Autoimmune Overlap Syndromes: A Comprehensive Review of the Rheumatology-Endocrinology Interface
Dr Neeraj Manikath, claude.ai
Abstract
Background: Autoimmune overlap syndromes represent a complex group of conditions characterized by the coexistence of multiple autoimmune disorders affecting both endocrine and rheumatologic systems. These syndromes pose significant diagnostic and therapeutic challenges due to their heterogeneous presentations and multisystem involvement.
Objective: To provide a comprehensive review of autoimmune overlap syndromes, with particular emphasis on polyglandular autoimmune syndromes and the intersection between autoimmune thyroid disease and rheumatic conditions.
Methods: A systematic review of current literature was conducted, focusing on recent advances in understanding the pathophysiology, clinical presentation, and management of autoimmune overlap syndromes.
Results:Autoimmune overlap syndromes encompass a spectrum of conditions including polyglandular autoimmune syndromes (APS types 1-4), mixed connective tissue disorders, and the emerging recognition of thyroid-rheumatic overlap phenomena. These conditions share common immunological pathways and genetic predispositions while presenting unique clinical challenges.
Conclusions:Early recognition and multidisciplinary management of autoimmune overlap syndromes are crucial for optimal patient outcomes. Future research should focus on personalized therapeutic approaches and biomarker development for improved diagnostic accuracy.
Keywords: Autoimmune overlap syndromes, polyglandular autoimmune syndrome, thyroid autoimmunity, rheumatic diseases, endocrinology, multisystem autoimmunity
---
Introduction
Autoimmune overlap syndromes represent a fascinating and clinically challenging intersection of immunology, endocrinology, and rheumatology. These conditions, characterized by the simultaneous presence of multiple autoimmune disorders, challenge traditional disease classification systems and require a multidisciplinary approach to diagnosis and management. The recognition of these syndromes has evolved significantly over the past decades, with improved understanding of shared pathogenic mechanisms and genetic predispositions.
The clinical significance of autoimmune overlap syndromes lies not only in their individual complexity but also in their potential to provide insights into fundamental mechanisms of autoimmunity. These conditions often present with overlapping clinical features that may initially suggest a single autoimmune disorder, only to reveal additional manifestations over time. This temporal evolution underscores the importance of long-term monitoring and the need for clinicians to maintain a high index of suspicion for additional autoimmune manifestations.
---
Polyglandular Autoimmune Syndromes: Classification and Clinical Spectrum
APS Type 1 (Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy)
APS Type 1, also known as APECED syndrome, represents the most severe form of polyglandular autoimmune syndromes. This rare condition is caused by mutations in the AIRE (Autoimmune Regulator) gene, which plays a crucial role in central immune tolerance. The classic triad consists of chronic mucocutaneous candidiasis, hypoparathyroidism, and primary adrenal insufficiency. However, the clinical spectrum extends far beyond this triad, encompassing a wide range of endocrine and non-endocrine manifestations.
The pathophysiology of APS Type 1 involves defective negative selection of T cells in the thymus, leading to the escape of autoreactive T cells into the periphery. This fundamental defect in immune tolerance results in the production of multiple organ-specific autoantibodies and subsequent organ dysfunction. The condition typically manifests in childhood, with chronic candidiasis often being the first presenting feature, followed by hypoparathyroidism and adrenal insufficiency.
Non-endocrine manifestations of APS Type 1 include ectodermal dystrophy, chronic hepatitis, malabsorption syndromes, and increased susceptibility to certain malignancies. The hepatic involvement may progress to cirrhosis and hepatocellular carcinoma, making regular surveillance essential. Dental enamel defects and nail dystrophy are common ectodermal manifestations that may provide early diagnostic clues.
APS Type 2 (Schmidt Syndrome)
APS Type 2 is the most common form of polyglandular autoimmune syndrome, characterized by the association of primary adrenal insufficiency with autoimmune thyroid disease and/or type 1 diabetes mellitus. Unlike APS Type 1, this condition typically manifests in adulthood and has a strong genetic component involving HLA class II genes, particularly HLA-DR3 and HLA-DR4.
