Abstract

Objectives. Autoimmune diseases have been associated with some organ non-specific rheumatological disorders such as rheumatoid arthritis and systemic lupus erythematosus; however, few studies have been performed in an extensive cohort of children with juvenile idiopathic arthritis (JIA). Our objective was to evaluate the thyroid function and the prevalence of antithyroid antibodies, autoimmune thyroiditis and coeliac disease in children with JIA.

Methods. One hundred and fifty-one children (120 female, 31 male, median age 8.3 yr, range 2.4–16.9 yr) with JIA were evaluated. All patients underwent thyroid function tests (u-TSH, free T4 and free T3), antithyroglobulin (TgA) and antiperoxidase (TPOA) antibodies, antigliadin, anti-endomysium and antitransglutaminase antibodies. All patients with raised thyroid stimulating hormone levels, low thyroid hormone levels or positive TPOA and/or TgA values had a thyroid high-resolution sonography examination. Coeliac disease was confirmed by jejunal biopsy if the specific antibodies profile was positive. One hundred and fifty-eight age- and sex-matched Caucasian children from the same geographical area acted as controls.

Results. Fourteen (9.3%) patients showed subclinical hypothyroidism, 17 (11.9%) patients showed autoimmune thyroiditis with nine patients also showing a non-homogeneous thyroid parenchyma at ultrasound evaluation. Coeliac disease was demonstrated in 10 (6.6%) patients. Compared with controls, JIA patients had higher prevalence of subclinical hypothyroidism (P<0.01), autoimmune thyroiditis (P<0.0001) and coeliac disease (P<0.005).

Conclusions. JIA children have an increased prevalence of autoimmune thyroiditis, subclinical hypothyroidism and coeliac disease. These data seem to suggest careful monitoring of thyroid function, thyroid autoantibodies and coeliac disease in JIA children.

Juvenile idiopathic arthritis (JIA) is a chronic inflammatory disease characterized by chronic synovitis, and sometimes associated with extra-articular manifestations, mainly fever, rash, pericarditis and uveitis [1]. Associated autoimmune diseases, such as thyroid and coeliac diseases, have been previously described, mainly in adult rheumatoid arthritis [2–4], whilst only a few data are available for large series of JIA [5, 6].

In this study, we evaluate the thyroid function and the prevalence of antithyroid antibodies and autoimmune thyroiditis along with coeliac disease in a large cohort of Italian children affected by JIA.

Patients and methods

Our study included 151 patients (120 females, 31 males, median age 8.3 yr, range 2.4–16.9 yr), all fulfilling the revised criteria for the diagnosis of JIA [7], consecutively admitted to our Paediatric Rheumatology Unit between January 1991 and January 2003. Ninety-two out of 151 JIA children had oligoarticular, 49 polyarticular and 10 systemic onset, during the first 6 months of disease.

For each patient, demographic data, type of JIA onset, age at diagnosis and family history for autoimmune diseases up to second-degree relatives were entered. During the family history, the following autoimmune diseases were considered: autoimmune thyroid diseases, rheumatoid arthritis and other rheumatological disorders, coeliac disease, type 1 diabetes mellitus, vitiligo, alopecia, multiple sclerosis, and inflammatory bowel disease.

From January 2002 and March 2003, all 151 patients underwent tests for antigliadin (AGA), anti-endomysium (EmA) and antitransglutaminase (tTG) antibodies, thyroid function (u-TSH, FT4, FT3) and thyroid autoimmunity (antithyroglobulin or TgA and antiperoxidase or TPOA antibodies).

Thyroid function

Free T4 (FT4), free T3 (FT3) and u-TSH serum levels were determined by immunometric assays (Immulite™ 2000 Third Generation, DPC Diagnostic Products Corporation, Los Angeles, CA, USA). Within- and between-run coefficients of variation was less than 12.5% for u-TSH, less than 7.5% for FT4 and less than 9.1% for FT3. The normal range of thyroid hormones and thyroid-stimulating hormone (thyrotropin) were, respectively, FT4 0.8–1.9 ng/dl, FT3 1.9–4.8 pg/ml and u-TSH 0.4–4.0 μIU/ml.

Subclinical hypothyroidism was defined as u-TSH level >4.0 μIU/ml together with normal serum thyroid hormone levels. Overt hypothyroidism was defined as raised u-TSH together with a decreased serum thyroid hormone level.

Autoimmune thyroiditis screening

Thyroid autoimmunity was evaluated by fluorescence enzymatic immunoassays of TgA and TPOA antibodies, considering TgA ≥50 IU/ml and TPOA ≥100 IU/ml as positive values.

All patients with raised TSH levels, low thyroid hormone levels or positive TPOA and/or TgA values underwent thyroid high-resolution sonography examination.

Diagnosis of autoimmune thyroiditis was considered with elevated TPOA and/or TgA values, and elevated TSH levels and/or typical hypoechogenicity of the thyroid ultrasound [8]. The thyroid was considered hypoechogenic when its signal was equal to or below the echogenicity of the surrounding neck muscles.

Coeliac disease screening

Immunoglobulin (Ig)A and IgG AGA were measured using an enzyme-linked immunosorbent assay (ELISA). IgA EmA were assayed by a standard immunofluorescence method using cryostat sections of monkey oesophagus. Serum IgA tTG antibodies were assayed with specific ELISA.

Diagnosis of coeliac disease was confirmed by performing small intestine biopsy if the specific autoantibody profile was positive.

Controls

One hundred and fifty-eight Italian children (100 females, 58 males, median age 8.7 yr; range 2.3–16.7 yr), age- and sex-matched from the same geographical area, admitted to our hospital for minor surgical interventions, acted as controls.

Informed consent was obtained from all children and/or their parents. The study protocol was approved by our hospital's Ethics Committee.

Statistical analysis

The χ2-test or Fisher's exact test, when appropriate, were used to compare differences between cases and controls. Bonferroni's correction for multiple comparisons was applied, where due. Statistical tests were two-tailed, and considered significant when P<0.05.

Results

The prevalence of familial autoimmunity, thyroid dysfunction, autoimmune thyroiditis and coeliac disease in JIA patients and controls is summarized in Tables 1 and 2.

Table 1.

Characteristics and presence of thyroid and coeliac diseases in 151 children with JIA and controls

    JIA patients   
  Oligoarticular Polyarticular Systemic Controls JIA vs controls 
Number of subjects 151 92 (58.1%) 49 (37.6%) 10 (4.2%) 158  
Relatives with autoimmune disorders 55 (36.4%) 33 (60%) 20 (36.4%) 2 (3.6%) 11 (6.9%) P<0.0001 
Subclinical hypothyroidism 14 (9.3%) 13 (93%) 1 (7%) – 4 (2.5%) P<0.01 
Autoimmune thyroiditis 17 (11.9%) 10 (59%) 7 (41%) – 2 (1.2%) P<0.0001 
Subclinical hypothyroidism and autoimmune thyroiditis 2 (1.3%) 2 (100%) – – – NS 
Coeliac disease 10 (6.7%) 7 (70%) 3 (30%) – 1 (0.6%) P<0.005 
Coeliac disease and autoimmune thyroiditis 3 (1.9%) 2 (67%) 1 (33%) – – NS 
    JIA patients   
  Oligoarticular Polyarticular Systemic Controls JIA vs controls 
Number of subjects 151 92 (58.1%) 49 (37.6%) 10 (4.2%) 158  
Relatives with autoimmune disorders 55 (36.4%) 33 (60%) 20 (36.4%) 2 (3.6%) 11 (6.9%) P<0.0001 
Subclinical hypothyroidism 14 (9.3%) 13 (93%) 1 (7%) – 4 (2.5%) P<0.01 
Autoimmune thyroiditis 17 (11.9%) 10 (59%) 7 (41%) – 2 (1.2%) P<0.0001 
Subclinical hypothyroidism and autoimmune thyroiditis 2 (1.3%) 2 (100%) – – – NS 
Coeliac disease 10 (6.7%) 7 (70%) 3 (30%) – 1 (0.6%) P<0.005 
Coeliac disease and autoimmune thyroiditis 3 (1.9%) 2 (67%) 1 (33%) – – NS 

Familial autoimmunity

Fifty-five patients had a positive family history for autoimmune diseases, showing a significant difference compared with controls (36.4 vs 6.8%; P<0.0001), namely 30 of psoriasis, 19 of rheumatoid arthritis (two of JIA), 12 of autoimmune hypothyroidism, five of autoimmune hyperthyroidism, five of coeliac disease, five of type 1 diabetes mellitus, four of multiple sclerosis, four of connective tissue diseases, three of inflammatory bowel disease, two of vitiligo and one of alopecia.

