European Journal of Cardiovascular Medicine

Rheumatoid arthritis (RA) is an autoimmune, chronic, systemic condition that mostly focuses on women and has a prevalence rate of around 0.5 -1 percent in the world population of adults[1,2]. In addition to its recognized articular demonstration, RA is associated with other autoimmune diseases with the most prevalent being autoimmune thyroid disease (AITD). AITD is defined as Hashimoto thyroiditis, Graves disease and antibody-positive cases of euthyroid states; it is by far the most common autoimmune disease in the general population[1]. Epidemiologic studies indicate that 6 -34 per cent of patients with established RA have biochemical thyroid dysfunction, and the frequency increases to almost 38 per cent when the inclusion of circulating anti-thyroid antibodies in case closed down[2-4]. The latest meta-analysis of 35,708 patients confirmed that RA imparts over a two-fold increase in developing any kind of thyroid dysfunction with the best suggestion being hypothyroidism (odds ratio =2.25)[2].

There is an overlap which can be explained by shared genetic susceptibility. The two diseases are both enriched in polymorphism with HLA-DRB1, PTPN22, CTLA-4 and STAT4 genes that are involved in antigen presentation and T -Cell regulation[1][5]. Even in the genetically susceptible individuals, the presence of environmental modifiers such as cigarette smoking and vitamin-D deficiency increases this risk even more[1]. RA and AITD also exhibit similarities at the mechanism: Elevated Th17/Treg imbalance, augmented pro inflammatory cytokines (IL-6, TNF-a) and B cell hyperactivation resulting in autoantibody production[1,6]. Even analyses of synovial fluids have detected the presence of anti-thyroid peroxidase antibodies and reverse triiodothyronine in the inflamed joints indicating a thyroid based antigenic imprint at loci of articular pathology[1].

Clinically, thyroid pathology seems to accelerate the severity of RA. It has been demonstrated that cross-sectional and longitudinal cohorts with RA, overt and subclinical hypothyroidism have increased Disease Activity Score-28 (DAS-28) and elevated ESR/ CRP and reduced treatment response, compared to the euthyroidgroup[6,7]. Subclinical hypothyroidism is particularly prevalent, possibly comprising 40 percent of the thyroid dysfunctions in RA and is often accompanied by anti-TPO positivity[3,8]. On the other hand restoration of euthyroidism has also been linked to improvement of swelling and pain of the joints which suggests that there is an inflammatory element mediated by thyroid hormones or immunologic alternative to them which is reversible.

An extra-articular morbidity can increase as well due to comorbid thyroid disease. Hypothyroidism is another condition that on its own increases the risk of atherosclerotic cardiovascular disease by three-fold, but combined with systemic inflammation due to RA it is another accelerating factor in the progression of endothelial dysfunction and thrombosis [1]. Superseding Mendelian-randomisation evidence indicates that there is a two-way causal association: RA-susceptibility genes modestly predispose to genetically determined hypothyroidism and RA-associated variants boost hypo- and hyperthyroid autoimmunity odds[9]. It is worth noting that the odds of concurrent thyroid dysfunction have been associated with female sex, longer duration of RA, high titer rheumatoid factor or anti-CCP antibodies as well as ANA positivity[7,8].

In the light of these clashing data recent guidelines have proposed routine screening of thyroid-stimulating hormone and even anti-TPO antibodies at RA diagnosis and annually thereafter, particularly in women and in patients with high disease activity or intractable fatigue[3,7,10]. Prompt diagnosis can facilitate the substitution of levothyroxine in time or start antithyroid treatment, improve the stratification of cardiovascular risks and possibly enhance sensitivity to disease-modifying antirheumatic drugs.

In brief, the majority of patients with RA have a comorbidity of thyroid dysfunction, mainly in subclinical and overt hypothyroidism. Its occurrence indicates common biological mechanisms of autoimmunity, associations with increased inflammatory load and poorer systemic morbidities. This makes it important that in the mainstream management of RA thyroid assessment is incorporated to ensure overall management of the disease.

