Hypothyroidism and Arthritis: Understanding the Link

Your thyroid is a butterfly-shaped gland located in your neck, just under your Adam’s apple. Its job: to produce and store hormones that help regulate your metabolism (or the rate at which cells perform their duties). Thyroid hormone helps control how fast your heart beats, how quickly you burn calories, and your body temperature. It also helps keep your brain, muscles, and other organs working as they should. Too little hormone production (called hypothyroidism) slows your body down; too much (or hyperthyroidism) sends it into overdrive.

What does a joint condition like arthritis have to do with this tiny gland? Research has shown people with rheumatoid arthritis (RA) are more likely to develop a thyroid condition such as hypothyroidism. “Estimates suggest between 15 percent and 25 percent of patients with RA will develop thyroid disease sometime during their lifetime,” says Eric Matteson, MD, rheumatologist and professor of medicine at Mayo Clinic in Rochester, Minnesota. In comparison, about 10 percent to 12 percent of adults in the general population develop thyroid disease.

The connection appears to go both ways: People living with autoimmune thyroid disease are also at higher risk for developing rheumatoid arthritis. One study published in the American Journal of Medicine found that about 14 percent of people with Hashimoto’s thyroiditis — a condition in which your immune system attacks your thyroid and often leads to hypothyroidism — had another autoimmune disorder, most commonly RA.

What Exactly Is Hypothyroidism?

This condition occurs when your thyroid gland is underactive, which means that it can’t make enough thyroid hormone to keep your body running normally. You have hypothyroidism if you have little thyroid hormone in your blood. When cells can’t get enough of this hormone, the body’s processes slow down.

“Thyroid hormone is a necessary hormone, thus a dysregulation for thyroid hormone changes the whole body,” says Alexa Simon Meara, MD, assistant professor in the division of immunology and rheumatology at The Ohio State University Wexner Medical Center. Signs of hypothyroidism vary, depending on the severity of the hormone deficiency. Symptoms tend to develop slowly, often over several years, and may include:

• Fatigue
• Increased sensitivity or intolerance to cold
• Weight gain
• Dry skin and hair
• Constipation
• Puffy face
• Muscle aches
• Forgetfulness
• Depression
• Enlarged thyroid gland (goiter)

What Causes Hypothyroidism?

The most common cause of hypothyroidism is the autoimmune disease Hashimoto’s thyroiditis. In this disorder, the immune system mistakenly targets and damages the thyroid, causing inflammation and leading to an underactive thyroid.

Other causes of hypothyroidism include thyroid surgery, radiation therapy to treat certain cancers, thyroiditis (or inflammation of the thyroid gland), and certain medications.

Why Do Rheumatoid Arthritis and Hypothyroidism Often Coexist?

While the link between the two conditions isn’t fully understood, experts do know that having one autoimmune disease raises your risk of developing another. “Patients with rheumatoid arthritis are more likely to develop any number of other autoimmune conditions, including autoimmune thyroid dysfunction,” says Dr. Matteson. “The link relates to the systemic abnormal response of the immune system leading to involvement of other organ systems.”

Another potential connection: There may be shared genetic predispositions to both RA and autoimmune thyroid disease, adds Dr. Matteson.

Does Hypothyroidism Cause Joint Pain?

It can, according to the Mayo Clinic. Hypothyroidism may lead to joint pain and stiffness, as well as muscle aches and tenderness particularly in the shoulders and hips. In RA, however, swelling occurs in affected joints, while hypothyroidism can cause swelling of the soft tissue in the hands, arms, legs and feet, and even puffiness in the face in some people, explains Dr. Matteson.

Both RA and hypothyroidism can also cause carpel tunnel syndrome, a condition that causes numbness, tingling, and other symptoms in the hand and arm.

Increased Cardiovascular Risk for Rheumatoid Arthritis and Hypothyroidism

Just having RA means your heart attack risk is as much as 68 percent higher than it is for someone without RA. An underactive thyroid can further contribute to heart disease risk because it may cause a slow heart rate, a rise in cholesterol, an increase in fluid around the heart, and heart failure.

Research suggests having the two conditions together may drive up cardiovascular risk. According to Dutch research, women with inflammatory arthritis and hypothyroidism had more than three times the risk for cardiovascular disease, compared to people who didn’t have either condition.

How Is Hypothyroidism Diagnosed?

With well-controlled RA, your doctor may suspect thyroid disease if you have unusual swelling in your hands, arms, legs and feet, or even unusual fatigue and weight gain, says Dr. Matteson. “Thyroid tests will help to sort this out,” he says.