The pathogenesis of APS Type 2 involves molecular mimicry and epitope spreading, leading to cross-reactive immune responses against multiple endocrine organs. The condition shows a strong female predominance and often clusters in families, suggesting significant genetic predisposition. The temporal sequence of manifestations varies, but thyroid dysfunction often precedes the development of adrenal insufficiency.
Clinical presentation may be insidious, with patients developing symptoms of one endocrine disorder while subclinical dysfunction of other glands may already be present. This underscores the importance of comprehensive endocrine screening in patients presenting with any component of the syndrome. The prognosis is generally favorable with appropriate hormone replacement therapy, though the risk of developing additional autoimmune conditions remains elevated throughout life.
APS Type 3 and Type 4
APS Type 3 encompasses autoimmune thyroid disease associated with other autoimmune conditions excluding adrenal insufficiency and hypoparathyroidism. This classification includes several subtypes based on the associated conditions: Type 3A (thyroid disease with type 1 diabetes), Type 3B (thyroid disease with pernicious anemia), and Type 3C (thyroid disease with vitiligo, alopecia, or other autoimmune conditions).
APS Type 4 represents a more recently recognized category that includes various combinations of autoimmune endocrine disorders that do not fit into the classical APS 1-3 classifications. This category highlights the expanding recognition of autoimmune overlap syndromes and the need for flexible diagnostic criteria to accommodate the diverse presentations observed in clinical practice.
---
Thyroid-Rheumatic Overlap Syndromes
Pathophysiological Mechanisms
The relationship between autoimmune thyroid disease and rheumatic conditions represents one of the most clinically relevant areas of autoimmune overlap. Shared genetic susceptibility, common environmental triggers, and overlapping immune pathways contribute to the frequent coexistence of these conditions. The molecular mimicry between thyroid antigens and connective tissue components may explain the development of rheumatic manifestations in patients with thyroid autoimmunity.
Thyroid hormones have direct effects on connective tissue metabolism, influencing collagen synthesis and degradation. Thyroid dysfunction can therefore lead to musculoskeletal symptoms that may mimic or exacerbate rheumatic conditions. Conversely, chronic inflammation associated with rheumatic diseases may affect thyroid function through various mechanisms, including cytokine-mediated effects on thyroid hormone metabolism and the development of thyroid autoantibodies.
Clinical Manifestations and Diagnostic Challenges
Patients with thyroid-rheumatic overlap syndromes often present with a complex array of symptoms that may initially suggest a single diagnosis. Arthralgia, myalgia, and fatigue are common to both thyroid disorders and rheumatic conditions, making differential diagnosis challenging. The presence of multiple autoantibodies, including thyroid-specific antibodies (anti-TPO, anti-thyroglobulin, anti-TSH receptor) and rheumatic disease-associated antibodies (ANA, anti-CCP, rheumatoid factor), may provide diagnostic clues.
Hashimoto's thyroiditis frequently coexists with rheumatoid arthritis, with studies showing increased prevalence of thyroid autoantibodies in patients with rheumatoid arthritis compared to the general population. This association appears to be bidirectional, with thyroid dysfunction also being more common in patients with established rheumatic diseases. The overlap extends beyond rheumatoid arthritis to include systemic lupus erythematosus, Sjögren's syndrome, and systemic sclerosis.
Graves' Disease and Rheumatic Manifestations
Graves' disease, characterized by thyroid-stimulating immunoglobulin-mediated hyperthyroidism, can present with various rheumatic manifestations. Thyroid acropachy, a rare but distinctive manifestation of Graves' disease, shares clinical features with rheumatoid arthritis, including digital clubbing and periosteal new bone formation. The hyperthyroid state itself can cause muscle weakness, osteoporosis, and accelerated bone turnover, which may be mistaken for primary rheumatic conditions.
The orbital manifestations of Graves' disease (Graves' orbitopathy) involve autoimmune inflammation of extraocular muscles and orbital tissues, demonstrating the systemic nature of the autoimmune process. This condition may coexist with other autoimmune disorders, including myasthenia gravis, creating complex overlap syndromes that require careful multidisciplinary management.
