimed at gathering evidence about this topic.

Methods: Familial autoimmunity was investigated in five major autoimmune diseases, namely, rheumatoid arthritis, systemic lupus erythematosus, autoimmune thyroid disease, multiple sclerosis and type 1 diabetes mellitus. Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were followed. Articles were searched in Pubmed and Embase databases.

Results: Out of a total of 61 articles, 44 were selected for final analysis. Familial autoimmunity was found in all the autoimmune diseases investigated. Aggregation of autoimmune thyroid disease, followed by systemic lupus erythematosus and rheumatoid arthritis, was the most encountered.

Conclusions: Familial autoimmunity is a frequently seen condition. Further study of familial autoimmunity will help to decipher the common mechanisms of autoimmunity.

Figure 1

How do autoimmune diseases cluster in families? A) Familial autoimmune disease. This classical concept indicates the same AD in diverse FDRs. In this case, a proband and a FDR (that is, the father) present with T1D. B) Familial autoimmunity. This new concept corresponds to the presence of different ADs in a nuclear family. C) Multiple autoimmune syndrome. This condition refers to the presence of three or more autoimmune diseases in the same subject. In this case, two brothers met criteria for the syndrome. Moreover, this pedigree also meets criteria for familial autoimmunity. D) Polyglandular autoimmune syndrome type II. In this family, however, familial autoimmune disease and familial autoimmunity coexist. The results of HLA genes (that is, A, B, DRB1, DQB1) typing are shown in colors (by reverse dot blot using InnoLipa Kit). A suggestive linkage among the HLA loci is observed. In these diagrams, people are represented by symbols: circles for female and squares for male, and the bottom line represents the offspring of the couple above. Solid symbols represent affected individuals. Symbol with a diagonal line indicates deceased individual. AdD, Addison's disease; AITD, autoimmune thyroid disease; APS, antiphospholipid syndrome; FDRs, first degree relative; MS, multiple sclerosis; PA, pernicious anemia; SLE, systemic lupus erythematosus; SS, Sjögren's syndrome; T1D, type 1 diabetes; VIT, vitiligo.

Figure 2

Flow diagram of current study. AITD, autoimmune thyroid disease; MS, multiple sclerosis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; T1D, type 1 diabetes.

Figure 3

Flowchart summarizing the search results.

Figure 4

Forest plots depicting odds ratios for specific autoimmune diseases in first degree relatives. Familial autoimmunity has to be seen as a two way relationship depending on which member of the nuclear family is the proband. Therefore, grouping meta-analysis by the disease present in FDRs is equivalent to analyzing it by the disease present in the proband. The figure shows four different analyses. From top to bottom autoimmune thyroid disease (A), type 1 diabetes mellitus (B), inflammatory bowel disease (C) and familial autoimmunity (D) assessed as an outcome. The summary effect (random effect model) is depicted as a diamond at the bottom of each analysis. The lateral points of each diamond indicate confidence intervals for this estimate. ^aNumbers represent different subgroups within the study.

Figure 5

Forest plots depicting odds ratios for familial autoimmunity. The figure shows two different analyses. From top to bottom: (A) rheumatoid arthritis (RA), (B) multiple sclerosis (MS). Autoimmune diseases in first degree relatives through all the studies from a specific autoimmune disease present in the proband were analyzed. The summary effect (random effect model) is depicted as a diamond at the bottom of each analysis. The lateral points of each diamond indicate confidence intervals for this estimate. ^aNumbers represent different subgroups within the study.

Figure 6

Forest plots depicting risk ratios for familial autoimmunity in probands with AITD and MS. The figure shows two different analyses. From top to bottom: autoimmune thyroid disease (A) and multiple sclerosis (B). The summary effect (random effect model) is depicted as a diamond at the bottom of each analysis. The lateral points of each diamond indicate confidence intervals for this estimate. ^aNumbers in the study name represent different subgroups within the study. AITD, autoimmune thyroid disease; MS, multiple sclerosis.

Figure 7

Forest plots depicting risk ratios for familial autoimmunity in probands with T1D and RA. The figure shows two different analyses. From top to bottom: type 1 diabetes mellitus (A) and rheumatoid arthritis (B). The summary effect (random effect model) is depicted as a diamond at the bottom of each analysis, the lateral points of which indicate confidence intervals for this estimate. ^aNumbers in the study name represent different subgroups within the study. RA, rheumatoid arthritis; T1D, type 1 diabetes.

Figure 8

Familial autoimmunity. The vertical axis corresponds to the proband's disease and each disease individually. In the horizontal axis diseases present in first degree relatives are shown. Each color belongs to the proband's disease. The figure only includes significant results and may serve as a guide for clinical practice in order to search ADs in FDRs of probands. Note that familial autoimmune disease is excluded. AA, alopecia areata; AdD, Addison's disease; AS, ankylosing spondylitis; AITD, autoimmune thyroid disease; CD, celiac disease; CrD, Crohn's disease; FDR, first degree relative; IBD, inflammatory bowel disease; IIM, idiopathic inflammatory myositis; JDM, juvenile dermatomyositis; JRA, juvenile rheumatoid arthritis; JSLE, juvenile systemic lupus erythematosus; MAS, multiple autoimmune syndrome; MG, myasthenia gravis; MS, multiple sclerosis; PA, pernicious anemia; PAN, polyarteritis nodosa; PBC, primary biliary cirrhosis; PSO, psoriasis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SS, Sjögren's syndrome; SSc, systemic sclerosis; T1D, type 1 diabetes; UC, ulcerative colitis; VIT, vitiligo; WG, Wegener's granulomatosis. Note: Although AS is considered an auto inflammatory more than autoimmune disease [76] we show the results obtained.