Rheumatic and autoimmune thyroid disorders: A causal or casual relationship?

AUTREV-01625; No of Pages 7 Autoimmunity Reviews xxx (2014) xxx–xxx

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Review

Rheumatic and autoimmune thyroid disorders: A causal or casual relationship? Khalil Bourji, Mariele Gatto, Franco Cozzi, Andrea Doria ⁎, Leonardo Punzi Rheumatology Unit, Department of Medicine-DIMED, University of Padova, Italy

a r t i c l e

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Article history: Received 7 September 2014 Accepted 23 September 2014 Available online xxxx

a b s t r a c t A number of dysfunctions may affect the thyroid gland leading either to hyper- or hypothyroidism which are mediated by autoimmune mechanisms. Thyroid abnormalities may represent an isolated alteration or they may be the harbinger of forthcoming disorders as is the case of well-characterized polyendocrine syndromes. Also, they may precede or follow the appearance of rheumatic manifestations in patients affected with connective tissue diseases or rheumatoid arthritis. The mechanisms by which autoimmune thyroid disorders may be linked to systemic autoimmune diseases have not been fully unraveled yet, however alterations of common pathways are suggested by shared genetic variants affecting autoantigen presentation and regulation of the immune response. On the other hand, the higher prevalence of autoimmune thyroid disorders over rheumatic diseases compels the chance of a mere causal concomitancy in the same patient. The aim of our paper is to provide an overview of available data on thyroid involvement in different rheumatic diseases and to go over the main rheumatic manifestations in the context of autoimmune thyroid diseases. © 2014 Elsevier B.V. All rights reserved.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . Thyroid involvement in rheumatic diseases . . . . . 2.1. Sjögren syndrome (SS) . . . . . . . . . . 2.2. Systemic Lupus Erythematosus (SLE) . . . . 2.3. Rheumatoid arthritis (RA) . . . . . . . . . 2.4. Systemic sclerosis (SSc) . . . . . . . . . . 2.5. Polymyalgia rheumatica (PMR) and vasculitis 3. Rheumatic manifestations in thyroid diseases . . . . 3.1. Joint and bone manifestations . . . . . . . 3.2. Muscular manifestations . . . . . . . . . . 3.3. Neurologic manifestations . . . . . . . . . 4. Anti-thyroid drug (ATD) induced RM . . . . . . . . 5. Conclusions . . . . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . . . Conflicts of interest . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction

⁎ Corresponding author at: Rheumatology Unit, Department of Medicine, University of Padova, Via Giustiniani, 2, 35128 Padova, Italy. Tel.: +39 049 8212190; fax: + 39 049 8212191. E-mail address: [email protected] (A. Doria).

Thyroid gland involvement in autoimmune diseases (AIDs) is well described and a pathogenic link may exist between immune-mediated thyroid disorders and rheumatic diseases with autoimmunity being a common feature [1,2]. However, thyroid affections are more common in the general population than AIDs; therefore, casual occurrence should be carefully considered.

http://dx.doi.org/10.1016/j.autrev.2014.10.007 1568-9972/© 2014 Elsevier B.V. All rights reserved.

Please cite this article as: Bourji K, et al, Rheumatic and autoimmune thyroid disorders: A causal or casual relationship?, Autoimmun Rev (2014), http://dx.doi.org/10.1016/j.autrev.2014.10.007

