Autoimmune thyroid disease and rheumatoid arthritis: where the twain meet.

Autoimmune thyroid disease (AITD) is the most prevalent autoimmune disease. It shares multiple genetic, clinical, and serologic characteristics with rheumatoid arthritis (RA). Although frequently described as a classic form of single-organ autoimmunity, the AITD disease burden in a subset of patients extends well beyond the thyroid gland. This review explores the complex interaction between the two diseases and the clinical consequences when they overlap. Beyond the well-known effects of AITD on thyroid function in RA, there is mounting evidence of the association of both conditions impacting the presentation and outcomes of diabetes, metabolic syndrome, and cardiovascular disease. An increasing number of studies suggest that there are negative effects of AITD on RA disease activity both in the presence and in the absence of thyroid dysfunction. Recent evidence suggests that AITD may not only worsen the cumulative damage of RA through higher disease activity but may also worsen secondary osteoarthritis changes. Less well-known is the significant association between AITD and chronic widespread pain syndromes including fibromyalgia. Importantly, the presence of fibromyalgia, which is increased in RA patients, appears to be further increased when it overlaps with AITD. Lastly, we probe the possible influence of AITD interacting with RA on fertility and clinical depression. Key Points • Autoimmune thyroid disease is the most common autoimmune disease and is frequently associated with rheumatoid arthritis. • Autoimmune thyroid disease can present with osteoarthritis, inflammatory arthritis, and chronic widespread pain syndromes. • The co-occurrence of autoimmune thyroid disease and rheumatoid arthritis may worsen disease activity and exacerbate other disease manifestations including cardiovascular disease, fertility, and depression. • The overlap of rheumatoid arthritis with autoimmune thyroid disease needs further research and should be sought in general clinical practice.

Association of the anti-thyroid peroxidase antibody with chronic hand pain in older adults in the Third National Health and Nutrition Examination Survey: a cross-sectional study.

Background: Autoimmune thyroid disease (AITD) is the commonest autoimmune disease. Although viewed as a classic form of single-organ autoimmunity, AITD is increasingly associated with non-thyroid sequelae including musculoskeletal manifestations and chronic pain syndromes. However, large population-based studies are needed. Objectives: To examine the relationships between chronic hand pain and the AITD autoantibodies, anti-thyroid peroxidase antibody (TPOAb), and anti-thyroglobulin antibody (TgAb), in the Third National Health and Nutrition Examination Survey (NHANES III). Design: This is a cross-sectional study. Methods: We examined data from NHANES III on 4820 persons aged 60 years or older with respect to hand pain and its association with TPOAb and TgAb. Log-binomial regressions were fit to examine the associations between the anti-thyroid autoantibodies and hand pain. Results: Positive TPOAb was associated with a higher prevalence of hand pain than negative TPOAb [prevalence ratio (PR) = 1.158, p = 0.048] in the unadjusted model. This association was no longer significant after controlling for age, body mass index, gender, and diabetes (p = 0.313). When positive TPOAb was considered as a categorical variable with four levels, the highest quartile was associated with hand pain in the unadjusted (PR = 1.489, p = 0.005) and adjusted models (PR = 1.325, p = 0.042). There was no significant association between TgAb and hand pain when covariates were controlled for. Conclusion: TPOAb may be associated with the presence of chronic hand pain in persons aged over 60 years, especially at higher serum levels.

Association of anti-thyroid antibodies with radiographic knee osteoarthritis and chondrocalcinosis: a NHANES III study.