Data source:

The sample will consist of patients that are diagnosed with the disease, RA, and are being asked to seek medical care at the Sri Aurobindo Medical College and Post Graduate Institute-Indore

(SAMC &PGI), Hospital during the study period. Any patient who will present to the SAMC outpatient department (OPD) will be given an opportunity to volunteer to participate in the study after being made aware of the purpose of the study. All the patients will sign informed written consent before participation. The patient data will be collected on a pre-structured proforma.

Inclusion Criteria:

• All the diagnosed cases of Rheumatoid Arthritis (RA) visiting the medicine department (OPD/IPD) of the SAMC\&PGI who give voluntary consent.

Exclusion Criteria:

• Patients who have a history of the other rheumatic diseases (i.e., systemic sclerosis [SS], systemic lupus erythematosus [SLE]).
• People with a malignancy history.
• Drug users but the drugs have been demonstrated to produce thyroid malfunction.
• Those that have had thyroid surgeries before.

Sample Size: Evaluation with the formula shows that a sample of about 65 patients will be required. The resulting formula of calculation of the final sample size results in the adjusted sample size of 65.

Procedure Planned:

Rheumatoid Arthritis cases that will be diagnosed in the SAMC\&PGI OPD/ICU/IPD will be closely examined. Relevant medical history, as well as detailed history, will be obtained of each participant. Patients will receive both clinical and laboratory examination to analyze their thyroid activity and other aspects.

Investigation Details:

In all patients suffering Rheumatoid Arthritis, the following laboratory investigations will be done:

1. Complete Blood Count (CBC)
2. Erythrocyte Sedimentation Rate (ESR)
3. C reactive Protein (CRP)
4. Rheumatoid Factor (RA Factor)
5. Free Triiodothyronine (FT4), Free Thyroxine (FT3),
6. Thyroid Stimulating Hormone (TSH)
7. Anti-thyroid peroxidase antibodies (Anti-TPO Ab)

Data Collections and Methods:

Relevant data will be collected using a pre-designed and structured proforma that will be filled with the information about the patients. They will take blood samples to be tested in the laboratory and the findings will go directly in the proforma. The proforma will have elaborate sections to record demographic profile, clinical history, medical history, and findings of laboratory tests of the patients.

Table 1: Demographic and Clinical Profile of Patients (n=65)

This was a study that was carried out on 65 patients with rheumatoid arthritis (RA) where the average age of this study was observed to be 49.2 11.6 years with the age range being 22-74 years. There was a definite preponderance of females, i.e. 55 (84.6) female patients and 10 (15.4) male patients as per the documented epidemiology of RA.

Table 2: Hematological Profile (CBC)

Hematological test would indicate the presence of anemia as the average level of hemoglobin amounted to 10.9}_ 1.4 g/dL, with 68 percent of patients presenting a subnormal indication. On an average (7.8 2.3 x109/L), the count of white blood cells was within normal limits, but 12 percent of the patients had raised counts. Mean PLT count was also up on average to 336 + 78 x109/L and 18 patients had thrombocytosis.

Table 3: Thyroid Function Test Results

The evaluation of thyroid functions showed disturbances in a fair part of patients with RA. The average of FT3 was 2.9 pg/mL (0.5) and FT4 1.0 ng/dL (0.3), which is within the normal range of most of the patients. The cohort was found to have TSH which was elevated in 35 percent of the cohort with a mean of 5.1 + 2.7 mu IU/ml, suggesting high prevalence of subclinical or overt hypothyroidism.

Table 4: Inflammatory and Autoimmune Markers

Most patients were positive with the presence of markers of inflammation. The erythrocyte sedimentation rate (ESR) was averagely 43.5 mm/hr +/- 17.8 mm/hr and in 84 percent of the patients, the values were increased. C-reactive protein (CRP) was also elevated in 76, the mean being 21.3 +- 11.6 mg/L. RA factor was positive in 80 per cent of the patients which makes them seropositive. More importantly, the presence of the anti-thyroid peroxidase antibodies (anti-TPO Ab), which is an indicator of autoimmune thyroiditis, was present in 29.2 percent of our patients and emphasises the important auto-immune over-lap between RA and thyroid malfunction.