2

K. Bourji et al. / Autoimmunity Reviews xxx (2014) xxx–xxx

In this paper we report an overview on previous and recent papers analyzing thyroid involvement in different rheumatic diseases, and go over the main rheumatic manifestations (RM) in the context of thyroid diseases and anti-thyroid drug uses. 2. Thyroid involvement in rheumatic diseases Autoimmune thyroid diseases are the most frequent autoimmune endocrine disorders. Chronic autoimmune thyroiditis (CAT), also called chronic lymphocytic thyroiditis or Hashimoto's thyroiditis, represents the cornerstone of this category. It is the most common and extensively studied organ-specific autoimmune disorder in humans [3]. 2.1 . Sjögren syndrome (SS) SS is a chronic autoimmune disorder that affects exocrine glands mainly salivary and lachrymal glands with lymphocytic infiltration and clinical mouth and eye dryness. SS is commonly associated with autoimmune thyroid manifestations. Retrospective studies carried out in cohorts of patients either with primary autoimmune thyroid affections or with primary SS, reported a high prevalence of both entities [4,5]. A highly significant association between the presence of thyroid auto-antibodies and sicca syndrome has been reported [6]. A study by Kelly et al. [7] showed a prevalence of thyroid alterations of 14% among 100 SS patients, with hypothyroidism being found in 11% and hyperthyroidism in 3%. Later on, Perez et al. [8] studied the thyroid function of 33 patients with SS and found thyroid disease and thyroid dysfunction in 45% of these patients, being autoimmune thyroiditis in 24%, hypothyroidism in 33% and hyperthyroidism in 6%. Antithyroperoxidase (TPO) antibodies, anti-thyroglobulin (TG) antibodies, anti-thyroxine antibodies and antitriiodiothyronine antibodies were positive in 45%, 18%, 42% and 36% of patients, respectively. This study suggests that SS and thyroid disease are more frequently associated than previously thought. In 1996, we evaluated the prevalence of thyroid disorders in 121 consecutive patients with primary SS classified according to Vitali's criteria [9], in 74 patients with rheumatoid arthritis (RA) and in 404 controls. As compared with controls, patients with SS were more likely to have anti-microsomal (Mi) antibodies (9% vs. 17.6%; p b 0.05), and both SS and RA patients displayed significantly higher levels of anti-TG antibodies compared with controls (13.4% and 10.9% vs. 1%, respectively, p b 0.0001). The prevalence of CAT was 7.4% in SS and 6.7% in RA. Our results supported the concept that thyroid disease is more common in primary SS than in RA and controls [10]. Another large cohort study showed a prevalence of 36% of thyroid disease in patients with a diagnosis of SS; however, this prevalence was not significantly higher than in controls [11]. In a study on 1138 patients with Systemic Lupus Erythematosus (SLE), 169 had a diagnosis of SS. Thyroid diseases were more frequently observed in patients with SLE-SS than in SLE alone (29.6% vs. 12.7%; p b 0.05) [12]. More recently, Caramaschi et al. reported a prevalence of 27% of Hashimoto thyroiditis among patients with SS diagnosis [13]. 2.2. Systemic Lupus Erythematosus (SLE) A correlation between SLE and thyroid-AIDs has been suggested since a long time by White et al. [14] and Hijmans et al. [15]. However, these results were challenged by Scofield in 1996, who found SLE patients to have just slight or no risk of autoimmune thyroid disease compared with age- and sex-matched population [16]. Later on, the same author observed more thyroid diseases in patients with SLE-SS than in SLE alone [12]. In a cross sectional study on 133 patients (69 affected with SLE and 64 affected with RA), Chan et al. [17] observed that 13 % of SLE patients and 6.3% of RA patients had subclinical hypothyroidism. Furthermore, anti-TPO antibodies were detected in

23.2% of SLE and 10.9% of RA patients. In another large cohort study, involving 300 patients with SLE, the prevalence of hypothyroidism in SLE was higher than in the normal population (5.7% vs. 1%), while that of hyperthyroidism (1.7%) was not significantly different. In addition, 14% of SLE patients had anti-thyroid antibodies, rising up to 68% in the subgroup with thyroid disease (p b 0.001) [18]. On the other hand, antinuclear antibody (ANA) positivity can often be found in patients affected with Hashimoto's thyroiditis bearing no pathogenic effect.

2.3. Rheumatoid arthritis (RA) The presence of a correlation between RA and thyroid dysfunction is still debated. Since the first studies published about this topic, conflicting evidences were reported [19,20]. In a prospective controlled study by Shiroky et al., evidence of thyroid diseases was observed in 30% of women with RA (mostly hypothyroidism) compared with 11% in a matched control group [21]. However, another study showed similar percentages but with no significant difference between cases and controls [22]. More recent studies suggest that there is no difference in the prevalence of thyroid disease in patients with RA compared with the general population or with patients affected with other rheumatic diseases. Accordingly, McCoy et al. did not demonstrate a significant difference in the presence or development of thyroid disease in RA patients when compared to non-RA patients [23]. Furthermore, a Colombian study carried out in a cohort of 800 patients with RA found that the prevalence of autoimmune thyroid disease was 9.8% and the anti-TPO antibodies were positive in 37.8% while the anti-TG antibodies were positive in 20.8% of patients [24].

