International Journal for Doctor of Medicine and  Medical Students (IJDMMS)

Abstract

Rheumatoid arthritis (RA) is a systemic autoimmune disease frequently associated with other autoimmune conditions, including autoimmune thyroid diseases (AITD). Thyroid autoantibodies—primarily anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-Tg)—are commonly detected in RA patients, even in the absence of overt thyroid dysfunction. This review examines whether thyroid autoantibodies in RA serve merely as markers of immune dysregulation or actively contribute to tissue damage and disease progression. Evidence suggests a higher prevalence of thyroid autoantibodies in RA compared to the general population, with possible links to increased disease activity and systemic inflammation. Understanding this relationship may improve screening strategies and holistic management of RA patients.

Introduction

Rheumatoid arthritis is a chronic inflammatory autoimmune disorder characterized by symmetric polyarthritis and progressive joint destruction, with significant systemic manifestations. Autoimmunity in RA is not organ-restricted; rather, it reflects a broader immune dysregulation that predisposes patients to multiple autoimmune comorbidities.

Autoimmune thyroid diseases, such as Hashimoto’s thyroiditis and Graves’ disease, are among the most frequently reported autoimmune conditions coexisting with RA. Thyroid autoantibodies, especially anti-TPO and anti-Tg, can be detected years before clinical thyroid disease develops. Their presence in RA raises an important question: do these antibodies merely reflect generalized autoimmunity, or do they actively participate in inflammatory and tissue-damaging processes?

Objectives

       1.  To assess the association between thyroid autoantibodies and RA disease activity

       2.  To explore potential pathogenic mechanisms linking thyroid autoantibodies to systemic and joint damage

       3.  To determine whether thyroid autoantibodies act as markers or mediators of disease in RA

Methods

A narrative review of published literature was conducted using peer-reviewed articles focusing on:

       •   Rheumatoid arthritis and autoimmune thyroid disease overlap

       •   Prevalence of anti-TPO and anti-Tg antibodies in RA

•   Associations between thyroid autoantibodies, inflammatory markers, and RA disease severity

Observational studies, cross-sectional analyses, and meta-analyses published in English were included. Emphasis was placed on studies evaluating immunological mechanisms and clinical outcomes.

Keywords

Rheumatoid arthritis; thyroid autoantibodies; anti-thyroid peroxidase; anti-thyroglobulin; autoimmune comorbidity; systemic inflammation

Results

       •   RA patients demonstrate a significantly higher prevalence of thyroid autoantibodies compared to healthy controls.

       •   Anti-TPO antibodies are more commonly detected than anti-Tg antibodies in RA populations.

       •   2-3 studies report associations between thyroid autoantibody positivity and:

       •   Higher RA disease activity scores (DAS28)

       •   Elevated inflammatory markers (ESR, CRP)

       •   Increased risk of subclinical or overt hypothyroidism

       •   Thyroid autoantibodies may coexist even in euthyroid RA patients, suggesting immune activation independent of thyroid dysfunction.

Prevalence of Thyroid Autoantibodies in Rheumatoid Arthritis

3 - 4 studies consistently demonstrate an increased prevalence of thyroid autoantibodies in patients with rheumatoid arthritis compared to the general population. Anti-thyroid peroxidase (anti-TPO) antibodies are the most frequently detected, followed by anti-thyroglobulin (anti-Tg) antibodies.

Association with Thyroid Dysfunction

RA patients positive for thyroid autoantibodies exhibit a significantly higher risk of developing thyroid dysfunction, particularly hypothyroidism. Subclinical hypothyroidism is the most common abnormality observed, characterized by elevated thyroid-stimulating hormone (TSH) with normal free T4 levels.

Longitudinal studies suggest that anti-TPO–positive RA patients have a 2–4-fold increased risk of progressing to clinical hypothyroidism over time.