---
Mixed Connective Tissue Disease and Endocrine Overlap
Mixed connective tissue disease (MCTD) represents a prototypical overlap syndrome in rheumatology, characterized by features of systemic lupus erythematosus, systemic sclerosis, and polymyositis/dermatomyositis. The defining serological marker is the presence of antibodies against U1-ribonucleoprotein (anti-U1-RNP). While traditionally considered a primarily rheumatologic condition, MCTD frequently involves endocrine manifestations.
Thyroid dysfunction is common in MCTD, with both hypothyroidism and hyperthyroidism reported. The mechanisms underlying thyroid involvement in MCTD are multifactorial, including direct autoimmune targeting of thyroid tissue, drug-induced thyroid dysfunction, and systemic inflammation effects. Adrenal insufficiency, though less common, has also been reported in association with MCTD, particularly in patients with concurrent systemic lupus erythematosus features.
The overlap between MCTD and endocrine disorders extends beyond thyroid dysfunction to include diabetes mellitus, both type 1 and type 2. The inflammatory nature of MCTD may contribute to insulin resistance, while the autoimmune component may lead to pancreatic beta-cell destruction. This dual pathophysiology necessitates careful monitoring of glucose metabolism in patients with MCTD.
---
Systemic Lupus Erythematosus and Endocrine Complications
Systemic lupus erythematosus (SLE) serves as an excellent model for understanding autoimmune overlap syndromes, given its multisystem involvement and frequent association with other autoimmune conditions. Endocrine manifestations in SLE are diverse and may result from direct autoimmune targeting, medication effects, or systemic inflammation.
Thyroid involvement in SLE is well-documented, with increased prevalence of both hypothyroidism and hyperthyroidism compared to the general population. The presence of antiphospholipid antibodies in SLE patients may contribute to thyroid dysfunction through vascular mechanisms. Additionally, the use of hydroxychloroquine and corticosteroids in SLE management can affect thyroid function, adding complexity to the clinical picture.
Adrenal involvement in SLE may manifest as primary adrenal insufficiency due to autoimmune adrenalitis or secondary adrenal insufficiency related to hypothalamic-pituitary axis suppression from chronic corticosteroid use. The distinction between these mechanisms is crucial for appropriate management and has implications for corticosteroid tapering strategies.
---
Sjögren's Syndrome and Polyglandular Involvement
Sjögren's syndrome, characterized by lymphocytic infiltration of exocrine glands leading to sicca symptoms, frequently presents as part of broader autoimmune overlap syndromes. The condition shows strong associations with thyroid autoimmunity, with studies demonstrating increased prevalence of thyroid dysfunction in patients with Sjögren's syndrome compared to controls.
The pathophysiological link between Sjögren's syndrome and thyroid disease involves shared genetic susceptibility factors and common immune pathways. Both conditions are characterized by lymphocytic infiltration of target organs and the production of organ-specific autoantibodies. The temporal relationship between these conditions varies, with some patients developing thyroid dysfunction before sicca symptoms and others showing the reverse pattern.
Beyond thyroid involvement, Sjögren's syndrome may be associated with other endocrine disorders, including diabetes mellitus and adrenal dysfunction. The chronic inflammatory state characteristic of Sjögren's syndrome may contribute to insulin resistance and metabolic dysfunction. Additionally, the use of immunosuppressive medications in severe cases may have endocrine side effects that require monitoring.
---
Diagnostic Approaches and Biomarkers
The diagnosis of autoimmune overlap syndromes requires a systematic approach that combines clinical assessment, laboratory testing, and imaging studies. The complexity of these conditions necessitates the use of multiple diagnostic modalities and often requires longitudinal follow-up to establish the full spectrum of involvement.