2.4. Systemic sclerosis (SSc) Since the pioneering study by Becker et al. [25] reporting just one case of scleroderma out of 506 patients followed at the Mayo Clinic for Hashimoto's thyroiditis, several studies investigated a possible relationship between SSc and autoimmune thyroid disorders [26,27]. Some years later, Molteni et al. [28] evaluated the frequency of anti-thyroid antibodies and analyzed genetic association with the HLA class II antigens in 85 patients with SSc. The proportions of patients with anti-TG and anti-TPO antibodies were 12% and 19%, respectively. Subjects with positive anti-TPO antibodies showed a higher frequency of the HLA-DR15 allele compared with anti-TPO negative patients, suggesting that HLA-DR15 may be an immunogenic marker associated with antibodies against TPO. Later on, another Italian research group showed that TSH (thyroid stimulating hormone) levels and anti-TPO antibodies were significantly higher in female patients with SSc than in the sex-matched control group (mean TSH levels 3.6 vs. 1.6 μU/ml, TPO 115 vs. 24 IU/ml, p b 0.05) yet no statistically significant difference was noticed in the prevalence of subclinical hyperthyroidism among these groups [29]. Higher prevalence of hypothyroidism in 110 SSc patients compared with 80 healthy controls was reported in a Mexican cross-sectional study (19% vs. 1.3%, p b 0.01) [30]. Assessing the thyroid function of 160 female patients 79 with SSc and 81 with osteoarthritis (OA), Marasini et al. found 31 out of 160 women (19%) displaying thyroid dysfunction, being either hyperthyroidism in 6 (4%) or hypothyroidism in 25 (16%). Hyperthyroidism was observed more frequently in women with OA compared with SSc while prevalence of hypothyroidism was higher in SSc patients, yet not statistically significant [31]. Recently, Danielidis et al. [32] reported an increase in prevalence of anti-TPO antibodies but not of anti-TG antibodies in SSc patients compared to healthy controls (27.5% vs. 14%, p = 0.016) with a statistical significance only in limited cutaneous SSc.

Please cite this article as: Bourji K, et al, Rheumatic and autoimmune thyroid disorders: A causal or casual relationship?, Autoimmun Rev (2014), http://dx.doi.org/10.1016/j.autrev.2014.10.007

K. Bourji et al. / Autoimmunity Reviews xxx (2014) xxx–xxx

2.5. Polymyalgia rheumatica (PMR) and vasculitis

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Table 2 Prevalence of rheumatic manifestations in patients with autoimmune thyroid diseases.

In spite of several studies aimed to investigate thyroid gland involvement in the context of PMR, no clear association has been described yet. Dent and Edwards [33] found 7 patients with PMR or giant cell arthritis (GCA) out of 250 females (2.8%) with autoimmune thyroid disease. Other two prospective controlled studies have excluded any association between thyroid diseases and PMR or GCA [34,35]. Few case reports were presented describing patients with vasculitis and thyroid disease [36,37], yet data are too scarce to draw a significant association. Studying a cohort of 33 patients with Behçet's disease (BD), Akdeniz et al. [38] found lower baseline levels of both TSH and TRH-stimulated TSH, but normal thyroid function in BD patients compared to healthy controls. Another study did not show any difference in thyroid function tests or anti-thyroid antibody titers between BD patients and healthy controls except for fT4 levels, which were significantly lower in BD patients [39]. Moreover, false positivity or cross reactivity induced by the presence in the serum of anti-thyroid or anti-neutrophil cytoplasm antibodies (ANCA) may occur. Indeed, TPO and myeloperoxidase (MPO) molecules contain cross-reactive epitopes that are exposed in denatured molecules and may cause false positive antibody findings in solid phase immunoenzymatic assays [40]. Learning from available data, subclinical thyroid alterations and anti-thyroid antibody positivity seem a common finding in the context of systemic autoimmune diseases, however overt thyroid dysfunction is less frequently observed. A tantalizing relationship may be suggested in diseases where glands are more frequently affected i.e. SS (Table 1). Noteworthy, anti-thyroid antibodies are often non-pathogenic (apart from Graves' disease), rather they are produced due to the abnormal antigen availability deriving from a cytotoxic-mediated damage of the thyroid gland, which could be enhanced in systemic autoimmune diseases. 3. Rheumatic manifestations in thyroid diseases Rheumatic manifestations (RM) are the clinical signs and symptoms that usually characterize rheumatic syndromes or diseases; however, in our and other experience it is not rare to find these manifestations characterizing other non-rheumatic diseases, e.g. thyroid diseases. Indeed, the joints, muscles, and nervous system are the most common sites of RM in thyroid diseases (Table 2). 3.1. Joint and bone manifestations The most frequent joint manifestations in CAT are arthritis or arthralgia. In 1984, LeRiche and Bell [41] proposed that a benign form of seronegative polyarthritis resembling mild RA be found in euthyroid patients with CAT. Similar findings were later confirmed by our [42] and others' [43] reports. In our study, we included 33 patients affected with CAT and presenting with unclassified arthritis with a median follow-up of 6.42 years (range 4–13). Patients were subdivided into two groups i.e. polyarthritis (16 patients) and oligoarthritis (17 patients). At the end of follow-up, 8 out of the 16 patients with polyarthritis developed severe RA, characterized by bone erosions, high levels of synovial fluid

