|Year : 2018 | Volume
| Issue : 1 | Page : 5-10
Frequency of rheumatoid arthritis in patients with autoimmune thyroid disease: a case–control study
Hafez A Abd-Elhafeez1, El-Sayed El-Meghawry2, Sabry Al-Azhary2, Khaled N Elfayoumy2, Tarek Emran3, Ahmad R Amin2, Saad Alzokm4
1 Internal Medicine Department, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
2 Internal Medicine Department, New Damietta Faculty of Medicine, Al-Azhar University, Damietta, Egypt
3 Clinical Pathology Department, New Damietta Faculty of Medicine, Al-Azhar University, Damietta, Egypt
4 Rheumatology Department, New Damietta Faculty of Medicine, Al-Azhar University, Damietta, Egypt
|Date of Submission||15-Jan-2018|
|Date of Acceptance||10-May-2018|
|Date of Web Publication||27-Jul-2018|
Khaled N Elfayoumy
Al-Azhar University Hospital, 2 El-Megawra Al-Saada Street, New Damietta 34517, Damietta Governorate
Source of Support: None, Conflict of Interest: None
Introduction Hashimoto’s thyroiditis and Graves’ disease both constitute autoimmune thyroid diseases (AITD) that frequently coexist with other autoimmune disorders (AID). This study was conducted to evaluate the frequency of rheumatoid arthritis (RA) in patients diagnosed with AITD in relation to the general population.
Patients and methods This was a cross-sectional case–control study, conducted on 103 patients with AITD of either Hashimoto’s thyroiditis or Graves’ disease with positive antithyroid peroxidase (TPOAb). A group 100 volunteers, matched for age and sex, with normal thyroid function and negative history of AID, were investigated for the prevalence of RA in the general population (control group). Participants in the study were tested for thyroid profile, rheumatoid factor (RF), erythrocyte sedimentation rate, and C-reactive protein. When appropriate, anticitrullinated peptide antibody was checked.
Results Patients with AITD had a higher frequency of RA than the control (P=0.031). Thyroid profile showed no significant difference between patients with and without RA within the group of AITD. In that group, a positive correlation between titers of both RF and TPOAb was observed (r=0.474, P<0.001). The coexistence of RA with AITD was noticed to be associated with higher RF, C-reactive protein, and TPOAb titers as well as. the presence of type 2 diabetes mellitus, other AID and family history of RA.
Conclusion RA is more prevalent in patients with AITD than the general population, and the underlying autoimmunity is likely to be the link. Our data highlight the importance of screening thyroid patients for RA especially if present with type 2 diabetes mellitus, another AID, or having a family history of RA.
Keywords: autoimmune, thyroid, rheumatoid arthritis
|How to cite this article:|
Abd-Elhafeez HA, El-Meghawry ES, Al-Azhary S, Elfayoumy KN, Emran T, Amin AR, Alzokm S. Frequency of rheumatoid arthritis in patients with autoimmune thyroid disease: a case–control study. Egypt J Obes Diabetes Endocrinol 2018;4:5-10
|How to cite this URL:|
Abd-Elhafeez HA, El-Meghawry ES, Al-Azhary S, Elfayoumy KN, Emran T, Amin AR, Alzokm S. Frequency of rheumatoid arthritis in patients with autoimmune thyroid disease: a case–control study. Egypt J Obes Diabetes Endocrinol [serial online] 2018 [cited 2020 Feb 17];4:5-10. Available from: http://www.ejode.eg.net/text.asp?2018/4/1/5/237769
| Introduction|| |
Patients with autoimmune thyroid diseases (AITD), namely Graves’ disease and Hashimoto’s thyroiditis, are at increased risk of developing other autoimmune diseases (AID) . In particular, the association between thyroid disease and rheumatoid arthritis (RA) has been recognized . Furthermore, the manifestations of both diseases occasionally overlap and mimic each other . Most of the researchers evaluated the occurrence of thyroid disorders in the context of RA showing high prevalence ,,. Furthermore, patients with RA were found to be at three times higher risk of having thyroid autoantibodies than healthy controls .