Table 5: Prevalence of Thyroid Dysfunction

According to thyroid hormone levels and TSH levels 23 patients (35.4) out of them have diagnosed with thyroid dysfunction. In them, subclinical hypothyroidism was found in 13 patients (20.0%) and overt hypothyroidism in 8 patients (12.3%). Hyperthyroidism was also unlikely with only, 2 patients (3.1%) having it. Most of the patients (42, or 64.6%) had aneuthyroid state. These findings indicate that hypothyroid diseases, especially subclinical type, are quite prevalent within the RA cohort, and could be a reasonable screening procedure.

The cross-sectional study conducted on 65 rheumatoid arthritis (RA) subjects has found high level of thyroid dysfunction (35.4%) with the prevalence of subclinical hypothyroidism (20%) outpacing overt (12.3%) and hyperthyroidism (3.1%). According to the discovery of 29.2 percent of anti-thyroid peroxidase (anti-TPO) antibodies and 35 percent of elevated thyroid-stimulating hormone (TSH) levels, a reasonable autoimmune thyroid element of RA was demonstrated.

This happens to be similar to the other regional and international reports. One study in a sample case of 50 patients in RA in Eastern India reported an incidence of 14 percent having a dysfunction in the thyroid which was generally founded in subclinical and overt hypothyroidism; 22 percent of the patients with RA with abnormality in thyroid had positive anti-TPO as compared to that in controls, this was highly significant[11]. Atzeni et al. evaluated 70 RA patients in Italy and reported 37 percent anti-TPO-positive, and they demonstrated increased TSH in 7.1 percent of the cases (after this group was proved negative to the disease) [12]. Among 100 RA women in a Polish study, 16 percent had thyroid dysfunction (PRN: mainly subclinical hypothyroidism) than 9 percent of controls, and also anti-TPO was similar (15 percent vs. 18 percent)[13].

In a systematic review with meta analysis of 35,708 RA patients included in 29 studies, the pooled odds ratio of RA patients compared with study-based non-RA subjects was 2.25 (95 percent confidence interval 1.782.84), which was hypothyroid[14]. The findings above further contribute to the cause of greater risk of thyroid dysfunction among RA and concurs to adopting the habit of screening thyroid as a standard practice[14]. In addition to this, this risk of having clinical hypothyroidism was observed to be 1.67 times higher in a cohort study in Taiwan which found that the chances of this condition was also higher in women and elderly subjects with RA compared to their matched controls[15].

RA is also defined by the prevalence of subclinical hypothyroidism that could be connected to the autoimmune-like pathology, i.e. T-cell-dysregulation, autoantibodies production, and chronic inflammation. The genetic factors (e.g. HLA- DRB1 alleles) also contribute to the synchronicity of RA and Autoimmune thyroid disease. The presence of anti-TPO antibodies in a series of euthyroid RA patients suggests a prodrome of the-immune attack on the thyroid and the patients with such an expression should be observed over time, in case, the RA can access thyroid dysfunction in the actual form.

At the clinical practice, subclinical hypothyroidism can either cause increments in fatigue, weight gain, as well as joint stiffness that are related with RA or it can conceal them since it poses as RA exacerbation or interferes with control of RA. The prognosis of RA thyroid dysfunction can be improved because of the early diagnosis and treatment of the issue resulting in the overall control of the disease; improved response to antirheumatic treatment, and improved life quality.

The study proves that there is a high incidence of thyroid disorder, especially subclinical and overt hypothyroidism, in Rheumatoid Arthritis (RA) patients. The results indicate that thyroid abnormalities are significant comorbidities in RA which might worsen the disease activity as well as inflammation. This hints more on the autoimmune overlap between RA and thyroid by the existence of anti-thyroid peroxidase antibodies. The early identification and intervention of dysfunctional thyroid among patients with RA may be improved through periodic monitoring of thyroid dysfunction among patients who exhibit high activity of disease or whose symptoms persist and such precaution would help manage the disease and enhance the quality of life of such patients. Thus, thyroid evaluation ought to have role in RA management to facilitate the articular and extra-articular manifestations of the disease.

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