Serological Testing
Comprehensive autoantibody testing forms the cornerstone of diagnosis in autoimmune overlap syndromes. The panel should include organ-specific antibodies (anti-TPO, anti-thyroglobulin, anti-TSH receptor, anti-GAD, anti-IA2, anti-21-hydroxylase) and systemic autoantibodies (ANA, anti-dsDNA, anti-Smith, anti-Ro/SSA, anti-La/SSB, anti-Scl-70, anti-centromere, anti-Jo1, anti-U1-RNP).
The interpretation of autoantibody results requires careful consideration of clinical context, as the presence of autoantibodies does not always correlate with clinical disease activity. Some antibodies may be present years before clinical manifestations develop, while others may fluctuate with disease activity. The concept of "autoimmune tautology" suggests that the presence of one autoimmune condition increases the likelihood of developing others, making comprehensive screening important even in asymptomatic patients.
Functional Assessment
Functional assessment of potentially affected organs is crucial for early detection of subclinical dysfunction. This includes thyroid function tests (TSH, free T4, free T3), adrenal function assessment (morning cortisol, ACTH stimulation test), pancreatic function (glucose tolerance testing, C-peptide levels), and parathyroid function (calcium, phosphate, PTH levels).
The timing and frequency of functional assessments should be individualized based on the specific overlap syndrome, genetic risk factors, and presence of relevant autoantibodies. Some patients may require lifelong monitoring, particularly those with high-risk genetic backgrounds or strong family histories of autoimmune diseases.
Imaging and Tissue Diagnosis
Imaging studies may provide valuable information about organ involvement and help guide management decisions. Thyroid ultrasound can detect structural abnormalities and guide biopsy decisions in patients with nodular disease. Cross-sectional imaging may be useful for evaluating adrenal morphology and detecting other organ involvement.
Tissue diagnosis through biopsy may be necessary in selected cases, particularly when the diagnosis is uncertain or when there are concerns about malignancy. Thyroid fine-needle aspiration, salivary gland biopsy in suspected Sjögren's syndrome, and muscle biopsy in suspected inflammatory myopathies may provide definitive diagnostic information.
---
Therapeutic Approaches and Management Strategies
The management of autoimmune overlap syndromes requires a multidisciplinary approach that addresses both the individual components and the syndrome as a whole. Treatment strategies must consider the complex interactions between different organ systems and the potential for therapeutic interventions to affect multiple aspects of the condition.
Hormone Replacement Therapy
Hormone replacement therapy forms the cornerstone of treatment for endocrine manifestations of overlap syndromes. Thyroid hormone replacement in hypothyroidism, corticosteroid replacement in adrenal insufficiency, and insulin therapy in type 1 diabetes require careful dosing and monitoring. The presence of multiple endocrine disorders may complicate replacement therapy, as the treatment of one condition may affect the metabolism or requirements of others.
Thyroid hormone replacement in patients with concurrent adrenal insufficiency requires special consideration, as thyroid hormone can precipitate adrenal crisis in patients with untreated adrenal insufficiency. The general principle is to initiate corticosteroid replacement before starting thyroid hormone therapy, though this approach must be individualized based on the severity of each condition.
Immunosuppressive Therapy
Immunosuppressive therapy may be indicated for the rheumatic components of overlap syndromes, particularly when there is evidence of active inflammation or progressive organ damage. The choice of immunosuppressive agents must consider the potential effects on endocrine function and the risk of opportunistic infections.
Corticosteroids, while effective for inflammatory conditions, can have significant endocrine side effects, including suppression of the hypothalamic-pituitary-adrenal axis, glucose intolerance, and osteoporosis. Long-term corticosteroid use requires careful monitoring and strategies to minimize adverse effects, including bone protection measures and diabetes screening.
Disease-modifying antirheumatic drugs (DMARDs) such as methotrexate, hydroxychloroquine, and biological agents may be used for rheumatic manifestations. Hydroxychloroquine has the additional benefit of potentially improving glucose metabolism in patients with concurrent diabetes. However, these agents may have their own endocrine effects and drug interactions that require consideration.
Emerging Therapies
Recent advances in understanding the pathophysiology of autoimmune diseases have led to the development of targeted therapies that may be particularly relevant for overlap syndromes. B-cell depletion therapy with rituximab has shown promise in certain autoimmune conditions and may be considered in severe cases of overlap syndromes.