Rheumatic manifestations

Prevalence (%)

References

Polyarthralgia Arthritis Gout attack Thyroid acropachy Adhesive capsulitis Fibromyalgia Carpal tunnel syndrome

18.7–98 18.7 7.1 1 10.9 59 30–32.5

[3,52] [3] [48] [53,54] [61] [52] [61,83]

interleukin (IL)-1b and increased frequency of HLA DR4. The remainder 8 patients of this group had a mild arthritis, without bone erosions and well responding to symptomatic drugs. Patients with oligoarthritis had a mild course, with frequent spontaneous remissions. Hypothyroidism was present in 4 out of 8 (50%) patients with RA, in 3 out of 8 (37.5%) patients with non-RA polyarthritis and in 7 out of 17 (41.2%) patients with oligoarthritis. Bone erosions were observed on X-ray in 4 out of 8 (50%) patients with RA, but in none with non-RA polyarthritis and oligoarthritis. We concluded that a variety of inflammatory arthropathies can be found in association with CAT which are characterized by a mild and non-erosive evolution; their course does not seem to be influenced by thyroid dysfunction and displays a clinical pattern similar to that found in connective tissue diseases. Intra-articular production of anti-thyroid antibodies was suggested by some authors [44] as a part of the pathogenesis of arthritis associated with CAT. These observations were subsequently confirmed by our group, by demonstrating that in two cases anti-thyroid antibodies, in particular anti-Mi antibodies, were observed in synovial fluid 1 year prior to their detection in the serum, thus revealing a harboring CAT [45]. Few cases of acute crystal-induced arthritis have been reported. Despite the association between hypothyroidism and chondrocalcinosis (CC) suggested by Dorwart and Schumacher [46], different authors did not find a significant difference in the frequency of CC in patients with hypothyroidism and matched controls. In a prospective study of 100 patients with hypothyroidism and 100 controls matched by age and sex, radiologic signs of CC were detected in 17 patients with hypothyroidism and in 10 controls, CC was not significantly more frequent among hypothyroid patients than in controls [47]. A significant increase in both gout attacks and hyperuricemia was reported by Giordano et al. [48] in patients with hypothyroidism, which was attributed to a decreased renal plasma flow and impaired glomerular filtration leading to hyperuricemia. Arthralgia and especially polyarthralgia (PA) are among the most frequent musculoskeletal symptoms occurring in patients with CAT [3]. Although frequently observed, arthralgia is difficult to classify, may it be isolated or associated with myalgia; acute, episodic or chronic, affecting one or few joints or being polyarticular [43,49]. We studied a group of patients affected with PA, in an attempt to characterize their main clinical manifestations, outcome and response to the therapy [50]. Accordingly, we selected 20 consecutive patients affected with CAT and complaining with PA yet without any evidence of any known rheumatic disease. Eight patients had normal thyroid function, 2 were

Table 1 Prevalence of thyroid dysfunction and anti-thyroid antibodies in patients with rheumatoid arthritis and connective tissue diseases. Disease

Rheumatoid arthritis Systemic Lupus Erythematosus Sjögren syndrome Systemic sclerosis