OBJECTIVES: To examine the relationships between radiographic knee osteoarthritis (RKOA), symptomatic radiographic knee osteoarthritis (sRKOA), and chondrocalcinosis, as outcome variables, and the autoimmune thyroid disease (AITD) autoantibodies, anti-thyroid peroxidase antibody (TPOAb) and anti-thyroglobulin antibody (TgAb), in the Third National Health and Nutrition Examination Survey (NHANES III) data source. METHODS: NHANES III provided data on 2291 persons over the age of 60 years that included the osteoarthritis variables of interest RKOA, sRKOA and chondrocalcinosis, and the thyroid autoantibodies TPOAb and TgAb. A log-binomial regression model was fit to examine the relationships between anti-thyroid autoantibodies and RKOA. Modified Poisson regression models were employed for the thyroid autoantibodies compared to sRKOA and chondrocalcinosis. RESULTS: Patients with higher levels of TPOAb were more likely to have chondrocalcinosis [prevalence ratio (PR) 1.247, 95% confidence interval (CI) 1.051, 1.479, p = 0.012]. A piecewise regression analysis indicated that this relationship between TPOAb and chondrocalcinosis was only observed when TPOAb was above 35 IU/ml (PR 1.482, 95% CI 1.233, 1.781, p < 0.001). Levels equal to or below 35 IU/ml were not associated with chondrocalcinosis. TPOAb was not associated with RKOA or sRKOA, and TgAb was not significantly related to any of the outcomes. CONCLUSION: There was no association of AITD autoantibodies TPOAb and TgAb with RKOA or sRKOA. However, there may be an association of TPOAb with the presence of chondrocalcinosis.

Rheumatic associations of autoimmune thyroid disease: a systematic review.

To investigate specific disease patterns in the rheumatic manifestations associated with autoimmune thyroid disease (AITD) through a systematic literature review. We performed a systematic review using the Medline OVID, PubMed, EMBASE, and Web of Science databases through May 2018 for experimental and observational studies that explored the association of AITD with degenerative joint disease (DJD), osteoarthritis (OA), chronic widespread pain (CWP) and fibromyalgia syndrome (FMS), and seronegative inflammatory arthritis (IA). A total of 2132 articles were identified. After title and abstract screening and removal of duplicates, 66 articles were retrieved for full text review. Eighteen studies were deemed eligible for inclusion. Six observational studies reported up to 45% prevalence of DJD in AITD. Hand and spinal DJD were reportedly associated with higher odds of AITD. Twelve observational studies were retrieved reporting up to 62% prevalence of FMS in AITD patients. Four studies described the occurrence of seronegative IA in AITD patients. The rheumatic associations of AITD may manifest specific patterns of disease distinct from those of other well-defined autoimmune syndromes and contribute significantly to disease burden.

Association of spinal degenerative disc disease with thyroid autoimmunity.

OBJECTIVES: Autoimmune thyroiditis (ATD) has been linked to various forms of arthritis. The relationship with spinal degenerative disc disease (DDD) is not known. We studied the association between ATD and spinal DDD. METHODS: We performed a cross-sectional analysis of patients who had data on both anti-thyroid peroxidase antibodies (TPOAb) and anti-thyroglobulin antibodies (TgAb) from January 1997 to January 2014 in Clinical Looking Glass (CLG), a data analysis software platform. Spinal DDD was confirmed by radiological diagnosis. RESULTS: Of the 7698 patients for whom the TPOAb and TgAb values were available, 4383 patients with complete data for the following covariates; age, gender, race, ethnicity, smoking, diabetes, body mass index and thyroid stimulating hormone (TSH) levels, were included. Thirty-three percent had ATD, while 67% did not. The unadjusted odds ratio (OR) of having spinal DDD with ATD was 1.5 (95% confidence interval (CI)1.3, 1.7), p<0.001. After adjustment for covariates, ATD remained associated with a higher frequency of spinal DDD, OR 1.8 (95% CI 1.6, 2.2), p<0.001. Stratifying by BMI and TSH levels showed similar results. Additional analyses excluding patients with known connective tissue diseases and spondyloarthritis (SpA) also showed consistent results. CONCLUSIONS: ATD is associated with increased frequency of spinal DDD independent of BMI and TSH levels, and among those without connective tissue diseases or SpA. This finding suggests that there may be an important link between thyroid autoimmunity and spinal DDD.