Janus kinase (JAK) inhibitors represent another class of targeted therapy that may have applications in autoimmune overlap syndromes. These agents can modulate multiple inflammatory pathways simultaneously, potentially addressing the systemic nature of overlap syndromes. However, their use in endocrine autoimmune conditions requires further study.
Lifestyle Modifications and Supportive Care
Lifestyle modifications play an important role in the management of autoimmune overlap syndromes. Dietary interventions, including gluten-free diets in patients with celiac disease components, may be necessary. Regular exercise can help maintain bone health and cardiovascular fitness, though exercise prescriptions may need modification based on the specific manifestations present.
Psychological support is often necessary, given the chronic nature of these conditions and their impact on quality of life. Patients may benefit from counseling, support groups, and stress management techniques. The complexity of managing multiple conditions can be overwhelming, and patient education is crucial for optimal self-management.
---
Prognosis and Long-term Outcomes
The prognosis of autoimmune overlap syndromes varies widely depending on the specific components involved, the timing of diagnosis, and the adequacy of treatment. Early diagnosis and appropriate management can significantly improve outcomes and prevent complications. However, the chronic nature of these conditions means that patients require lifelong monitoring and may develop additional autoimmune manifestations over time.
Factors Affecting Prognosis
Several factors influence the prognosis of autoimmune overlap syndromes. The age at onset is important, with childhood-onset conditions often having more severe manifestations and greater potential for long-term complications. The presence of certain genetic markers, such as specific HLA alleles, may predict disease severity and progression.
The speed of progression and the number of organs involved also affect prognosis. Patients with rapidly progressive disease or involvement of critical organs such as the heart, lungs, or kidneys may have worse outcomes. Conversely, patients with slowly progressive disease limited to readily treatable manifestations may have excellent long-term outcomes.
Surveillance and Monitoring
Long-term surveillance is essential for patients with autoimmune overlap syndromes, as they remain at risk for developing additional autoimmune conditions throughout their lives. Surveillance protocols should be individualized based on the specific syndrome, genetic risk factors, and family history. Regular monitoring may include periodic autoantibody testing, functional assessments of at-risk organs, and screening for malignancies when appropriate.
The frequency of surveillance varies depending on the specific condition and individual risk factors. Patients with APS Type 1 require more intensive monitoring given their high risk of developing additional manifestations, while patients with more limited overlap syndromes may require less frequent surveillance.
Quality of Life Considerations
The impact of autoimmune overlap syndromes on quality of life can be substantial, affecting physical function, psychological well-being, and social relationships. Fatigue is a common symptom that can significantly impact daily activities and work performance. Pain and stiffness from rheumatic manifestations can limit mobility and function.
The complexity of managing multiple conditions can create a significant treatment burden, with patients often requiring multiple medications, frequent medical appointments, and ongoing monitoring. This can lead to treatment fatigue and adherence challenges. Healthcare providers must work with patients to develop manageable treatment regimens that balance efficacy with quality of life considerations.
---
Future Directions and Research Opportunities
The field of autoimmune overlap syndromes continues to evolve, with new syndromes being recognized and our understanding of existing conditions deepening. Several areas of research hold promise for improving diagnosis and treatment of these complex conditions.
Precision Medicine Approaches
The development of precision medicine approaches based on genetic profiling, biomarker identification, and personalized risk assessment represents a major opportunity for improving outcomes in autoimmune overlap syndromes. Genetic testing can help identify patients at high risk for developing additional autoimmune conditions, allowing for earlier intervention and more targeted surveillance.
Pharmacogenomics may also play a role in optimizing treatment selection and dosing. Understanding how genetic variations affect drug metabolism and response can help clinicians choose the most effective therapies while minimizing adverse effects. This is particularly relevant for immunosuppressive medications, where the balance between efficacy and toxicity is critical.