Relationship with Rheumatoid Arthritis Disease Activity

5-6 investigations report a positive correlation between thyroid autoantibody positivity and increased RA disease activity. Patients with detectable anti-TPO or anti-Tg antibodies tend to demonstrate:

       •   Higher Disease Activity Score in 28 joints (DAS28)

       •   Elevated erythrocyte sedimentation rate (ESR)

       •   Increased C-reactive protein (CRP) levels

Additionally, antibody-positive patients may experience more frequent disease flares and prolonged inflammatory activity, although findings vary across studies.

Inflammatory and Immunological Associations

RA patients with thyroid autoantibodies show heightened systemic immune activation. Elevated levels of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interferon-γ (IFN-γ) have been reported in this subgroup. These cytokines play central roles in both RA pathogenesis and autoimmune thyroid disease, supporting the hypothesis of shared immunological mechanisms.

Demographic and Clinical Correlates

Thyroid autoantibody positivity in RA is more commonly observed in:

       •   Female patients

       •   Individuals with longer disease duration

       •   Patients with seropositive RA (rheumatoid factor and/or anti-CCP positivity)

Age and smoking status appear to influence prevalence, though results remain inconsistent across populations.

Impact of Antirheumatic Therapy

The effect of disease-modifying antirheumatic drugs (DMARDs) and biologic agents on thyroid autoantibody levels remains inconclusive. Some studies suggest that TNF inhibitors may reduce systemic inflammation without significantly altering thyroid autoantibody titers, indicating that these antibodies may persist despite adequate RA disease control.

Risk of cumulative damage including OA (spine and periphery) in RA with AITD

Autoimmune thyroid disorders are associated with peripheral OA and spinal degenerative disc disease. A study from the Third National Health and Nutrition Examination Survey (NHANES III) demonstrated an association between elevated TPOAb concentrations (> 35 IU/mL) and knee chondrocalcinosis, which is typically associated with OA.

Hand OA is of particular interest as the major drivers of the disease are genetic, endocrine, and metabolic factors. Unlike other forms of OA, such as of the knee or hip, mechanical risk factors such as the influence of gravity are less likely to propel the progression of hand OA . In the previous study demonstrating chondrocalcinosis in association with AITD in NHANES III, an association with radiographic, tibiofemoral knee OA was not demonstrated . Therefore, hand OA may be more specific for understanding the association between AITD and OA. One study using an in-hospital patient cohort found that those with hand OA had nearly 5 times the odds of having AITD . In another NHANES III study, symptomatic hand OA was found to be more prevalent in subjects 60 years and older with TPOAb or TgAb than those without.Hand pain is a salient manifestation of several autoimmune diseases including arthritis and chronic widespread pain syndromes

Conclusion

The frequent detection of thyroid autoantibodies in RA patients supports the concept of shared autoimmune susceptibility, possibly driven by genetic factors (e.g., HLA-DR alleles), cytokine dysregulation, and loss of immune tolerance. From one perspective, thyroid autoantibodies act as markers of systemic autoimmunity, reflecting a broader breakdown in immune regulation.

However, emerging evidence suggests a potential mediator role, whereby thyroid autoantibodies contribute to chronic inflammation through immune complex formation, complement activation, and cytokine release. This may exacerbate systemic inflammatory burden and indirectly influence joint pathology.

Clinically, the presence of thyroid autoantibodies in RA patients has important implications. Routine screening may allow early detection of thyroid dysfunction, prevent complications, and improve quality of life. Further mechanistic studies are needed to clarify whether targeting shared autoimmune pathways could benefit both RA and thyroid disease.

References

       1.  McCoy SS, Crowson CS, Gabriel SE, Matteson EL. Prevalence and outcomes of autoimmune thyroid disease in rheumatoid arthritis. Arthritis Care Res.

       2.  Raterman HG, Jamnitski A, Lems WF, et al. Autoantibodies to thyroid antigens in rheumatoid arthritis. Ann Rheum Dis.

       3.  Antonelli A, Ferrari SM, Corrado A, Di Domenicantonio A, Fallahi P. Autoimmune thyroid disorders. Autoimmun Rev.

       4.  Boelaert K, Newby PR, Simmonds MJ, et al. Prevalence and relative risk of other autoimmune diseases in subjects with autoimmune thyroid disease. Am J Med.

       5.  Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet.