|Year : 2015 | Volume
| Issue : 1 | Page : 53-63
Autoimmune thyroid disorders in seropositive versus seronegative rheumatoid arthritis
Mohamed K Ghitany, Eiman A Soliman, Maha E Bondok, Shahinda A Elmaadawy MS
Department of Internal Medicine, Faculty of Medicine, University of Alexandria, Cairo, Egypt
|Date of Web Publication||6-Jul-2015|
Shahinda A Elmaadawy
Department of Internal Medicine, Faculty of Medicine, Alexandria University, Cairo
Source of Support: None, Conflict of Interest: None
Autoimmune diseases are chronic conditions initiated by the loss of immunological tolerance to self-antigens; they represent a heterogeneous group of disorders that afflict specific target organs or multiple organ systems. Autoimmune thyroid disease (AITD) is a common organ-specific autoimmune disorder affecting mostly middle-aged women. AITD is a term that includes various clinical forms of autoimmune thyroiditis; among these diseases, Hashimoto's thyroiditis and Graves' disease are the two most common types and share many features immunologically. Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to severe disability and premature mortality. Given the same pathogenic mechanisms, autoimmune diseases tend to cluster together, and hence this study was designed to investigate the relationship between AITD and RA, particularly seropositive versus seronegative subtypes.
Patients and methods
The study included 70 patients with evidence of RA. Their diagnosis was based on the 2010 American College of Rheumatology (ACR)-EULAR classification criteria, and they were subclassified into two groups: group I, comprising 35 patients with seropositive RA (positive to one or both seromarkers), and group II, comprising 35 patients with seronegative RA (negative to both seromarkers). Twenty healthy age-matched and sex-matched controls constituted group III. All of the studied participants underwent detailed history-taking and physical examination, focusing on RA duration of illness, clinical features suggestive of thyroid dysfunction, and disease activity score (DAS28). We determined the complete blood count, erythrocyte sedimentation rate, C-reactive protein, urea, creatinine, alanine aminotransferase, aspartate aminotransferase, thyroid stimulating hormone (TSH), serum total T3 (TT3), serum total T4 (TT4), rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP), anti-thyroid peroxidase (anti-TPO), thyroglobulin Ab, and TSH receptor antibody (TRAb) levels, and also performed a neck ultrasound.
It was found that erythrocyte sedimentation rate, C-reactive protein, RF, and anti-CCP were significantly higher in RA patients versus controls, particularly in seropositive versus seronegative patients. No significant difference was found between the studied groups as regards TSH, T3, and T4 levels; however, hypothyroidism was found to be more common than hyperthyroidism in RA patients (29 vs. 3% in group I and 9% in group II). Anti-TPO and antithyroglobulin were significantly higher in RA patients versus controls (P < 0.001) and specifically in seropositive (1301.9 ± 1716.0 and 1750.0 ± 1866.2, respectively) versus seronegative patients (799.4 ± 1597.7 and 898.1± 988.11, respectively). TRAbs were detectable in a small subset of RA patients (6% regardless of the serostatus) with significant difference between patients and controls (P = 0.006). Ultrasonographic features of thyroiditis were significantly evident in RA patients versus controls (P = 0.001). A positive correlation was found between RA autoantibodies (RF and anti-CCP) and thyroid autoantibodies (mainly anti-TPO and TRAbs) (P = 0.007, 0.012, 0.004, and 0.035, respectively).
Thyroid dysfunction and AITD are common in RA patients, with hypothyroidism being the most common disorder, which is prevalent in 29% of patients regardless of their serostatus. This association was independent of disease activity assessed by DAS28. Increased incidence of thyroid autoimmunity was seen in seropositive RA versus seronegative RA patients, as evidenced by higher levels of thyroid autoimmune markers in the former. TRAbs were detectable in a small subset of patients with RA.
Keywords: autoimmune thyroid disorders, rheumatoid arthritis, seropositive, seronegative, thyroid peroxidase antibodies, TSH receptor antibodies
|How to cite this article:|
Ghitany MK, Soliman EA, Bondok ME, Elmaadawy SA. Autoimmune thyroid disorders in seropositive versus seronegative rheumatoid arthritis. Egypt J Obes Diabetes Endocrinol 2015;1:53-63
|How to cite this URL:|
Ghitany MK, Soliman EA, Bondok ME, Elmaadawy SA. Autoimmune thyroid disorders in seropositive versus seronegative rheumatoid arthritis. Egypt J Obes Diabetes Endocrinol [serial online] 2015 [cited 2020 Oct 1];1:53-63. Available from: http://www.ejode.eg.net/text.asp?2015/1/1/53/159997
| Introduction|| |
Autoimmune diseases (ADs) are chronic conditions initiated by the loss of immunological tolerance to self-antigens; they represent a heterogeneous group of disorders that afflict specific target organs or multiple organ systems. The chronic nature of these diseases places a significant burden on the utilization of medical care, increases direct and indirect economic costs, and diminishes the quality of life  .
ADs affect a significant proportion of the population, with more than 4% of the European population suffering from one or more of these diseases. Although all ADs share similarities in basic immunological mechanisms, in other aspects such as clinical manifestations and age of onset they vary widely , .
Autoimmune thyroid disease (AITD) is a common organ-specific autoimmune disorder affecting mostly middle-aged women. AITD is a term that includes various clinical forms of autoimmune thyroiditis, such as Graves' disease, Hashimoto's (goitrous) thyroiditis, atrophic autoimmune hypothyroidism, postpartum thyroiditis, and thyroid-associated orbitopathy; two other rare types of AITDs include silent thyroiditis and iatrogenic thyroiditis  . Among these diseases, Hashimoto's thyroiditis and Graves' disease are the two most common types and share many features immunologically.