Biomarker Development
The development of better biomarkers for diagnosis, prognosis, and treatment monitoring is a key research priority. Traditional autoantibodies, while useful, may not capture the full complexity of overlap syndromes. New approaches, including proteomic and metabolomic profiling, may identify novel biomarkers that provide better prognostic information.
Biomarkers that can predict which patients are likely to develop additional autoimmune manifestations would be particularly valuable. This could allow for preventive interventions or more intensive monitoring in high-risk patients. Similarly, biomarkers that can monitor treatment response and predict flares could help optimize therapy.
Therapeutic Targets
The identification of new therapeutic targets based on improved understanding of overlap syndrome pathophysiology represents another important research direction. The focus on shared pathways between different autoimmune conditions may lead to therapies that can address multiple components of overlap syndromes simultaneously.
Targeting the fundamental mechanisms of immune tolerance and autoimmunity may provide more effective treatments than addressing individual disease components separately. This could include approaches to restore immune tolerance, such as antigen-specific immunotherapy or regulatory T-cell enhancement.
Technology Integration
The integration of digital health technologies, including wearable devices, smartphone applications, and telemedicine platforms, may improve the management of autoimmune overlap syndromes. These technologies could facilitate better monitoring of symptoms, medication adherence, and disease activity. They may also enable more frequent contact between patients and healthcare providers, allowing for earlier detection of changes in condition status.
Artificial intelligence and machine learning approaches may help identify patterns in complex clinical data that could improve diagnosis and treatment selection. These approaches could be particularly valuable for overlap syndromes, where the complexity of presentations can make diagnosis challenging.
---
Conclusions
Autoimmune overlap syndromes represent a complex and challenging area of clinical medicine that requires a multidisciplinary approach to diagnosis and management. The intersection of rheumatology and endocrinology in these conditions highlights the interconnected nature of autoimmune diseases and the importance of comprehensive patient assessment.
Key principles for managing these conditions include maintaining a high index of suspicion for additional autoimmune manifestations, implementing comprehensive screening protocols, and coordinating care across multiple specialties. Early diagnosis and appropriate treatment can significantly improve outcomes and prevent complications.
The field continues to evolve with new syndrome recognition, improved understanding of pathophysiology, and development of targeted therapies. Future research focusing on precision medicine approaches, biomarker development, and novel therapeutic targets holds promise for further improving outcomes for patients with these complex conditions.
Healthcare providers caring for patients with autoimmune overlap syndromes must stay current with evolving diagnostic criteria and treatment approaches while maintaining focus on the individual patient's needs and quality of life. The complexity of these conditions requires not only medical expertise but also effective communication and coordination among healthcare team members.
As our understanding of autoimmune overlap syndromes continues to advance, the goal remains to provide comprehensive, personalized care that addresses the multisystem nature of these conditions while optimizing patient outcomes and quality of life. The intersection of rheumatology and endocrinology in these syndromes provides a unique opportunity to advance our understanding of autoimmunity and develop more effective therapeutic approaches.