The transcription, translation, transport-trail and autoimmunity: Guilt by association.

The autoimmune connective tissue diseases (ACTD) are a group of diseases which share clinical features and genetic inheritance. They are characterized by systemic autoimmunity and autoantibody production with a striking predilection for cellular components involved in transcription, translation and cellular transport. Although multiple triggers of autoimmunity have been proposed for this group of diseases including microbial agents such as viruses and bacteria, drugs, ultraviolet light, environmental toxins, stress, hormones and heavy metals, the prominence of autoantibodies to components of the transcription, translation, cellular transport-trail (TTTT) suggests that the agent(s) triggering the autoimmune response potentially utilize the TTTT. For the ACTD, viruses and viral agents are the likely triggers of autoimmunity as a result of aberrant viral latency with the production of autoantibodies to the components of the cellular TTTT machinery through multiple mechanisms, perhaps including molecular mimicry, bystander activation and epitope spreading.

Association of antithyroid peroxidase antibody with fibromyalgia in rheumatoid arthritis.

To investigate how autoimmune thyroiditis (ATD) affects the clinical presentation of established rheumatoid arthritis (RA) with particular reference to fibromyalgia and chronic widespread pain (CWP). A cohort of 204 patients with RA for whom the presence or absence of autoimmune thyroid antibodies was documented was examined for the relationships between thyroid autoantibodies and fibromyalgia or CWP. We identified 29 % who tested positive for antithyroid peroxidase antibodies (TPOAb). The anti-thyroglobulin antibody (TgAb) was found in 24 %. Among the thyroid autoantibody-positive patients, 40 % had a diagnosis of fibromyalgia or CWP versus 17 % for antibody negative patients. Logistic regression analyses (adjusted by age, sex, diabetes and BMI) indicated that TPOAb-positive patients were more likely to have fibromyalgia or CWP, with an odds ratio (OR) of 4.641, 95 % confidence interval (CI) (2.110-10.207) P < .001. Adjusting for spinal degenerative disc disease did not change the association with fibromyalgia, OR 4.458, 95 % CI (1.950-10.191), P < .001. The OR between TgAb and fibromyalgia was not significant (P > .05). Additional logistic regression analyses (adjusted by age, sex and BMI) indicated a significant relationship between TPOAb and fibromyalgia or CWP in patients without diabetes and those without hypothyroidism (OR of 4.873, 95 % CI (1.877-12.653), P = .001 and OR of 4.615 95 % CI (1.810-11.770), P = .001, respectively). There may be a positive association between the ATD antibody TPOAb, and fibromyalgia syndrome and CWP in patients with established RA.

Rheumatic symptoms in autoimmune thyroiditis.

Autoimmune thyroiditis (ATD) is generally regarded as a classic example of single organ autoimmunity with a high association with endocrine thyroid disorders. However, it is closely associated with several autoimmune diseases including rheumatologic syndromes and has long been known to have several rheumatic manifestations particularly in association with hypothyroidism. More recently, it has also been implicated in rheumatologic syndromes in the absence of hypothyroidism or subclinical hypothyroidism. There is also an emerging body of evidence that ATD is highly linked to chronic generalized pain syndromes including fibromyalgia. This review examines the rheumatic symptoms of ATD described in the current literature and discusses the clinical relevance of ATD in general rheumatology.

Fibromyalgia and chronic widespread pain in autoimmune thyroid disease.

Fibromyalgia and chronic widespread pain syndromes are among the commonest diseases seen in rheumatology practice. Despite advances in the management of these conditions, they remain significant causes of morbidity and disability. Autoimmune thyroid disease is the most prevalent autoimmune disorder, affecting about 10 % of the population, and is a recognized cause of fibromyalgia and chronic widespread pain. Recent reports are shedding light on the mechanisms of pain generation in autoimmune thyroid disease-associated pain syndromes including the role of inflammatory mediators, small-fiber polyneuropathy, and central sensitization. The gradual elucidation of these pain pathways is allowing the rational use of pharmacotherapy in the management of chronic widespread pain in autoimmune thyroid disease. This review looks at the current understanding of the prevalence of pain syndromes in autoimmune thyroid disease, their likely causes, present appreciation of the pathogenesis of chronic widespread pain, and how our knowledge can be used to find lasting and effective treatments for the pain syndromes associated with autoimmune thyroid disease.