In the other direction, a few studies have been designed to probe the prevalence of RA in patients with AITD ,.
In general, the concept of polyautoimmunity has been widely accepted, and the ‘preclinical screening’ of patients with AITD for secondary AID is highly recommended ,.
The aim of this study was to estimate the frequency of RA in patients with AITD in relation to the healthy control.
| Patients and methods|| |
This cross-sectional, case–control study was conducted over a year on 103 patients with AITD attending the outpatient clinic at Al-Azhar University Hospital, New Damietta, Egypt for a routine follow-up. Of these, 79 patients had Hashimoto’s thyroiditis, and 24 had Graves’ disease. Well-controlled (or with borderline biochemical control) patients already diagnosed to have Graves’ or hypothyroidism with positive antithyroid peroxidase antibodies (TPOAb) (measured by chemiluminscence, Siemens Healthcare Products Ltd, Surrey, UK) were included in the study. Conversely, those who had undergone thyroidectomy were excluded. A group of 100 volunteers, matched for age and sex, with normal thyroid function and without a history of AID, were tested for the prevalence of RA in the general population.
All included patients completed a structured questionnaire seeking a personal and family history of common AID, including RA, as well as history of thyroid disorders. A full clinical examination stressing on the signs of RA was performed. The Disease Activity Score 28 was calculated for patients diagnosed to have RA.
The participants of the study were tested for the serum levels of thyroid stimulating hormone, free triiodothyronine, free thyroxine, and rheumatoid factor (RF; Omega Diagnostic, Alva, Scotland, UK), in addition to erythrocyte sedimentation rate and C-reactive protein (CRP; Omega Diagnostic).
Anticitrullinated peptide antibody (Diametra, Spello PG, Italy) was done only for suspicious rheumatoid cases who showed negativity for RF. Levels above 10 IU/ml were considered positive. Diagnosis of RA was achieved by a specialist based on the 2010 ACR/EULAR classification criteria .
All statistical calculations were performed using SPSS, version 19 (SPSS Inc., Chicago, Illinois, USA). Quantitative data were expressed as the mean±SD, and analyzed by the independent sample paired t-test. In contrast, qualitative data were expressed as number and percentage, and analyzed by χ2-test. The correlation was done using Pearson’s correlation test. P value was considered significant if less than 0.05.
The study was approved by the Local Research Ethics Committee of the Faculty of Medicine, Al-Azhar University. A written informed consent was provided by all the participants, and the study was conducted according to the Declaration of Helsinki.
| Results|| |
The study enrolled 103 patients (86 women and 17 men) with an AITD of either Hashimoto’s thyroiditis (n=79) or Graves’ disease (n=24) and 100 volunteers. The mean age of the thyroid group was 39.29±10.09 years, and the duration of the thyroid disease ranged from 3 months to 9 years ([Table 1] and [Table 2]).
|Table 1 Comparison between cases with autoimmune thyroid diseases and control group|
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|Table 2 Demographic and clinical features of thyroid patients with and without rheumatoid arthritis|
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Eleven (10.7%) patients with AITD were found to have RA. This was significantly higher than that of the control group (3%). The Disease Activity Score 28-CRP was nearly comparable (4.95 and 3.85, respectively). Three rheumatoid cases in Hashimoto’ subgroup were negative for RF, but they revealed anticitrullinated peptide antibody positivity with the following titers: 86, 68, and 76 IU/ml. Conversely, positive RF was the role in all Graves’ patients with RA.