Thyroid dysfunction

Hypothyroidism

Hyperthyroidism

Anti-TPO

%

[Ref]

%

[Ref]

%

[Ref]

%

[Ref]

%

Anti-TG [Ref]

7–30 7 14–45 19–26

[9,21,22,24] [18] [7,8,13] [29,31]

7–26 5.7 11–33 16–21

[21,22] [18] [7,8] [29,31]

1–3 1.7 3–6 4–5

[21,22] [18] [7,8] [29,31]

12–38 12 45 17–39

[22,24] [18] [8] [28,29,31]

15–21 9 18 12–19

[22,24] [18] [8] [28,29,31]

Anti-TPO: anti-thyroperoxidase; anti-TG: anti-thyroglobulin antibodies.

Please cite this article as: Bourji K, et al, Rheumatic and autoimmune thyroid disorders: A causal or casual relationship?, Autoimmun Rev (2014), http://dx.doi.org/10.1016/j.autrev.2014.10.007

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K. Bourji et al. / Autoimmunity Reviews xxx (2014) xxx–xxx

affected with hyperthyroidism and 10 with hypothyroidism. Hypothyroid patients had never been treated for thyroid disease previously and were enrolled for a 24-month follow-up in order to observe the effect of thyroxine treatment on PA. All 20 patients underwent laboratory investigations and were clinically assessed by analyzing the number of tender joints (TJC), visual analog scale (VAS), duration of PA (number of days), and intake of acetaminophen. At baseline, correlations were found between TJC and anti-Mi (r = 0.782; p b 0.001), TSH (r = 0.651; p = 0.001) and erythrocyte sedimentation rate (r = 0.511; p = 0.021). During the follow-up, we found a progressive yet slow improvement of PA (TJC, VAS and days of PA), in 10 patients with hypothyroidism treated with thyroxine, with statistical significance being only reached after 12 months. Thyroxine might have had some therapeutic effect also through an influence on the activity and evolution of CAT [51]. In a recent retrospective study carried out in 46 patients with CAT and normal TSH levels referred to rheumatologists for general body pain or joint pain but without a definite rheumatic disease, 45 out of 46 patients (98%) had PA and 12 patients (26%) had active synovitis of hand and/or wrist [52]. Thyroid acropachy is a rare osteo-articular complication of long standing Graves' disease (GD), being a component of the Graves' triad (exophthalmos, pretibial myxedema, and acropachy) with a prevalence of 1%, usually occurring many years after the onset of thyroid disorders [53,54]. Clinical presentation may range from asymptomatic clubbing of terminal phalanges of hands and feet to soft tissue swelling [55]. On radiographs, diaphyseal proliferation with nodular fibrosis of the periosteal areas and sub-periosteal bone formation is characteristic [56,57]. Ultrasound imaging shows hypo-echoic material superficial to the bone, consistent with periosteal edema [58]. Adhesive capsulitis (AC) also known as “frozen shoulder” can be primary idiopathic and affects 2–3% of general population, most commonly women over 50 years. Trauma, avascular necrosis and osteoarthritis may predispose a patient to secondary AC. Hyperthyroidism and other systemic diseases such as diabetes or RA are associated with secondary AC [59]. Several studies reported a high prevalence of AC in case of thyrotoxicosis [60,61]. Thyroid hormones, T3 in particular, are shown to have a direct and essential role in bone and cartilage development throughout childhood and adults [62]. Direct action of T3 on growth plate chondrocytes is well described [63], as well as, its effect on bone remodeling cycle [62]. Subsequently, hyperthyroidism is associated with accelerated bone remodeling, reduced bone density, osteoporosis and an increased fracture risk [64,65]. However, the reversibility of bone loss with therapy is unclear, with a wide disagreement between studies [66–69]. 3.2. Muscular manifestations Myalgia, fibromyalgia (FM) and muscle weakness with or without CK (creatine kinase) elevation are common muscular presentations of thyroid diseases, particularly hypothyroidism [70,71]. Some reports have found clinical and biochemical features of muscle dysfunction even in subclinical hypothyroidism [72], defined as the presence of elevated TSH with normal thyroid hormone levels. Recently, several cases of myalgia have been reported in patients with CAT and normal thyroid hormones [52]. This latter study emphasized the presence of FM in 59% (27 out of 46) of patients. Moreover, the prevalence of thyroid autoimmunity (at least one positive thyroid antibody: anti-TPO or anti-TG) was significantly higher in FM patients than in the control group (34.4 vs. 18.8%, p = 0.025) [73]. In keeping with these results, Suk et al. found a higher prevalence of anti-TPO antibodies in FM patients than in healthy controls (28 out of 149 patients, 19%; 5 out of 68 healthy controls, 7%; p = 0.04) [74]. Hoffman's syndrome (HS) is rare form of hypothyroid myopathy described in several case reports [75–77], and is characterized by pseudo-hypertrophy (increase muscle mass), severe muscle stiffness,