---
References
1. Eisenbarth GS, Gottlieb PA. Autoimmune polyendocrine syndromes. N Engl J Med. 2004;350(20):2068-2079. doi:10.1056/NEJMra030158
2. Husebye ES, Perheentupa J, Rautemaa R, Kämpe O. Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J Intern Med. 2009;265(5):514-529. doi:10.1111/j.1365-2796.2009.02090.x
3. Betterle C, Garelli S, Presotto F. Diagnosis and classification of autoimmune polyendocrine syndrome. Autoimmun Rev. 2014;13(4-5):431-440. doi:10.1016/j.autrev.2014.01.044
4. Frommer L, Kahaly GJ. Type 3 polyglandular autoimmune syndrome: expanding galaxy of autoimmunity. Front Endocrinol (Lausanne). 2023;14:1236878. doi:10.3389/fendo.2023.1236878
5. Ruggeri RM, Vicchio TM, Cristani M, et al. Oxidative stress and advanced glycation end products in Hashimoto's thyroiditis. Front Endocrinol (Lausanne). 2016;7:171. doi:10.3389/fendo.2016.00171
6. Tagoe CE, Zezon A, Khattri S. Rheumatic manifestations of autoimmune thyroid disease: the other autoimmune disease. J Rheumatol. 2012;39(6):1125-1129. doi:10.3899/jrheum.120022
7. Shoenfeld Y, Twig G, Katz U, Sherer Y. Autoantibody explosion in systemic lupus erythematosus: more than 100 different antibodies found in SLE patients. Semin Arthritis Rheum. 2004;34(2):501-537. doi:10.1016/j.semarthrit.2004.07.002
8. Antonelli A, Ferrari SM, Corrado A, Di Domenicantonio A, Fallahi P. Autoimmune thyroid disorders. Autoimmun Rev. 2015;14(2):174-180. doi:10.1016/j.autrev.2014.10.016
9. Borchers AT, Keen CL, Shoenfeld Y, Gershwin ME. Surviving the butterfly and the wolf: mortality trends in systemic lupus erythematosus. Autoimmun Rev. 2004;3(6):423-453. doi:10.1016/j.autrev.2004.04.002
10. Kassan SS, Moutsopoulos HM. Clinical manifestations and early diagnosis of Sjögren syndrome. Arch Intern Med. 2004;164(12):1275-1284. doi:10.1001/archinte.164.12.1275
11. Brent GA. Clinical practice. Graves' disease. N Engl J Med. 2008;358(24):2594-2605. doi:10.1056/NEJMcp0801880
12. Lazurova I, Benhatchi K, Rovensky J, Kozakova D, Wagnerova H, Tajtakova M. Autoimmune thyroid disease and rheumatoid arthritis. Bratisl Lek Listy. 2009;110(9):543-545.
13. Innocencio RM, Romaldini JH, Ward LS. Thyroid autoantibodies in autoimmune diseases. Medicine (Baltimore). 2004;83(5):280-286. doi:10.1097/01.md.0000141097.52006.a7
14. Raterman HG, van Halm VP, Voskuyl AE, Simsek S, Dijkmans BAC, Nurmohamed MT. Rheumatoid arthritis is associated with a high prevalence of hypothyroidism that amplifies its cardiovascular risk. Ann Rheum Dis. 2008;67(2):229-232. doi:10.1136/ard.2007.072751
15. Punzi L, Betterle C. Chronic autoimmune thyroiditis and rheumatic manifestations. Joint Bone Spine. 2004;71(4):275-283. doi:10.1016/j.jbspin.2003.06.005
16. Mammen AL, Mammen PP. Autoimmune thyroid disease in women. JAMA. 2005;293(10):1227-1239. doi:10.1001/jama.293.10.1227
17. 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. 2010;123(2):183.e1-183.e9. doi:10.1016/j.amjmed.2009.06.030
18. Cutolo M, Sulli A, Pizzorni C, Accardo S. Anti-centromere antibodies in patients with Raynaud's phenomenon: 5-year follow-up study. Rheumatology (Oxford). 2008;47(8):1197-1200. doi:10.1093/rheumatology/ken208
19. El-Sherif WT, El Gendi SS, Ashmawy MM, Ahmed HM, Mahmoud RA. Thyroid disorders and autoantibodies in systemic lupus erythematosus and rheumatoid arthritis patients. Egypt J Immunol. 2004;11(2):81-90.