The occurrence of RA arthritis was associated with a longer thyroid illness duration, higher erythrocyte sedimentation rate, higher TPOAb, RF, and CRP titers, and with the existence of positive RF, type 2 diabetes mellitus (T2DM), other AID, and family history of RA ([Table 2] and [Table 3]). In that context, however, there was no significant difference between Graves’ disease and Hashimoto’s thyroiditis ([Table 4]).
|Table 3 Laboratory findings of thyroid patients with and without rheumatoid arthritis|
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Out of nine thyroid patients who experienced the coexistence of another AID, vitiligo was present in six cases. The other three patients had a documented premature ovarian failure, idiopathic thrombocytopenic purpura, or bullous pemphigoid.
On testing the correlation between the titers of both RF and TPOAb in a cohort of thyroid population, we found a significant positive correlation (r=0.474, P<0.001) ([Figure 1]). Similar correlations were found in the subgroups of Hashimoto’s thyroiditis and Graves’ disease (r=0.363, P<0.001, r=0.766, P<0.001, respectively).
|Figure 1 Correlation between rheumatoid factor (RF) and thyroid peroxidase (TPO) antibody titers in patients with autoimmune thyroid disease (r=0.474, P<0.001).|
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| Discussion|| |
In this study, the prevalence of RA in patients with AITD was 10.7%, and this was significantly higher than that found in healthy control. The coexistence of both disorders may imply their tendency to overlap due to similar immunological mechanisms and genetic susceptibility .
Although the close association between AITD and RA has been well acknowledged, the prevalence of RA among patients with AITD varies considerably. In a study of Boelaert et al. , RA was prevalent in 3.15% of patients with Graves’ disease and 4.24% of patients with Hashimoto’s thyroiditis. In a Colombian study, however, AITD was coexisting with RA in as high as 21% of cases . This suggests the role of environmental factors or ethnic variability.
It has previously been proposed that the link between AITD and RA may be attributed to the underlying thyroid dysfunction. In our results, however, there were no significant differences concerning the levels of thyroid stimulating hormone, free triiodothyronine, and free thyroxine between rheumatoid and nonrheumatoid thyroid patients. Thus, it seems likely that autoimmunity, rather than a direct action of the thyroid hormones, is responsible for that link .
The above explanation is supported by evidence denoting the occurrence of rheumatic diseases even in ‘euthyroid AITD’, or that they are more frequent in ‘autoimmune’ thyroid patients rather than those having other thyroid etiologies ,,.
From the pathological point of view, it has been suggested that a polyclonally accelerated production of autoantibodies by both thyroid and immune cells may be the mechanism responsible for the coexistence of non-organ-specific autoantibodies with AITD . In other words, the overlap of autoantibodies may be clarified by a malfunctioning T-cell and B-cell regulation causing reactions against autoantigens producing RF and thyroid autoimmunity .
In that context, we observed a positive correlation between titers of both RF and TPOAb in thyroid patients (r=0.474, P<0.001). This correlation continued in Hashimoto’s and Graves’ subgroups (r=0.363, P<0.001, r=0.766. P<0.001, respectively). In addition, patients with RA showed higher TPOAb titers than those without rheumatoid (P<0.001, respectively).
Supportive data for this close association came from the study of Cárdenas Roldán et al. , who studied patients with RA, and observed that 37.8% were positive for TPOAb and 20.8% for antithyroglobulin antibodies. Similar findings were reported in the study of Atzeni et al. . Furthermore, a significant positive correlation between TPOAb and even rheumatoid activity has been observed .
In our results, more than half of the thyroid patients diagnosed to have RA had told a positive family history of RA (P<0.001). Also, they showed a higher frequency of other AID than non-RA patients (P=0.021).
In the study of Rojas-Villarraga et al. , familial autoimmunity was a risk factor for polyautoimmunity. Moreover, Trbojević et al.  reported the co-occurrence of AID in family groups and the transition from one clinical picture to another within the same individual over time. Also, the results of Boelaert et al.  were in agreement of that.