muscle weakness and painful muscle cramps, with typical involvement of gastrocnemius, deltoid and trapezius muscles. An association between HS and Myasthenia Gravis has been reported in a patient with hypothyroidism [78]. Although HS has been reported only in adults, a similar syndrome was described in children, i.e. the “Kocher– Debre–Semelaigne” syndrome which is a rare autosomal recessive disorder characterized by cretinism and associated with muscular pseudo-hypertrophy but without painful muscle cramps [79]. 3.3. Neurologic manifestations Neurologic involvement in thyroiditis is well recognized in literature, with carpal tunnel syndrome (CTS) being the prototype of this involvement. CTS results from the compression of the median nerve which can be evoked by either an extrinsic or intrinsic compression e.g. thickening of the transverse ligament in metabolic disorders, tendonitis, carpal synovitis, pregnancy or endocrine disorders, and its prevalence in the general population is estimated to be around 3.8% [80]. In a controlled study on 26 patients with primary hypothyroidism and 24 healthy controls, 19 out of 26 patients (73%) complained symptoms of CTS, but among them only 6 patients had an abnormal nerve conduction study (23%). All control subjects had normal electrophysiology study results and normal sensibility testing [81]. Others [61,82] reported a prevalence of CTS in hypothyroidism of about 30%. In a case–control, cross-sectional study, 40 patients with a definite diagnosis of clinical hypothyroidism and 40 healthy control subjects were evaluated by electromyography and nerve conduction studies; among hypothyroid patients 32.5% had CTS while none of controls had CTS. In this study, median nerve latency (mV) was significantly higher in hypothyroid patients than in controls (4.2 vs. 3.4 mV; p b 0.001) and median nerve conduction velocity (m/s) was significantly lower in patients than in controls (57 vs. 62 m/s; p = 0.008), suggesting that patients with untreated primary hypothyroidism more frequently developed CTS [83]. Following an inverse approach, Suresh and Morris [84] examined thyroid function in a cohort of 206 patients with CTS. Only two cases (1.5%) of hypothyroidism were reported. Although the prevalence of CTS varied widely among these different studies, CTS seems more common in patients with thyroiditis than in general population [80,83]. RM in autoimmune thyroid disorders are frequently observed, however the definition of RM encompasses a variety of manifestations with different basis, being either inflammatory or degenerative. In this regard, tendonitis are common in autoimmune thyroid disorders as well as in other endocrine diseases since hormonal abnormalities are likely to influence thickness of subcutaneous layers and soft tissue edema leading to tendon compression. Similar observations may apply to non-specific joint and muscle manifestations, since thyroid dysfunction may per se influence the feeling of pain and muscle weakness, with no activation immune-mediated mechanisms. 4. Anti-thyroid drug (ATD) induced RM Medical treatment of hyperthyroid states in particular GD is usually the initial approach considered to restore normal thyroid function, while long term strategy comprises different options, e.g. one- to two-year courses of anti-thyroid drugs, radioactive iodine or eventually surgery [85]. Among the anti-thyroid drugs (ATDs), thionamides (methimazole — MTM, propylthiouracil — PTU and carbimazole) are the most commonly used. They are endowed with minor or major side effects. Minor side effects are relatively common and can affect ~5% of patients. They include skin reactions (urticarial or macular rashes), arthralgia and gastrointestinal disturbances [86]. These minor reactions may respond to antihistamines if added to ATDs or ATD switching. However, ATD discontinuation is promptly recommended in case of arthralgia to avoid its progression to severe migratory polyarthritis [87].