Hypothyroidism is diagnosed with a physical exam for symptoms and results from a blood test that measures the levels of thyroid-stimulating hormone (TSH). An abnormally high TSH means hypothyroidism. It indicates the thyroid gland is being asked to make more of the hormone thyroxine (T4) because there isn’t enough T4 in the blood.

Sometimes doctors may run another blood test to measure T4 levels, if needed.

How Is Hypothyroidism Treated if You Have RA?

Hypothyroidism is treated the same whether or not you have RA, explains Dr. Meara. The goal is to get thyroid hormone back to normal levels. It’s also important to continue to manage your RA and keep it under good control to help manage symptoms and for your overall health.

Hypothyroidism can’t be cured, but in most cases, it can be completely controlled. Standard treatment involves a daily dose of the synthetic thyroid hormone levothyroxine (Levo-T, Synthroid). It comes in pill form, works just like your own body’s thyroid hormone, and helps bring hormones back to normal levels, thus reversing hypothyroid symptoms.

“Medications used to replace thyroid hormone do not interfere with RA medications,” adds Dr. Matteson. Your doctor will determine the best dose initially and over time.

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Association between rheumatoid arthritis and thyroid dysfunction: A meta-analysis and systematic review

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Antibodies to thyroid hormones in rheumatoid arthritis | Gontar

Metabolic and degenerative changes in connective tissue largely determine the pathogenesis and clinical picture of various diseases. A significant proportion of the pathology of the joints, musculoskeletal system, connective tissue are rheumatic diseases, the most common of which is rheumatoid arthritis (RA). It affects 0.5-1% of the world’s population, which is about 63 million patients. In the Russian Federation, RA accounts for 38.2% of the total number of people with disabilities due to diseases of the musculoskeletal system [17].

At present, RA is considered as a chronic systemic inflammatory disease that leads to damage not only to the joints and periarticular tissues, but also to the autonomic and central nervous systems, the endocrine system, with a possible violation of their relationship, which leads to an additional complication of the course of the underlying disease [10 ].

Clinicians are aware of frequent manifestations of endocrine gland function pathology in patients with RA in the form of goiter, hypothyroidism, chronic adrenal insufficiency, etc. Thyroid hormones (thyroid gland) increase the activity of metabolic processes, stimulate lipogenesis, increase the absorption of glucose by adipose and muscle tissue, activate gluconeogenesis and glycogenolysis [19]. Thyroid hormones (triiodothyronine – T ₃ , thyroxine – T ₄ ) enhance both resorption and synthesis of bone tissue, the production of glycosaminoglycans and proteoglycans in the connective tissue. An increase in their amount in the body leads to an acceleration of bone tissue metabolism due to an increase in the number and activity of osteoclasts, and also stimulates osteoblastic function, which is expressed in an increase in bone formation markers in the blood [1, 11, 20]. With a lack of thyroid hormones, the activity of adenylate cyclase in the synovial membranes increases, which increases the production of hyaluronic acid by fibroblasts, leading to the accumulation of synovial fluid in the joints, and causes clinical manifestations of synovitis [20, 22].

Enzyme-linked immunosorbent assay (ELISA), used to determine the level of antibodies to the thyroid gland, is a fast, fairly sensitive and quite reliable method for diagnosing its autoimmune lesion. In clinical practice, it is customary to investigate antibodies directly to the thyroid tissue, the TSH receptor, and antibodies to thyroperoxidase [25, 26].

Autoantibodies to thyroid hormones (THAAA) directed specifically against T ₃ and T ₄ are less common. They have been known since 1956, when J. Robbins et al. [27] first described the presence of γ-binding y-globulin in the case of papillary adenocarcinoma of the thyroid gland, which was treated with iodine. S. Sakata, M. Matsuda, T. Ogava et al. [2, 9, 21, 28] also studied antibodies to thyroid hormones, and concluded that the prevalence of autoantibodies (anti-T ₃ and anti-T ₄ ) in the majority of the population is not typical, but their presence may increase in patients with hy- on-, hyperfunction of the thyroid gland and in autoimmune diseases not associated with the pathology of the thyroid gland. According to the conclusions of D. Thomas et al. [29, 32], even in the absence of any clinical or biochemical changes in the thyroid gland, the presence of these antibodies nevertheless reflects the early stages of the pathological process.

In the available literature, there is little information about the processes of antibody formation to thyroid hormones in rheumatic diseases. Therefore, assuming that the determination of antibodies directly to thyroid hormones can be a test for the diagnosis of autoimmune thyroid disease, it became necessary to study the possibility of their determination, as well as their role and effect on thyroid function in patients with RA.

The purpose of this work is to study the functional activity of the thyroid gland in RA and to identify the features of antibody genesis to T ₃ and T ₄ in patients with RA, depending on the activity and systemic manifestations of the underlying disease.