The hallmark of AITD is the production of antibodies to at least one of the main thyroid-specific autoantigens such as thyroglobulin (TG), thyroid peroxidase (TPO), thyroid stimulating hormone (TSH) receptor, and the relatively newly discovered sodium iodide transporter Ab  .
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint swelling, joint tenderness, and destruction of synovial joints, leading to severe disability and premature mortality , .
Given the presence of autoantibodies, such as rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP), which can precede the clinical manifestation of RA by many years ,,, , RA is considered an AD , . Autoimmunity and the overall systemic and articular inflammatory load drive the destructive progression of the disease.
It was found that AITD can be associated with other ADs including type 1 diabetes , , vitiligo  , Addison's disease  , and multiple sclerosis , . In contrast, RA as an AD can also cluster together with other ADs such as myasthenia graves, vitiligo, type 1 diabetes, and celiac disease  .
An important question was raised concerning the clustering of autoimmune diseases together represented by autoimmune thyroid diseases and rheumatoid arthritis particularly with regards to seropositive and seronegative subtypes, and hence the aim of our study.
| Aim|| |
The aim of this work was to study the following:
- Thyroid dysfunction (hyperthyroidism or hypothyroidism) in seropositive versus seronegative RA patients;
- Autoimmune thyroid markers [anti-TPO, anti-TG, anti-TSH receptor antibodies (anti-TRAbs)] in seropositive versus seronegative RA patients;
- The relation between autoimmune thyroid markers [anti-TPO, thyroglobulin antibodies (anti-TG), and particularly TRAbs] and RA autoantibodies (anti-CCP and RF).
| Patients and methods|| |
The study was carried out on 70 consecutive patients with RA who were attending the rheumatology outpatient clinic or were inpatients in Alexandria Main University Hospital. They were divided according to the results of their serological tests (RF and anti-CCP) into two groups: group I, which included 35 patients with seropositive RA (positive to one or both seromarkers), and group II, which included 35 patients with seronegative RA (negative to both seromarkers). A third group (group III) that included 20 healthy age-matched individuals who were not suffering from any rheumatologic disorder was considered as the control group.
Diagnosis of RA depended on the 2010 ACR-EULAR classification criteria  . A score of at least 6 out of 10 was needed for classification:
- Joint involvement was scored as follows: one large joint, 0; 2-10 large joints, 1; 1-3 small joints (with or without large joint affection), 2; 4-10 small joints (with or without large joint affection), 3; more than 10 joints (including at least one small joint), 5.
- Serology results were scored as follows (at least one test result is needed for classification): negative RF and negative anti-cyclic citrullinated peptide antibodies (ACPAs), 0; low-positive RF or low-positive ACPA, 2; high-positive RF or high-positive ACPA, 3.
- Acute-phase reactants (at least one test result is needed for classification) were scored as follows: normal C-reactive protein (CRP) and normal erythrocyte sedimentation rate (ESR), 0; abnormal CRP or abnormal ESR, 1.
- Duration of symptoms was scored as follows: less than 6 weeks, 0; 6 or more weeks, 1.
Patients receiving antithyroid drugs or corticosteroids or any immunosuppressive drugs known to alter the autoimmune markers or having a history of any thyroid disease or any other AD other than RA were excluded from the study.
All patients were subjected to the following:
Thorough history of the patients were taken with emphasis on symptoms of thyroid dysfunction (hypofunction or hyperfunction of the thyroid gland) and symptoms of RA focusing on joint affection or any other systemic affection.
Complete physical examination
Complete physical examination was carried out with emphasis on any signs of thyroid dysfunction (hypothyroidism mostly presented by weight gain, easy fatigability, lethargy, cold intolerance, hair fall, depression, constipation, and others; hyperthyroidism mainly presented by tachycardia, excessive sweating, nervousness, hyperdefecation, heat intolerance, menstrual irregularities in females, weight loss, myopathy, and others  ; joint examination for tenderness, swelling, deformity, and loss of function with disease activity score (DAS) for assessment of activity  . Joints on both right and left sides were assessed (five metacarpophalangeal joints, five proximal interphalangeal joints, knee, shoulder, elbow, and wrist). After assessment the results were interpreted as follows: less than 2.6, remission; 2.6-3.2, mild; 3.2-5.1, moderate; and more than 5.1, severe.
Venous blood samples were drawn from every participant after an overnight fast of 8 h, and the patients were subjected to the following laboratory investigations:
- Routine: complete blood picture, ESR, CRP, renal function tests (serum urea and serum creatinine), and liver function tests (SGOT and SGPT).
- Rheumatologic assay using enzyme-linked immunosorbent assay (ELISA) to evaluate the RF , (normal, <15 IU/ml) and ACPA  (normal, <25 U/ml).
- Hormonal assay using ELISA technique:Serum thyroid stimulating hormone (TSH):(27-29) normal values: 0.4-4.6 mIU/L (30,31) (TSH< 0.4 mIU/L is considered hyperthyroidism and TSH> 4.6 mIU/L is considered hypothyroidism, Serum total T3: (32-35) normal values :0.8-1. 9 ng/mL, serum total T4 :normal values: 4. 7-12. 8 ug/dl , .
- Thyroid autoantibodies using ELISA to evaluate serum anti-TPO antibodies  (normal, <50 IU/ml; borderline, 50-75 IU/ml; elevated, >75 IU/ml), serum anti-TG antibodies  (normal, <100 IU/ml; borderline, 100-150 IU/ml; elevated, >150 IU/ml), serum TRAbs , (negative, ≤1.1 U/l; equivocal, 1.1-1.5 U/l; positive, >1.5 U/l).
A neck ultrasound was taken using a high-resolution linear transducer (7.5 MHz) Magic Agile Device (Kontron System, France) for assessment of the thyroid gland  . Proper patient positioning was critical to performing a high-quality ultrasound. The patient was made to lie flat, and adequate neck extension was achieved by placing pillows under the shoulders. A coupling gel was then placed on the transducer to enhance image generation. The transducer was then moved over the patient's neck to obtain a series of images of the thyroid gland and other neck structures. Reports included measurement of thyroid gland size, architecture, blood flow on Doppler evaluation, presence of nodules, nodule size and characteristics, and any other periglandular pathology such as neck lymph nodes or parathyroid glands. In addition, evidence of compression or displacement of adjacent structures like the trachea or internal jugular vein was assessed , .
The size of the thyroid was calculated in milliliters as the sum of the volumes of both lobes (isthmus is neglected). The volume of one thyroid lobe was calculated as follows: V (ml) = width × depth × length × 0.479 (cm). The normal thyroid volume in females is lower than 18 ml and that in males is lower than 22 ml. The typical thyroid ultrasonography (TUS) appearance of autoimmune (Hashimoto's) thyroiditis includes focal or diffuse glandular enlargement with coarse, heterogeneous, and hypoechoic parenchymal echo-pattern. Presence of multiple discrete hypoechoic micronodules (1-6 mm size) is strongly suggestive of chronic thyroiditis. Fine echogenic fibrous septae may produce a pseudolobulated appearance of the parenchyma. Color Doppler may demonstrate slight to markedly increased vascularity of the thyroid parenchyma similar to thyroid inferno sign ,, .
Statistical analysis 
Data were fed into a computer and analyzed using IBM SPSS software (version 20.0; SPSS Inc., Chicago, Illinois, USA)  . Comparison between different groups regarding categorical variables was made using the χ2 -test. When more than 20% of cells had an expected count less than 5, correction for χ2 was conducted using Fisher's exact test or Monte Carlo correction. The distribution of quantitative variables was tested for normality using the Kolmogorov-Smirnov test, the Shapiro-Wilk test, and the D'Agstino test. Histograms and QQ plots were used for vision test. If the data were normally distributed, parametric tests were applied. If the data were abnormally distributed, nonparametric tests were used. For normally distributed data, comparison between more than two populations was made using the F-test (ANOVA) and the post-hoc test (Scheffe). For abnormally distributed data, the Kruskal-Wallis test was used to compare between different groups and pairwise comparison was made using the Mann-Whitney test. Significance test results are quoted as two-tailed probabilities. Significance was judged at the 5% level.
Informed consent was taken from each participant, and local ethical committee approval was obtained.
| Results|| |
Clinical and laboratory characteristics of rheumatoid arthritis patients (group I and group II) as compared with controls
The three studied groups were age matched ( [Table 1].
|Table 1 Clinical and laboratory characteristics of rheumatoid arthritis patients (group I and group II) compared with control (group III)|
Click here to view
RA duration was significantly higher in group I versus group II [Table 1].
ESR was significantly higher in group I than in group III, and higher in group II than in group III; CRP was higher in group I than in group III and higher in group II than in group III [Table 1].
RF was significantly higher in group I than in group II and group III, and higher in group II than in group III; anti-CCP was higher in group I compared with group II and group III [Table 1].
No significant statistical difference was observed among the studied groups as regards serum TSH, T3, and T4 [Table 1].
Significant statistical difference was observed between the studied groups as regards anti-TPO: it was higher in group I than in groups II and III, and higher in group II than in group III [Table 1].
Significant statistical difference was observed between the studied groups as regards anti-TG: it was higher in group I than in groups II and III, and higher in group II than in group III [Table 1].
Significant statistical difference was observed among the studied groups as regards TRAb levels: it was higher in group I compared with group II, and higher in group I compared with group III [Table 1].
It was observed that 88.6% of group I were female and 11.4% were male, whereas 94.3% of group II were female and 5.7% were male; in group III 80% were female and 20% were male [Figure 1].
According to the DAS28, 62.9% of group I had severe disease, 31.4% had moderate disease, and 5.7% had mild disease. In group II, 45.7% had severe disease, 45.7% had moderate disease, and 8.6% had mild disease [Figure 2].
|Figure 2: Comparison between the studied groups according to DAS 28 score.|
Click here to view
As regards the clinical picture of thyroid dysfunction in the three studied groups, in group I 62.9% of patients were clinically euthyroid, 22.9% were clinically hypothyroid, and 14.3% were clinically hyperthyroid; in group II 65.7% of patients were clinically euthyroid, 25.7% of patients were clinically hypothyroid, and 8.6% of patients were clinically hyperthyroid [Figure 3].
|Figure 3: Comparison of the clinical picture of thyroid disorders between the studied groups.|
Click here to view
It was found that hypothyroidism was more common than hyperthyroidism. In group I, 86.6% had normal TSH, 28.6% were hypothyroid, and 2.9% were hyperthyroid; as regards T3, 85.7% had normal T3 and 14.3% had abnormal T3; and as regards T4, 85.7% had normal T4 and only 14.3% had abnormal T4. In group II, as regards TSH, 62.9% had normal TSH, 28.6% were hypothyroid, and 8.6% were hyperthyroid; as regards T3, 91.4% had normal T3, whereas 8.6% had abnormal T3; and as regards T4, 94.3% had normal T4 and only 5.7% had abnormal T4. In group III, as regards TSH, 85% had normal TSH and 15% were hypothyroid, whereas as regards T3 and T4 100% had normal levels [Table 2].
|Table 2 The percentage of thyroid stimulating hormone, T3 and T4 among the studied groups|
Click here to view
It was found that, in group I, 100% were positive for anti-TPO and anti-TG, whereas as regards TRAbs 91.4% were negative, 5.7% were positive, and 2.9% were equivocal. In group II, 100% were positive for anti-TPO; as regards anti-TG, 82.9% were positive, 8.6% were equivocal, and 8.6% were negative; and as regards TRAbs 80% were negative, 14.3% were equivocal, and 5.7% were negative. In group III, 95% were negative for anti-TPO and 5% were equivocal; as regards anti-TG, 85% were negative, 10% were equivocal, and 5% were positive; and as regards TRAbs, 95% were negative and 5% were equivocal [Table 3].
|Table 3 The percentage of anti-thyroid peroxidase, antithyroglobulin, and thyroid stimulating hormone receptor antibodies among the studied groups|
Click here to view
Ultrasound evidence of thyroiditis in rheumatoid arthritis patients (group I and group II) compared with control (group III)
Evidence of thyroiditis was found in 34.3% of group I and 51.4% of group II versus no ultrasound evidence of thyroiditis in the control group. A statistically significant difference was observed between the studied groups as regards ultrasound evidence of thyroiditis (between group I and group III and between group II and group III), whereas there was no statistically significant difference between group I and group II [Table 4].
Correlation between rheumatoid factor and thyroid autoantibodies
There was a statistically significant positive correlation between RF and anti-TPO among all patients (seropositive and seronegative) with RA (r = 0.318, P = 0.007), as well as between RF and TRAbs (r = 0.300, P = 0.021), whereas there was no statistically significant correlation between RF and anti-TG (r = 0.234, P = 0.052) [Table 5] and [Figure 4] and [Figure 5].
|Table 5 Correlation between mean rheumatoid factor and anti-thyroid peroxidase, antithyroglobulin, and thyroid stimulating hormone receptor antibodies autoantibodies|
Click here to view
|Figure 4: The correlation between rheumatoid factor (RF) and anti-thyroid peroxidase (anti-TPO).|
Click here to view
|Figure 5: The correlation between rheumatoid factor (RF) and TSH receptor antibodies (TRAbs).|
Click here to view
Correlation between anti-cyclic citrullinated peptide and thyroid autoantibodies
There was a statistically significant positive correlation between anti-CCP and anti-TPO among all patients(seropositive and seronegative) with RA (r = 0.336, P = 0.004), as well as between anti-CCP and TRAbs (r = 0.252, P = 0.035), whereas there was no statistically significant correlation between anti-CCP and anti-TG (r = 0.204, P = 0.90) [Table 6] and [Figure 6] and [Figure 7].
|Table 6 Correlation of anti-cyclic citrullinated peptide with anti-thyroid peroxidase, antithyroglobulin, and thyroid stimulating hormone receptor antibodies autoantibodies|
Click here to view
|Figure 6: The correlation between anti-cyclic citrullinated peptide (anti-CCP) and anti-thyroid peroxidase (a nti-TPO).|
Click here to view
|Figure 7: The correlation between anti-cyclic citrullinated peptide (anti-CCP) and TSH receptor antibodies (TRAbs).|
Click here to view
| Discussion|| |
AITD is a term used to bring together a group of pathologies that involve thyroid dysfunction and an autoimmune response against this endocrine organ as its hallmark , . RA is an AD with chronic inflammation characterized by joint swelling, joint tenderness, and destruction of synovial joints, leading to severe disability and premature mortality [6, 7, 12, 13]. The relationship between RA and the thyroid gland has been studied extensively, with several studies demonstrating the autoimmune nature of thyroid dysfunctions in RA; however, the exact pathogenic mechanism is still unclear , .
We designed this work to study the presence of thyroid dysfunction (hyperthyroidism or hypothyroidism) in seropositive versus seronegative RA patients, as well as to study the presence of autoimmune thyroid markers such as anti-TPO, anti-TG, and particularly TRAbs in seropositive versus seronegative RA patients.
Our study showed no significant difference between patients with RA and controls in relation to age in agreement with the designed protocol of our study.
It was found that about 89% of our patients in group I (seropositive RA) were female versus 11% who were male, whereas in group II (seronegative RA) around 94% were female versus 6% who were male. Our results were consistent with other studies that showed female predominance in the course of RA, such as those performed by Kvien et al.  and Del RincÓn et al.  .
DAS28 as an indicator of disease activity in RA was assessed in our study and it was found that around 63% of group I (seropositive) had severe disease activity versus around 46% in group II (seronegative); 31% had moderate activity in group I versus 46% in group II; and 6% had mild activity in group I versus 9% in group II.
Clinical features of thyroid dysfunction, either hypothyroidism or hyperthyroidism, were thoroughly assessed in our study. Sixty-three percent of patients in group I (seropositive) versus 66% in group II (seronegative) were clinically euthyroid; 23% in group I versus 26% in group II had suggestive symptoms of hypothyroidism; and features of hyperthyroidism were consistent in 14% of patients in group I versus 9% of patients in group II.
RF has been widely used as a screening test for patients with arthritis. Moreover, it constitutes one of the classification criteria proposed by the ACR , . Relative to RF, more recently, anti-CCP has been attributed to RA. About 35-40% of RF-negative patients are ACPA positive  . ACPAs are now well suited as a frontline diagnostic test for RA, especially early RA. It should be mentioned that patients can be classified according to their RF and ACPAs assay into seropositive (positive to one or both of them) and seronegative (negative to both), and hence ACPAs in RF-negative patients can be helpful in confirming the diagnosis of RA. Moreover, a recent study by Binesh et al.  compared the diagnostic value of anti-CCP and RF in patients with RA and revealed that combination of anti-CCP and RF tests rather anti-CCP or RF alone gives the best results in the diagnosis of RA.
A significant statistical difference was observed among the studied groups regarding RF: it was higher in group I than in groups II and III, and higher in group II than in group III. As regards anti-CCP, significant statistical difference was observed between the studied groups: it was higher in group I compared with groups II and III.