Rheumatic manifestations of euthyroid, anti-thyroid antibody-positive patients.

The aim of this study is to define the rheumatic manifestations of euthyroid patients with chronic lymphocytic thyroiditis (CLT) but without a well-defined connective tissue disease. Forty-six consecutive patients with anti-thyroid peroxidase (αTPO) and/or anti-thyroglobulin antibodies (αTG), and normal thyroid function in the absence of a well-defined connective tissue disease were included in a case-cohort study. Arthralgias were a presenting complaint in 98 % of patients. Fibromyalgia syndrome was found in 59 % of patients. Raynaud's phenomenon occurred in 28 % and sicca symptoms in 26 % of patients. Two patients had seronegative arthritis resembling rheumatoid arthritis. Arthritis was radiographically present in 88 %, affecting the spine in 45 % of patients. Thyroid-stimulating hormone (TSH) levels positively correlated with levels of αTPO, but not with erythrocyte sedimentation rate (ESR) or αTG levels. A positive ANA was found in 24 % of patients. One patient developed subclinical hypothyroidism during the study. Rheumatic manifestations frequently occur in patients with CLT in the absence of overt thyroid dysfunction and mimic the presentation of the well-defined connective tissue diseases.

Rheumatic manifestations of autoimmune thyroid disease: the other autoimmune disease.

Autoimmune thyroid disease (AITD) is an inflammatory thyroiditis that in some cases is characterized by lymphocytic infiltration of the thyroid gland, also referred to as chronic lymphocytic thyroiditis or Hashimoto thyroiditis. Hashimoto thyroiditis is one of the commonest causes of hypothyroidism. Hypothyroidism has been associated with osteoarthritis (OA) and inflammatory forms of arthritis and with several well defined connective tissue diseases, which in turn can cause arthritis. The presence of arthritis in patients with AITD with normal thyroid function is now being increasingly recognized. There is also considerable evidence to suggest that AITD is highly associated with fibromyalgia syndrome. We review the current literature on the rheumatologic manifestations of AITD and describe the features in its presentation that set it apart from other forms of autoimmune arthritis.

Microangiopathic haemolytic anaemia resembling thrombotic thrombocytopenic purpura in systemic lupus erythematosus: the role of ADAMTS13.

Thrombotic thrombocytopenic purpura (TTP) is a rare but frequently fatal complication of SLE. It occurs in the context of both active and inactive lupus and carries a worse overall prognosis than idiopathic acquired TTP. Recent advances in the knowledge and treatment of TTP do not seem to have brought similar improvements in the management and outcome of TTP in SLE. The illumination of the role of the von Willebrand factor multimer protease, ADAMTS13 in idiopathic TTP continues to enhance our comprehension of the pathogenesis of the disease and has contributed to improvements in diagnosis and management. We explore the overlap of TTP and SLE, and discuss the current understanding of the involvement of ADAMTS13 and its implications for patients with this uncommon form of microangiopathic haemolytic anaemia.

Annexin-1 mediates TNF-alpha-stimulated matrix metalloproteinase secretion from rheumatoid arthritis synovial fibroblasts.