Materials and methods

We examined 75 patients with RA (61 (81.4%) women and 14 (18.6%) men) aged 25—78 years who were hospitalized at Clinical Hospital No. 25 of Volgograd. Of these, 35 (46.6%) women and 11 (14.6%) men belonged to the socially active population, i. e., were in the age groups up to 55 and 60 years, respectively. Thus, a significant (45 (60%)) part of patients with RA) belonged to working age. The mean age of the patients was 54.1 ± 11.6 years. The average duration of the disease is 9.47 ± 8.83 years.

The control group consisted of 30 practically healthy donors of the regional blood transfusion station aged 24 to 56 years (22 women and 11 men) who underwent a preliminary medical examination.

Diagnosis of RA was made on the basis of a thorough clinical, laboratory and instrumental examination of patients in accordance with the working classification and nomenclature of rheumatic diseases recommended by the III All-Union Congress of Rheumatologists, and according to the system of diagnostic criteria of the American Rheumatological Association (1987). The activity of the rheumatic process was assessed on the basis of clinical data, immunobiochemical parameters and the DAS 28 index (Disease Activity Score).

During the follow-up, the following was carried out: collection of complaints and anamnesis, examination, physical examination and a set of general laboratory tests, immunological tests were performed. The amount of TSH, free T ₄ (st. T ₄ ), total T ₃ (Alcor-Bio, St. Petersburg) and free T _{3 9 was determined by ELISA.0008 (St. T 3 ) (ZAO NVO Immunotech, Moscow), antibodies to TPO and TG (OOO “CHEMA-MEDICA”, Moscow). According to the indications, instrumental studies were performed: ECG, X-ray of the chest and joints, ultrasound of the heart, abdominal organs and thyroid gland. The study was carried out in accordance with the principles of the Declaration of Helsinki of the International Medical Association and recommendations on the ethics of biomedical research [31].}

The articular form of RA was noted in 45 (60%) people, and 23 (51%) of them had a polyarticular form of the disease. Systemic manifestations of RA were observed in 30 (40%) patients. Among patients with RA, signs of thyroid pathology were found in 11 (14.6%) cases. Of these, diffuse toxic goiter (DTG) with thyrotoxicosis was observed in 4 patients, primary hypothyroidism (increased TSH level) – in 2 patients, and an increase in the level of antibodies to TPO and TG – in 5 patients.

When determining the content of antibodies to T ₃ (anti-T ₃ ) and T ₄ (anti-T ₄ ) in blood serum by the method of solid-phase ELISA, immobilized granular antigenic preparations with magnetic properties were used in the modification T.P. Gontarya et al. [5, 6] with obtaining soluble forms of hormones T ₃ and T ₄ (from commercial preparations “Berlin-Chemie”, Germany). The results were expressed in units of optical density (opt. square units) and were considered positive if the extinction values ​​of the control group were exceeded by more than 2 hundred.

The obtained data were analyzed using the statistical program “Statistica 6.0” (StatSoft, USA). The data are presented as mean (M) and standard deviation (st), the calculation of the median (Me) and 25% and 75% percentiles were also used if the distribution of the indicator was different from normal. Statistical analysis was performed using the test x ² For qualitative data, Student’s /-test and Mann-Whitney test. Spearman’s correlation coefficient was used to assess the relationship between quantitative traits. The critical level of significance of differences was taken equal to 0.05.

Fig. 1. The number of antibodies to triiodothyronine (ordinate axis) in RA patients and healthy individuals (abscissa axis).

Results and discussion

According to the data obtained for determining the amount of antibodies to thyroid hormones T ₃ and T ₄ , it was found that the majority of patients with RA compared with the control group had an increased titer: anti-T ₃ — 0.143 ± 0.03 units opt. pl (in healthy individuals 0.028 ± 0.008 u opt. pl.) (Fig. 1) and anti-T ₄ – 0.146 ± 0.05 units opt. sq. (in healthy individuals 0.034 ± 0.008 units of opt. area) (Fig. 2). A rather high detection rate of anti-T ₃ (39%) and anti-T ₄ (45%) in patients with RA prompted us to study in detail the processes of autoantibody formation to thyroid hormones depending on the activity and form of RA.

The activity of the pathological process in RA was assessed on the basis of clinical data, immunobiochemical parameters, as well as the combined activity index Disease Activity Score — DAS 28, recommended by the American Rheumatology Association for use in research and clinical trials in patients with RA (1987). The values ​​of the DAS 28 index, which are 3.2 or less, corresponding to the I degree of RA activity, were detected in 20 (26.7%)

2. The number of antibodies to thyroxin (y-axis) in patients with RA and healthy individuals (abscissa).

people, DAS 28 over 3.2 to 5.1 (II degree of activity) – in 42 (41.3%) and DAS 28 over 5.1 (III degree) – in 23 (32%) patients.