Our study demonstrated a higher incidence of thyroid dysfunction (mainly hypothyroidism) in patients with RA, whether seropositive or seronegative, compared with controls. This is consistent with many studies, such as the one by El-Sherif et al.  in which was reported a higher incidence of thyroid dysfunction in patients with RA and also in their families versus normal individuals.
Another study by Shiroky et al.  conducted on 91 RA patients evaluated thyroid dysfunction and found that 30% of patients had evidence of thyroid disorders compared with 11% of controls. They concluded that thyroid dysfunction - namely, hypothyroidism - is three-fold higher in patients with RA versus controls  . However, a study conducted by Silman et al.  on 80 patients (41 male and 39 female; mean age 11.5 ± 4.1 years) demonstrated no significant difference in the incidence of AITDs in RA patients as compared with controls. They concluded that there was no need to screen routinely for the presence of thyroid dysfunction in patients with RA. This finding is most probably attributed to the fact that the study was conducted on young patients  .
In our study hypothyroidism was more prevalent than hyperthyroidism in patients with RA (both group I and group II): 29% of patients in both groups were hypothyroid, whereas 3% in group I and 9% in group II were hyperthyroid.
A strong evidence of higher incidence of hypothyroidism as compared to hyperthyroidism in patients with RA was found in many reviews and studies where in China 2003, Porkodi R et al. studied the prevalence of thyroid dysfunction on 800 patient with RA. The referred study showed 73% incidence of hypothyroidism versus 5% of his studied patients were hyperthyroid, this high incidence is mostly attributed to patient selection where those with known thyromegaly or evidence of thyroid dysfunction were included in the study  .
It was found that there was no statistically significant difference among the studied groups as regards mean serum TSH, T3, and T4 levels. However, Singh et al.  found a statistically significantly higher mean serum T4 level in patients with RA as compared with controls and correlated this increased incidence to the duration of illness of RA.
Moreover, in the study conducted by Wellby et al.  , mean serum TSH was within normal range in all of the studied RA patients, whereas there was significant decrease in serum T3 and T4 in patients compared with controls. This finding was probably because they studied the incidence of thyroid dysfunction in patients with recent-onset RA  .
It was shown in our study that, in patients with RA (group I and group II), there were higher mean levels of autoimmune thyroid markers - namely, anti-TPO and anti-TG antibodies - as compared with controls, suggesting increased incidence of AITDs. Moreover, in our study there was a statistically significant difference in the mean level of anti-TPO and anti-TG antibodies according to the serostatus of RA patients (higher levels in seropositive vs. seronegative patients).
Our results are consistent with those of Raterman et al.  who concluded from the CARRE' study conducted on 353 patients with RA that higher levels of TPO antibodies were present in patients with RA when compared with controls.
In our study it was found that in group I 100% were positive for anti-TPO and anti-TG, whereas in group II 100% were positive for anti-TPO, 82.9% were positive for anti-TG, 8.6% were equivocal, and 8.6% were negative. In group III, 95% were negative for anti-TPO and 5% were equivocal; as regards anti-TG, 85% were negative, 10% were equivocal, and 5% were positive. Similar results were found by Porkodi et al.  : anti-TPO antibodies were positive in 88% and anti-TG in 56% of RA patients.
Innocencio et al.  have reported positivity for anti-TG and anti-TPO of 32 and 4%, respectively. This was also emphasized by BaΊkan et al.  , who found positive anti-TPO and anti-TG in 2.6 and 5.1%, respectively, among 92 RA patients in Turkey.
In 2013, Koszarny et al.  measured the level of antithyrotropin receptor antibodies (TRAbs), and found that TRAbs were not detected in any of the RA patients. We detected the level of TRAbs in a small proportion of our RA patients (four patients were positive and six were equivocal): in group I (seropositive RA) the majority were negative for TRAbs (91.4%), 2.9% were equivocal, and 5.7% were positive, whereas in group II (seronegative RA) 80% were negative, 14.3% were equivocal, and 5.7% were positive for TRAbs.
Andonopoulos et al.  studied thyroid functions and immune profile in patients with RA. They measured thyroid functions, antibodies to TPO (anti-TPO), and TRAbs. He found a high level of anti-TPO in patients with RA, whereas no one had high TRAb levels. Moreover, he concluded that there was no detectable association between thyroid abnormalities and any serological RA findings in his study  .
In contrast to our study, Koga et al.  studied thyroid autoimmune disorders in patients with juvenile idiopathic arthritis. They measured the levels of anti-TPO, anti-TG, and thyroid receptor antibodies, both blocking and stimulatory ones, and concluded that high levels of both TSH receptor stimulatory and blocking antibodies were present in patients with RA with higher incidence of positivity to TSH receptor stimulatory than the blocking ones  .
Our study revealed a higher mean level of anti-TPO, anti-TG, and TRAbs in patients with RA regardless of their serostatus when compared with controls. Moreover, higher levels of anti-TPO, anti-TG, and TRAbs were detected in patients with seropositive RA (group I) versus seronegative RA (group II), suggesting a higher incidence of autoimmune process in seropositive versus seronegative patients.
In a trial to link the two ADs together, we observed a significant positive correlation between anti-TPO, TRAbs, and RF titer, but failed to observe any statistically significant positive correlation between anti-TG levels and RF.
In agreement with our results, Raterman et al.  concluded from his study conducted on 353 patient with RA that a higher percentage of anti-TPO-positive patients were among those with high RF titer with a significant positive correlation between the two autoantibodies.
In contrast, in the study by Yavasoglu et al.  , it was suggested that antithyroid autoantibodies are independent of the RF titer.