Annexins are intracellular molecules implicated in the down-regulation of inflammation. Recently, annexin-1 has also been identified as a secreted molecule, suggesting it may have more complex effects on inflammation than previously appreciated. We studied the role of annexin-1 in mediating MMP-1 secretion from rheumatoid arthritis (RA) synovial fibroblasts (SF) stimulated with TNF-alpha. TNF-alpha induced a biphasic secretion of annexin-1 from RA SF. Early (< or = 60 min), cycloheximide-independent secretion from preformed intracellular pools was followed by late (24 h) cycloheximide-inhibitable secretion requiring new protein synthesis. Exogenous annexin-1 N-terminal peptide Ac2-26 stimulated MMP-1 secretion in a dose- (EC(50) approximately 25 microM) and time- (8-24 h) dependent manner; full-length annexin-1 had a similar effect. Down-regulation of annexin-1 using small interfering RNA resulted in decreased secretion of both annexin-1 and MMP-1, confirming that annexin-1 mediates TNF-alpha-stimulated MMP-1 secretion. Erk, Jnk, and NF-kappaB have been implicated in MMP-1 secretion. Erk, Jnk, and NF-kappaB inhibitors had no effect on annexin-1 secretion stimulated by TNF-alpha but inhibited MMP-1 secretion in response to Ac2-26, indicating that these molecules signal downstream of annexin-1. Annexin-1 stimulation of MMP-1 secretion was inhibited by both a formyl peptide receptor antagonist and pertussis toxin, suggesting that secreted annexin-1 acts via formyl peptide family receptors, most likely FPLR-1. In contrast to its commonly appreciated anti-inflammatory roles, our data indicate that annexin-1 is secreted by RA SF in response to TNF-alpha and acts in an autacoid manner to engage FPRL-1, activate Erk, Jnk, and NF-kappaB, and stimulate MMP-1 secretion.

In vivo stabilization of mutant human transthyretin in transgenic mice.

Transthyretin (TTR) is a 55 kD homotetrameric serum protein transporter of retinol binding protein charged with retinol and thyroxine (T4). The highly amyloidogenic human TTR variant in which leucine at position 55 is replaced by proline (L55P TTR) is responsible for aggressive fatal amyloidosis with peripheral and autonomic neuropathy, cardiomyopathy and nephropathy. Mice bearing one or two copies of a 19.2 kB human genomic fragment containing the entire coding sequence and the known control regions of the L55P TTR transgene, failed to develop TTR amyloidosis even though their sera contained mutant human TTR. The frequency of TTR tissue deposition was increased when the L55P TTR transgene was bred onto a murine TTR-null background. Denaturation of sera from the transgenic animals and murine TTR-knockouts expressing the human L55P TTR transgene revealed that the TTR tetramer was much more stable in the presence of the murine protein because the TTR circulates as hybrid human/murine heterotetramers. Intraperitoneal administration of diflunisal, a non-steroidal anti-inflammatory drug that binds to TTR in its T4-binding site and inhibits fibril formation in vitro, to human L55P TTR transgenic animals in which the murine TTR gene had been silenced, also stabilizes the circulating mutant protein to in vitro urea denaturation.

Amyloidogenesis is neither accelerated nor enhanced by injections of preformed fibrils in mice transgenic for wild-type human transthyretin: the question of infectivity.

It is possible to accelerate amyloid formation in both the Senescence Accelerated Mouse, where ApoAIIC is the precursor, and in murine Amyloid A (AA) by the injection of preformed fibrils in the former and amyloid enhancing factor, which appears to consist of AA fibril fragments, in the latter. These two observations have raised the question of whether murine amyloids, like scrapie, are infectious. Injection of preformed fibrils into mice transgenic for many copies of the human wild-type transthyretin gene do not result in acceleration or enhancement of the process of deposition or the conversion of non-Congophilic deposits to fibrils.

Mice transgenic for human TTR have the same frequency of renal TTR deposition whether maintained in conventional or specific pathogen free environments.

Mice transgenic for many copies of the human wild type transthyretin gene were bred and maintained in a specific pathogen free environment until twelve months of age. At that time, half the animals were moved to a conventional animal facility. The incidence of both transthyretin and AA amyloid was the same in both groups at two years of age, indicating that in this model, the frequency, extent or nature of TTR-amyloid deposition did not differ significantly between conventional and specific pathogen-free environments.