Please cite this article as: Bourji K, et al, Rheumatic and autoimmune thyroid disorders: A causal or casual relationship?, Autoimmun Rev (2014), http://dx.doi.org/10.1016/j.autrev.2014.10.007

K. Bourji et al. / Autoimmunity Reviews xxx (2014) xxx–xxx

Major side effects or life-threatening effects are less common (agranulocytosis) with migratory polyarthritis and ANCA (anti-neutrophil cytoplasm antibodies)-vasculitis being the two major adverse effects of rheumatologic profile [86]. ANCA vasculitis induced by ATDs has been reported in a wide number of case reports with more common incidence in PTU treatment schemes [88–91]. MPO-ANCA is most frequently related to PTU-induced vasculitis [92,93]. This association could be explained by the structural similarity between TPO and MPO leading to crossreactivity [94] or the production of reactive intermediates between MPO and PTU capable of triggering inflammation [95,96]. In the context of ATDs, carbimazole-induced granulomatous eosinophilic vasculitis (Churg-Strauss vasculitis) and PTU-induced cryoglobulinemic vasculitis were reported [97,98]. Scattered cases of ATD-induced myositis are reported as well [99,100], with complete remission after stopping the medication. Last but not the least, bullous-SLE with arthralgia induced by methimazole was described in an Asian patient, followed by a generalized erythematous maculopapular rash [101].

Take-home messages

5. Conclusions

References

According to the available data, thyroid dysfunction seems more common in patients with rheumatic diseases than in the general population, though the high prevalence of autoimmune thyroid diseases in young or mid-aged women should be considered. SS and SLE patients were particularly more affected than patients with other rheumatic diseases. Notably, studies investigating the genomic of autoimmune thyroid disorders including genome-wide association studies [102–106] have characterized several susceptibility loci which are also shared by connective tissue diseases and especially SLE [107]. The strongest association for both SLE and autoimmune thyroid disorders is found with HLA haplotypes with HLA-B8 and -DR3 being prominent in autoimmune thyroid disease [104–106]. HLA-genes are known to influence the immune response being able to present either foreign or self-antigens to the immune cells thereby evoking an immune response. Interestingly, non-HLA genes are also likely to be involved in the development of both conditions. As an example, allelic variants of genes involved in the modulation of receptor-associated immune pathways e.g. PTPN22 (protein tyrosine phosphatase, non-receptor type 22) or heralding regulatory properties in lymphocytes e.g. FOXP3 (forkhead box P3) may confer susceptibility to SLE [107] and were found to be associated with autoimmune thyroid disorders in a number of studies [104,108]. Moreover, genes involved in regulation of T-B crosstalk may also influence autoimmune thyroid diseases as well as SLE occurrence, as is the case of CTLA-4 (cytotoxic T lymphocyte antigen-4) and CD40 loci [103,107–109]. Similarly to what is seen in systemic autoimmune disorders, an exogenous trigger on a favorable genetic background is usually required in order autoimmune thyroid disorders develop [108]. On the other hand, rheumatic manifestations in the context of autoimmune thyroid diseases may be misleading. Actually, non-specific joint and muscle manifestations such as arthralgias or myalgias as well as pain feeling may be influenced by alterations in thyroid function and hormone levels [110,111], which would be prominent in FM. Some reports are available reporting raises in CK levels during thyroid diseases [110,112,113] which are common findings in everyday rheumatology. In conclusion, data are still not convincing in order a clear causal link between autoimmune thyroid disorders and systemic rheumatic diseases can be drawn, which is also due to the high prevalence of autoimmune thyroid diseases in the general population. However, the association between signs and symptoms of both entities is sometimes significant, therefore it is reasonable and cost-effective to investigate thyroid function in patients with systemic autoimmune diseases.

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• Prevalence of autoimmune thyroid disorders is slightly higher in patients with systemic rheumatic autoimmune diseases compared with the general population. • It is likely that autoimmune thyroid disorders are associated with some connective tissue diseases, however no causal link can be established. • Thyroid dysfunction may induce common rheumatic manifestations such as myalgias, arthralgias or the persistent feeling of pain. • Investigating thyroid function in patients with autoimmune rheumatic diseases complaining of constitutional symptoms is advisable and cost-effective. Conflicts of interest Bourji Khalil, Gatto Mariele, Cozzi Franco, Doria Andrea, and Punzi Leonardo declare that they have no conflicts of interest.

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