Moreover, the prognostic autoantibody in RA - namely, anti-CCP - was also found to be significantly correlated with anti-TPO and TRAb levels in patients with RA. This finding goes with the previously discussed common autoimmune process involving both diseases; however, no statistically significant correlation was found between anti-TG and ACPAs. In 2011 Charles and colleagues did not find a relationship between the presence of thyroid autoantibodies and anti-CCP positivity , .
Evidence of thyroiditis by thyroid ultrasonography in our study was seen in 34% of patients in group I (seropositive) versus 51% in group II (seronegative), whereas none of the individuals in the control group showed any suggestive signs of thyroiditis on ultrasonography. No statistically significant difference was found in our study with respect to ultrasound findings between seropositive versus seronegative groups; however, a significant difference was observed between patients and controls.
In a study conducted by Przygodzka and Filipowicz-Sosnowska  , suggestive signs of thyroiditis in thyroid ultrasonography in RA patients were in the form of heterogenicity of thyroid tissue in 5% of patients and diffuse hypoechogenicity in 2%.
In 2010, Lee et al.  screened 110 RA patients for thyroid disorders by thyroid ultrasonography and came across an interesting finding: he detected a high incidence of papillary thyroid cancer in patients with RA and most of the thyroid cancer patients had a solid and hypoechoic pattern in thyroid ultrasonography.
| Conclusion|| |
Thyroid dysfunction and AITD are common in RA patients, with hypothyroidism being the most common disorder. Hypothyroidism is prevalent in 29% of patients regardless of their serostatus. This association is independent of disease activity assessed by DAS28. Increased incidence of thyroid autoimmunity was seen in seropositive RA versus seronegative RA patients, as evidenced by higher levels of thyroid autoimmune markers in the former. TRAbs were detectable in a small subset of patients with RA.
| Acknowledgements|| |
Conflicts of interest
There are no conflicts of interest.
| References|| |
Anaya JM, Shoenfeld Y, Correa PA, García-Carrasco M, Cervera R. Autoinmunidad y enfermedad autoinmune, corporaci´on para investigaciones biologicas. 1st ed. Colombia: Medellin; 2005.
Cooper GS, Bynum ML, Somers EC. Recent insights in the epidemiology of autoimmune diseases: improved prevalence estimates and understanding of clustering of diseases. J Autoimmun 2009; 33:197-207.
Goris A, Liston A. The immunogenetic architecture of autoimmune disease. Cold Spring Harb Perspect Biol 2012; 4:1-14.
Schott M, Scherbaum WA. Autoimmune thyroid disease. Dtsch Arztebl 2006; 103:A3023-A3032.
Ajjan RA, Kemp EH, Waterman EA, Waston PF, Endo T, Onaya T, et al
. Detection of binding and blocking auto antibodies to the human sodium iodide transporter in patients with autoimmune thyroid disease. J Clin Endocrinol Metab 2000; 85:2020-2027.
somäki H. Long-term outcome of rheumatoid arthritis. Scand J Rheumatol Suppl 1992; 95:3-8.
Wolfe F. The natural history of rheumatoid arthritis. J Rheumatol Suppl 1996; 44:13-22.
Aho K, Heliövaara M, Maatela J, Tuomi T, Palosuo T. Rheumatoid factors antedating clinical rheumatoid arthritis. J Rheumatol 1991; 18:1282-1284.
Aho K, von Essen R, Kurki P, Palosuo T, Heliövaara M. Antikeratin antibody and antiperinuclear factor as markers for subclinical rheumatoid disease process. J Rheumatol 1993; 20:1278-1281.
Nielen MM, van Schaardenburg D, Reesink HW, van de Stadt RJ, van der Horst-Bruinsma IE, de Koning MH, et al
. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum 2004; 50:380-386.
Rantapää-Dahlqvist S, de Jong BA, Berglin E, Hallmans G, Wadell G, Stenlund H, et al
. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum 2003; 48:2741-2749.
Firestein GS. Evolving concepts of rheumatoid arthritis. Nature 2003; 423:356-361.
Smolen JS, Aletaha D, Koeller M, Weisman MH, Emery P. New therapies for treatment of rheumatoid arthritis. Lancet 2007; 370:1861-1874.
Barker JM. Clinical review: type 1 diabetes-associated autoimmunity: natural history, genetic associations, and screening. J Clin Endocrinol Metab 2006; 91:1210-1217.
Tait KF, Marshall T, Berman J, Carr-Smith J, Rowe B, Todd JA, et al
. Clustering of autoimmune disease in parents of siblings from the type 1 diabetes Warren repository. Diabet Med 2004; 21:358-362.
Laberge G, Mailloux CM, Gowan K, Holland P, Bennett DC, Fain PR, Spritz RA. Early disease onset and increased risk of other autoimmune diseases in familial generalized vitiligo. Pigment Cell Res 2005; 18:300-305.
Kasperlik-Zaluska A, Czarnocka B, Czech W. High prevalence of thyroid autoimmunity in idiopathic Addison's disease. Autoimmunity 1994; 18:213-216.
Barcellos LF, Kamdar BB, Ramsay PP, DeLoa C, Lincoln RR, Caillier S, et al
. Clustering of autoimmune diseases in families with a high-risk for multiple sclerosis: a descriptive study. Lancet Neurol 2006; 5:924-931.
Broadley SA, Deans J, Sawcer SJ, Clayton D, Compston DA. Autoimmune disease in first-degree relatives of patients with multiple sclerosis. A UK survey. Brain 2000; 123(Pt 6):1102-1111.
Kumar V, Rajadhyaksha M, Wortman J. Celiac disease-associated autoimmune endocrinopathies. Clin Diagn Lab Immunol 2001; 8:678-685.
Hyrich KL, Symmons DP, Silman AJ OMERACT 7 Special Interest Group. Reconciling subject differences in recruitment to clinical trials and clinical practice. J Rheumatol 2005; 32:2475-2476.