20. Caturegli P, De Remigis A, Rose NR. Hashimoto thyroiditis: clinical and diagnostic criteria. Autoimmun Rev. 2014;13(4-5):391-397. doi:10.1016/j.autrev.2014.01.007
21. Sharp GC, Irvin WS, Tan EM, Gould RG, Holman HR. Mixed connective tissue disease--an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am J Med. 1972;52(2):148-159. doi:10.1016/0002-9343(72)90064-2
22. Aringer M, Costenbader K, Daikh D, et al. 2019 European League Against Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus Erythematosus. Arthritis Rheumatol. 2019;71(9):1400-1412. doi:10.1002/art.40930
23. Vitali C, Bombardieri S, Jonsson R, et al. Classification criteria for Sjögren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis. 2002;61(6):554-558. doi:10.1136/ard.61.6.554
24. Mavragani CP, Moutsopoulos HM. The geoepidemiology of Sjögren's syndrome. Autoimmun Rev. 2010;9(5):A305-A310. doi:10.1016/j.autrev.2009.11.004
25. Ramos-Casals M, Brito-Zerón P, Sisó-Almirall A, Bosch X. Primary Sjögren syndrome. BMJ. 2012;344:e3821. doi:10.1136/bmj.e3821
26. Cervera R, Khamashta MA, Font J, et al. Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1,000 patients. Medicine (Baltimore). 2003;82(5):299-308. doi:10.1097/01.md.0000091181.93122.55
27. Kahaly GJ, Frommer L. Polyglandular autoimmune syndromes. J Endocrinol Invest. 2018;41(1):91-98. doi:10.1007/s40618-017-0740-9
28. Husebye ES, Anderson MS, Kämpe O. Autoimmune polyendocrine syndromes. N Engl J Med. 2018;378(12):1132-1141. doi:10.1056/NEJMra1713301
29. Orlova EM, Sozaeva LS, Kareva MA, et al. Expanding the phenotypic and genotypic landscape of nonsyndromic monogenic diabetes due to mutations in the KCNJ11 gene. Diabetes Care. 2009;32(1):104-106. doi:10.2337/dc08-1183
30. Fierabracci A. Recent insights into the role and molecular mechanisms of the autoimmune regulator (AIRE) gene in autoimmunity. Autoimmun Rev. 2011;10(3):137-143. doi:10.1016/j.autrev.2010.08.019
31. Nielsen C, Ravn P, Moller M, Bendtzen K. Autoimmune polyendocrine syndrome type I: new perspectives on pathogenesis and treatment. Immunol Rev. 2005;204:252-264. doi:10.1111/j.0105-2896.2005.00240.x
32. Betterle C, Greggio NA, Volpato M. Clinical review 93: Autoimmune polyglandular syndrome type 1. J Clin Endocrinol Metab. 1998;83(4):1049-1055. doi:10.1210/jcem.83.4.4682
33. Neufeld M, Maclaren N, Blizzard R. Autoimmune polyglandular syndromes. Pediatr Ann. 1980;9(4):154-162. doi:10.3928/0090-4481-19800401-08
34. Zanchetta JR, Plotkin H, Filiberti RA. Bone and mineral metabolism in diabetes mellitus. World J Diabetes. 2014;5(6):737-753. doi:10.4239/wjd.v5.i6.737
35. Strieder TG, Prummel MF, Tijssen JG, Endert E, Wiersinga WM. Risk factors for and prevalence of thyroid disorders in a cross-sectional study among healthy female relatives of patients with autoimmune thyroid disease. Clin Endocrinol (Oxf). 2003;59(3):396-401. doi:10.1046/j.1365-2265.2003.01862.x
36. Wiersinga WM. Clinical relevance of environmental factors in the pathogenesis of autoimmune thyroid disease. Endocrinol Metab Clin North Am. 2010;39(2):283-292. doi:10.1016/j.ecl.2010.02.005
37. Weetman AP. Immunity, thyroid function and pregnancy: molecular mechanisms. Nat Rev Endocrinol. 2010;6(6):311-318. doi:10.1038/nrendo.2010.46
38. Tomer Y, Huber A. The etiology of autoimmune thyroid disease: a story of genes and environment. J Autoimmun. 2009;32(3-4):231-239. doi:10.1016/j.jaut.2009.02.007
39. Brent GA, Weetman AP. Hypothyroidism and thyroiditis. In: Melmed S, Polonsky KS, Larsen PR, Kronenberg HM, eds. Williams Textbook of Endocrinology. 13th ed. Elsevier; 2016:416-448.
40. Mariotti S, Caturegli P, Piccolo P, Barbesino G, Pinchera A. Antithyroid peroxidase autoantibodies in thyroid diseases. J Clin Endocrinol Metab. 1990;71(3):661-669. doi:10.1210/jcem-71-3-661