On comparing Graves’ disease with Hashimoto’s thyroiditis in our study, there was no significant difference regarding the prevalence of RA. Conversely, the study of Wiebolt et al.  reported a markedly higher clustering of additional autoimmunity in Hashimoto’s rather than Graves’ disease. However, this study targeted a wide scale of AID such as celiac disease, adrenal, β-cell, gastric, and adrenal autoimmunity.
Another important point in our results to be addressed is the high prevalence of T2DM in patients having both thyroid and RA diseases (45%). Actually, the relationship between T2DM and either RA or AITD has also been extensively studied. In a recent Danish study, the prevalence of diabetes mellitus in patients with RA was significantly increased versus that expected from the general population. The risk increased for those having rheumatoid for more than 4 years . Interestingly, the risk seems to be extended to both types of diabetes mellitus ,.
In contrast, there is also evidence to suggest an association between AITD and T2DM ,. Sarfo-Kantanka et al.  observed a high prevalence of thyroid autoimmunity in Ghanaian patients with T2DM. He added that thyroid autoimmunity in T2DM patients was significantly associated with poor glycemic control.
| Conclusion|| |
Patients with AITD had an increased risk of developing RA than the general population. The absence of a significant biochemical difference between thyroid patients with and without RA regarding the thyroid profile, together with the positive correlations between their autoantibodies, indicates an underlying immune mechanism. The risk of coexistence of RA with thyroid autoimmunity was augmented with higher titers of RF, CRP, and TPOAb, and was associated with the presence of T2DM, another AID, and a family history of RA.
All authors contributed to the study design, data collection and interpretation, drafting, and/or revision of the manuscript.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Bliddal S, Nielsen CH, Feldt-Rasmussen U. Recent advances in understanding autoimmune thyroid disease: the tallest tree in the forest of polyautoimmunity. F1000Res 2017; 6:1776.
Somers EC, Thomas SL, Smeeth L, Hall AJ. Are individuals with an autoimmune disease at higher risk of a second autoimmune disorder? Am J Epidemiol 2009; 169:749–755.
Stathatos N, Daniels GH. Autoimmune thyroid disease. Curr Opin Rheumatol 2012; 24:70–75.
Benamour S, Zeroual B, Fares L, El Kabli H, Bettal S. Rheumatoid arthritis in Morocco. Rev Rhum Mal Osteoartic 1992; 59:801–807.
Porkodi R, Ramesh S, Mahesh A, Kanakarani P, Rukmangathrajan S, Rajedran C. Thyroid dysfunction in systemic lupus erythematosus and rheumatoid arthritis. J Indian Rheumatol Assoc 2004; 12:88–97.
Shiroky JB, Cohen M, Ballachey ML, Neville C. Thyroid dysfunction in rheumatoid arthritis; a controlled prospective survey. Ann Rheum Dis 1993; 52:454–456.
Pan XF, Gu JQ, Shan ZY. Increased risk of thyroid autoimmunity in rheumatoid arthritis: a systematic review and meta-analysis. Endocrine 2015; 50:79–86.
Weetman AP. Diseases associated with thyroid autoimmunity: explanations for the expanding spectrum. Clin Endocrinol (Oxf) 2011; 74:411–418.
Vaidya B, Pearce SH, Charlton S, Marshall N, Rowan AD et al.
An association between the CTLA4 exone I polymorphism and early rheumatoid arthritis with autoimmune endocrinopathies. Rheumatology 2002; 41:180–183.
Falorni A, Laureti S, Santeusanio F. Autoantibodies in autoimmune polyendocrine syndrome type II. Endocrinol Metab Clin North Am 2002; 31:369–389.
Boelaert K, Newby PR, Simmonds MJ, Holder RL, Carr-Smith JD, Heward JM et al.
Prevalence and relative risk of other autoimmune diseases in subjects with autoimmune thyroid disease. Am J Med 2010; 123:1–9.
Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT et al.
Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010; 62:2569–2581.
Szyper-Kravitz M, Marai I, Shoenfeld Y. Coexistence of thyroid autoimmunity with other autoimmune diseases: friend or foe? Additional aspects on the mosaic of autoimmunity. Autoimmunity 2005; 38:247–255.