Chen JL, Chiu HW, Tseng YJ, Chu WC. Hyperthyroidism is characterized by both increased sympathetic and decreased vagal modulation of heart rate: evidence from spectral analysis of heart rate variability. Clin Endocrinol (Oxf) 2006; 64:611-616.
Fransen J, van Riel PL. The Disease Activity Score and the EULAR response criteria. Clin Exp Rheumatol 2005; 23(Suppl 39):S93-S99.
Pagana KD, Pagana TJ. Mosby's manual of diagnostic and laboratory tests. 4th ed. St. Louis: Mosby Elsevier; 2010.
Linker JB, Williams RC Jr. Tests for detection of rheumatoid factors. In: Rose R, Friedman H, Fahey JC, editors. Manual of clinical laboratory immunology. 3rd ed. Washington: American Society for Microbiology; 1985.
Pruijn GJ, Wiik A, van Venrooij WJ. The use of citrullinated peptides and proteins for the diagnosis of rheumatoid arthritis. Arthritis Res Ther 2010; 12:203.
Engall E. Enzyme immunoassay ELISA and EMIT. In: van Vunakis H, Langone JJ, editors. Methods in enzymology. New York: Academic Press; 1980. 419-439.
Uotila M, Ruoslahti E, Engvall E. Two-site sandwich enzyme immunoassay with monoclonal antibodies to human alpha-fetoprotein. J Immunol Methods 1981; 42:11-15.
Spencer CA, Takeuchi M, Kazarosyan M, MacKenzie F, Beckett GJ, Wilkinson E. Interlaboratory/intermethod differences in functional sensitivity of immunometric assays of thyrotropin (TSH) and impact on reliability of measurement of subnormal concentrations of TSH. Clin Chem 1995; 41:367-374.
Jensen E, Hyltoft Petersen P, Blaabjerg O, Hansen PS, Brix TH, Kyvik KO, Hegedüs L. Establishment of a serum thyroid stimulating hormone (TSH) reference interval in healthy adults. The importance of environmental factors, including thyroid antibodies. Clin Chem Lab Med 2004; 42:824-832.
Hamilton TE, Davis S, Onstad L, Kopecky KJ. Thyrotropin levels in a population with no clinical, autoantibody, or ultrasonographic evidence of thyroid disease: implications for the diagnosis of subclinical hypothyroidism. J Clin Endocrinol Metab 2008; 93:1224-1230.
Barker SB. Determination of protein bound Iodine. J Biol Chem 1984; 173:715-724.
Chopra IJ, Solomon DH, Ho RS. A radioimmunoassay of thyroxine. J Clin Endocrinol Metab 1971; 33:865-868.
Walker WHC. Introduction: an approach to immunoassay. Clin Chem 1977; 23:384.
Schuurs AH, van Weemen BK. Enzyme-immunoassay. Clin Chem Acta 1977; 81:1-40.
Mitsuma T, Nihei N, Gershengorn MC, Hollander CS. Serum triiodothyronine: measurements in human serum by radioimmunoassay with corroboration by gas-liquid chromatography. J Clin Invest 1971; 50:2679-2688.
Brown LP, Besch PK, Skelley DS, Buttram VC Jr, Brown LP, Besch PK, et al
. Overnight radioimmunoassay of human follicle-stimulating hormone. Clin Chem 1973; 19:197-200.
Ruf J, Toubert ME, Czarnocka B, Durand-Gorde JM, Ferrand M, Carayon P. Relationship between immunological structure and biochemical properties of human thyroid peroxidase. Endocrinology 1989; 125:1211-1218.
McKenzie JM, Zakarija M, Sato A. Humoral immunity in Graves' disease. Clin Endocrinol Metab 1978; 7:31-45.
Bolton J. Measurement of thyroid stimulating hormone receptor autoantibodies by ELISA. Clin Chem 1999; 45:2285-2287.
Kamijo K. TSH-receptor antibody measurement in patients with various thyrotoxicosis and Hashimoto's thyroiditis: a comparison of two two-step assays, coated plate ELISA using porcine TSH-receptor and coated tube radioassay using human recombinant TSH-receptor. Endocr J 2003; 50:113-116.
Tahir A, Ahidjo A, Yusuph H. Ultrasonic assessment of thyroid gland. J Thyroid Res 2011; 3:26-31.
Vaz C. Thyroid ultrasound 101:what is it? and what can i expect?. Thyroid 2009;19:1167-214.
Vaz C. Thyroid ultrasound 101:what is it? and what can i expect?. J Endocrinol Invest 2010; 33(5 Suppl):51-6.
Dvorakova M, Bilek R, Cerovska J, Hill M, Novák Z, Vavrejnová V, et al
. The volumes of the thyroid gland in adults aged years in the Czech Republic - determination of the norms. Vnitr Lek 2006; 5:18-65.
Skarpa V, Kousta E, Tertipi A, Anyfandakis K, Vakaki M, Dolianiti M, et al
. Epidemiological characteristics of children with autoimmune thyroid disease. Hormones (Athens) 2011; 10:207-214.
Scarpa V, Kousta E, Tertipi A, Vakaki M, Fotinou A, Petrou V, et al
. Treatment with thyroxine reduces thyroid volume in euthyroid children and adolescents with chronic autoimmune thyroiditis. Horm Res Paediatr 2010; 73:61-67.
Kotz S, Balakrishnan N, Read CB. Encyclopedia of statistical sciences. 2nd ed. Hoboken, New Jersey: Wiley-Interscience; 2006.
Kirkpatrick LA, Feeney BC. A simple guide to IBM SPSS statistics for version 20.0. Student ed. Belmont, CA: Wadsworth, Cengage Learning; 2013.