With an increase in the activity of the pathological process, an increase in St. T ₄ and decrease in St. T ₃ in the blood serum of patients with RA, i.e., a pattern of thyroid hormone imbalance was observed. We have found a significant correlation between the level of St. T ₄ and RA activity (r, = 0.26, p = 0.029) and inverse correlation between the amount of St. T ₃ and the activity of the pathological process in rheumatoid arthritis and amounted to (r, – 0.25, p = 0.03). The content of anti-T ₄ and anti-T ₃ in patients with RA was significantly higher than in the group of healthy individuals (p < 0.001), and progressed with an increase in the degree of disease activity: correlation coefficient of anti-T levels ₄ with the activity of the pathological process r _s was 0.32 (p = 0.023), and for anti-T ₃ and RA activity r _s = 0.24 (p = 0.049) (Table 1).

At high RA activity, free thyroxine concentrations were higher than those at minimal and moderate disease activity, while free triiodothyronine concentrations were lower. At the maximum activity of RA, a correlation was found between the concentration of free thyroxine and the level of antibodies to it (r, = 0. 6, p < 0.05) and the concentration of free triiodothyronine and the level of antibodies to it (r, = 0.3, p < 0.05).

To identify the relationship between the form of the disease, the amount of thyroid hormones and antibodies to them in RA patients, 3 groups were formed:

Table 1

Group 1 — healthy individuals, group 2 — patients with articular RA, and group 3 — patients with systemic RA (Table 2). Patients with systemic RA and impaired thyroid function (n = 6) were not included in the analysis. Maximum indicators of St. T ₄ , antibodies to T ₃ and T ₄ and the minimum level of St. T ₃ were observed in the 3rd group of RA patients, especially in the case of high activity of the pathological process.

The euthyroid state noted by us in RA patients without concomitant thyroid pathology differs qualitatively from that in healthy individuals, since this pathology develops a syndrome of low T ₃ (low T ₃ ) against the background of euthyroidism [15]. It is believed that Low T ₃ arises as a general response of the body as a compensatory reaction and reflects adaptive metabolic reactions and energy savings in a chronic inflammatory process. In addition, we noted a shift in the ratio of the levels of St. T ₃ and St. T ₄ in RA, which is possibly associated with changes in the metabolism of thyroid hormones in peripheral tissues, a decrease in the sensitivity of receptors to them in cells and target tissues, as well as a decrease in the activity of T ₄ -deiodase [3, 13, 14], which leads to a decrease in the level of T ₃ in serum, an increase in the content of reverse T ₃ and is often combined with an increase in the amount of T ₄ . With an increase in RA activity, there is an increase in protein breakdown, which leads to a more rapid accumulation of free forms of hormones in the blood [7, 17], and, possibly, a more intensive formation of autoantibodies to them already at the early stages of the disease. According to the literature, thyroid hormones are involved in the processes of immunogenesis and antibody formation, so thyroid pathology can be a factor contributing to the chronic course of RA [15].

When the thyroid gland is involved during RA, the pathological process intensifies, its course becomes more severe. An excess of thyroid hormones leads to a disruption in the formation of a general adaptation syndrome, patients become torpid to any therapy. The condition improves with a gradual decrease in the functional activity of the thyroid gland during treatment [18]. On the other hand, this can be explained by the fact that in addition to autoimmune mechanisms, an important role in thyroid damage is played by the direct influence of anti-inflammatory cytokines, which can enhance immune responses and additionally stimulate the production of thyroid hormones [8, 23, 24, 30]. The thyroid gland expresses interleukins when exposed to circulating immune complexes (which are produced in excess in RA), and cytokines, in turn, stimulate fibroblast proliferation, excess production of collagen and glycosaminoglycans, leading to narrowing of the joint space, the formation of bone outgrowths and a decrease in the functional activity of the joint [4, 12].

Conclusions

1. In the blood serum of a significant proportion of patients with RA, antibodies to thyroid hormones were found (in 45% – anti-T ₄ and in 39% – anti-T ₃ ), the content of which depends on the activity of the pathological process.
2. Revealed a significant decrease in the level of T ₃ and a tendency to increase T ₄ are proportional to the increase in RA activity, which should be considered as a syndrome of “low T ₃ ” in this disease.
3. Thyroid hormone antibodies can be used as an additional test to characterize RA activity along with traditional clinical and laboratory parameters.

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