Rojas-Villarraga A, Amaya-Amaya J, Rodriguez-Rodriguez A, Mantilla RD, Anaya JM. Introducing polyautoimmunity: secondary autoimmune diseases no longer exist. Autoimmune Dis 2012; 2012:254319.
Weetman AP. The immunopathogenesis of chronic autoimmune thyroiditis one century after Hashimoto. Eur Thyroid J 2013; 1:243–250.
Tagoe CE, Zezon A, Khattri S, Castellanos P. Rheumatic manifestations of euthyroid, anti-thyroid antibody-positive patients. Rheumatol Int 2013; 33:1745–1752.
Punzi L, Betterle C. Chronic autoimmune thyroiditis and rheumatic manifestations. Joint Bone Spine 2004; 71:275–283.
Fallahi P, Ferrari SM, Ruffilli I, Elia G, Biricotti M, Vita R et al.
The association of other autoimmune diseases in patients with autoimmune thyroiditis: review of the literature and report of a large series of patients. Autoimmun Rev 2016; 15:1125–1128.
Weetman A. Non-thyroid autoantibody in thyroid disease. Best Pract Res Clin Endocrinol Metab 2005; 19:17–32.
Cárdenas Roldán J, Amaya-Amaya J, Castellanos-de la Hoz J, Giraldo-Villamil J, Montoya-Ortiz G, Cruz-Tapias P et al.
Autoimmune thyroid disease in rheumatoid arthritis: a global perspective. Arthritis 2012; 2012:864907.
Atzeni F, Doria A, Ghirardello A, Turiel M, Batticciotto A, Carrabba M, Sarzi-Puttini P. Anti-thyroid antibodies and thyroid dysfunction in rheumatoid arthritis: prevalence and clinical value. Autoimmunity 2008; 41:111–115.
Koszarny A, Majdan M, Suszek D, Wielosz E, Dryglewska M. Relationship between rheumatoid arthritis activity and antithyroid antibodies. Pol Arch Med Wewn 2013; 123:394–399.
Trbojević B, Djurica S. Diagnosis of autoimmune thyroid disease. Srp Arh Celok Lek 2005; 133 (Suppl 1):25–33.
Wiebolt J, Achterbergh R, den Boer A, van der Leij S, Marsch E, Suelmann B et al.
Clustering of additional autoimmunity behaves differently in Hashimoto’s patients compared with Graves’ patients. Eur J Endocrinol 2011; 164:789–794.
Emamifar A, Levin K, Jensen Hansen IM. Patients with newly diagnosed rheumatoid arthritis are at increased risk of diabetes mellitus: an observational cohort study. Acta Reumatol Port 2017; 42:310–317.
Jiang P, Li H, Li X. Diabetes mellitus risk factors in rheumatoid arthritis: a systematic review and meta-analysis. Clin Exp Rheumatol 2015; 33:115–121.
Dong Q, Liu H, Yang D, Zhang Y. Diabetes mellitus and arthritis: is it a risk factor or comorbidity? A systematic review and meta-analysis. Medicine (Baltimore) 2017; 96:e6627.
Akbar DH, Ahmed MM, Al-Mughales J. Thyroid dysfunction and thyroid autoimmunity in Saudi type 2 diabetics. Acta Diabetol 2006; 43:14–18.
Perros P, McCrimmon RJ, Shaw G, Frier BM. Frequency of thyroid dysfunction in diabetic patients: value of annual screening. Diabet Med 1995; 12:622–627.
Sarfo-Kantanka O, Sarfo FS, Ansah EO, Yorke E, Akpalu J, Nkum BC, Eghan B. Frequency and determinants of thyroid autoimmunity in Ghanaian type 2 diabetes patients: a case–control study. BMC Endocr Disord 2017; 17:2.
[Table 1], [Table 2], [Table 3], [Table 4]