Eschler DC, Hasham A, Tomer Y. Cutting edge: the etiology of autoimmune thyroid diseases. Clin Rev Allergy Immunol 2011; 41:190-197.
Tomer Y, Huber A. The etiology of autoimmune thyroid disease: a story of genes and environment. J Autoimmun 2009; 32:231-239.
Kerimoviæ-Morina D. Autoimmune thyroid disease and associated rheumatic disorders. Srp Arh Celok Lek 2005; 133:55-60.
Shiroky JB, Cohen M, Ballachey ML, Neville C. Thyroid dysfunction in rheumatoid arthritis: a controlled prospective survey. Ann Rheum Dis 1993; 52:454-456.
Kvien TK, Uhlig T, Ødegård S, Heiberg MS. Epidemiological aspects of rheumatoid arthritis: the sex ratio. Ann N Y Acad Sci 2006; 1069:212-222.
Del Rincón I, Battafarano DF, Arroyo RA, Murphy FT, Escalante A. Heterogeneity between men and women in the influence of the HLA-DRB1 shared epitope on the clinical expression of rheumatoid arthritis. Arthritis Rheum 2002; 46:1480-1488.
Geng Y, Zhou W, Zhang ZL. A comparative study on the diversity of clinical features between the sero-negative and sero-positive rheumatoid arthritis patients. Rheumatol Int 2012; 32:3897-3901.
Westwood OM, Nelson PN, Hay FC. Rheumatoid factors: what's new? Rheumatology (Oxford) 2006; 45:379-385.
Kastbom A, Strandberg G, Lindroos A, Skogh T. Anti-CCP antibody test predicts the disease course during 3 years in early rheumatoid arthritis (the Swedish TIRA project). Ann Rheum Dis 2004; 63:1085-1089.
Binesh F, Salehabadi HS, Behniafard N, Ranginkaman K, Behniafard N. A comparative assessment of the diagnostic value of anti-cyclic citrullinated peptide antibodies and rheumatoid factor in rheumatoid arthritis. J Clin Exp Pathol 2014; 4:158. doi: 10.4172/2161-0681.1000158.
El-Sherif WT, El Gendi SS, Ashmawy MM, Ahmed HM, Salama MM. Thyroid disorders and autoantibodies in systemic lupus erythematosus and rheumatoid arthritis patients. Egypt J Immunol 2004; 11:81-90.
Silman AJ, Ollier WE, Bubel MA. Autoimmune thyroid disease and thyroid autoantibodies in rheumatoid arthritis patients and their families. Br J Rheumatol 1989; 28:18-21.
Porkodi R, Ramesh S, Mahesh A, Kanakarani P, Rukmangathrajan S, Rajendran PC. Thyroid dysfunction in systemic lupus erythematosus and rheumatoid arthritis. J Indian Rheumatol Assoc 2004; 12:88-90.
Singh B, Mittal BR, Bhattacharya A, Deodhar SD. A cross sectional evaluation of circulating thyroid hormonal profile in patients with rheumatoid arthritis. IJNM 2002; 17:68-72.
Wellby ML, Kennedy JA, Pile K, True BS, Barreau P. Serum interleukin-6 and thyroid hormones in rheumatoid arthritis. Metabolism 2001; 50:463-467.
Van Halm VP, Peters MJ, Voskuyl AE, Boers M, Lems WF, Visser M, et al
. Rheumatoid arthritis versus diabetes as a risk factor for cardiovascular disease: a cross-sectional study, the CARRE Investigation. Ann Rheum Dis 2009; 68:1395-1400.
Innocencio RM, Romaldini JH, Ward LS. High prevalence of thyroid autoantibodies in systemic sclerosis and rheumatoid arthritis but not in the antiphospholipid syndrome. Clin Rheumatol 2003; 22:494.
Baþkan BM, Filiz S, Aktekin LA, Yurdakul FG, Çýnar NK, Hatice B. Relationship between thyroid autoimmunity and depression, quality of life, and disease symptoms in patients with fibromyalgia and rheumatoid arthritis. Turk J Rheumatol 2010; 25:130-136.
Koszarny A, Majdan M, Suszek D, Wielosz E, Dryglewska M. Relationship between rheumatoid arthritis activity and antithyroid antibodies. Pol Arch Med Wewn 2013; 123:394-400.
Andonopoulos AP, Siambi V, Makri M, Christofidou M, Markou C, Vagenakis AG. Thyroid function and immune profile in rheumatoid arthritis. A controlled study. Clin Rheumatol 1996; 15:599-603.
Koga Y, Kuromaru R, Takada H, Hara T. Juvenile idiopathic arthritis associated with autoimmune thyroid disorders and autoimmune cholangitis. Rheumatology (Oxford) 2001; 40:942-943.
Raterman HG, van Halm VP, Voskuyl AE, Simsek S, Dijkmans BA, Nurmohamed MT. Thyroid peroxidase antibodies in rheumatoid arthritis. Ann Rheum Dis 2008; 67:229-232.
Yavasoglu I, Senturk T, Coskun A, Bolaman Z. Rheumatoid arthritis and anti-thyroid antibodies. Autoimmunity 2009; 42:168-169.
Charles PJ, Plant D, Chowdhury M, Worthington J, Venables P. Antibodies to thyroglobulin and thyroid peroxidase in rheumatoid arthritis: environmental and genetic associations. Ann Rheum Dis 2011; 70:A88-A89.
Przygodzka M, Filipowicz-Sosnowska A. Prevalence of thyroid diseases and antithyroid antibodies in women with rheumatoid arthritis. Pol Arch Med Wewn 2009; 119:39-43.
Lee YA, Song SH, Ran SHIY. Higher prevalence of coexisting papillary thyroid cancer as well as autoimmune thyroid diseases in patients with rheumatoid arthritis. Arthritis Rheum 2010; 62:1038.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]