Of these 55 families of JIA probands, 30 families (55%) had one relative, 12 families (22%) had two relatives and 13 families (23%) had three or more relatives with a history of autoimmune disorders. First-degree relatives accounted for 42% of reported familial autoimmune disorders, whilst second-degree relatives accounted for 58%.

Comparing the different types of onset, we observed that oligoarticular onset JIA patients showed an increased, although not significant, prevalence of familial autoimmunity (33 out of 55 families, 60%) compared with those with polyarticular onset (20 families, 36.4%) and systemic onset (two families, 3.6%).

Control group

Two female and two male subjects (2.5%) had subclinical hypothyroidism with negative antithyroid autoantibodies; two female subjects (1.2%) showed high titres of antithyroid autoantibodies with normal thyroid function, and in one of these typical hypoechogenicity of the thyroid was assessed. One female (0.6%) was positive for AGA and EmA antibodies with biopsy proven diagnosis of coeliac disease.

JIA patients

In the study group, 14 (9.3%) JIA patients (10 females, four males, median age 7.4 yr, range 2.3–14.9 yr) showed subclinical hypothyroidism. Two of these presented autoimmune thyroiditis. No cases of overt clinical and biochemical hypothyroidism were found among children with JIA.

Autoimmune thyroiditis were detected in 17 (11.9%) patients (16 females, one male, median age 9.2 yr, range 2.0–15.9 yr). Of these, six patients were found positive for TPOA, five for TgA and six for both. Among these patients, nine children (6%) had a hypoechogenic ultrasound pattern, compatible with autoimmune thyroiditis (Table 2).

Table 2.

Clinical and laboratory findings in JIA patients with subclinical hypothyroidism, autoimmune thyroiditis and coeliac disease

Number Sex Age (yr) JIA onset FT4 (ng/dl) FT3 (pg/ml) TSH (μIU/ml) TgA TPOA Coeliac disease 
2.0 Polyarticular 1.38 5.0 3.29 358 369 – 
2.3 Polyarticular 1.32 3.84 5.14 – – – 
2.5 Polyarticular 1.61 3.82 2.26 161 123 – 
3.2 Oligoarticular 1.20 3.91 1.57 250 – + 
3.3 Polyarticular 1.36 4.17 2.12 167 – – 
3.9 Oligoarticular 1.49 5.15 3.37 – – + 
3.9 Oligoarticular 1.22 3.40 2.83 – 100 – 
4.2 Oligoarticular 1.84 1.66 4.75 – – – 
4.6 Oligoarticular 1.34 3.36 6.14 – – – 
10 4.9 Oligoarticular 1.53 4.43 4.65 – – – 
11 6.3 Oligoarticular 1.32 3.61 4.28 – – – 
12 6.5 Oligoarticular 1.10 4.12 4.91 – – – 
13 6.8 Oligoarticular 1.37 3.34 4.71 – – – 
14 7.6 Oligoarticular 1.53 3.91 4.37 – – – 
15 7.6 Polyarticular 1.52 5.84 2.03 – 572 + 
16 7.9 Oligoarticular 1.49 4.10 5.10 – – – 
17 8.4 Oligoarticular 1.42 1.90 1.51 214 – + 
18 8.6 Polyarticular 1.11 3.71 1.54 – – + 
19 8.9 Oligoarticular 1.35 5.00 6.68 – – – 
20 9.4 Oligoarticular 1.47 4.59 2.89 445 117 – 
21 10.2 Oligoarticular 1.25 4.04 4.27 – – – 
22 10.3 Polyarticular 1.31 2.75 1.18 156 102 – 
23 11.0 Polyarticular 1.30 2.70 1.69 – – + 
24 11.2 Polyarticular 1.14 4.63 1.79 – 148 – 
25 11.8 Polyarticular 1.10 3.40 1.44 – – + 
26 12.0 Polyarticular 1.17 4.32 2.72 108 214 – 
27 12.0 Oligoarticular 1.32 3.54 2.58 – – + 
28 12.3 Oligoarticular 1.47 4.30 3.78 – 276 – 
29 12.4 Oligoarticular 1.37 5.00 5.39 – – + 
30 12.7 Oligoarticular 1.09 4.73 1.95 1000 2614 – 
31 13.2 Oligoarticular 1.11 3.88 4.27 1000 101 – 
32 13.3 Oligoarticular 1.00 2.13 2.20 – 174 – 
33 14.9 Oligoarticular 0.86 3.86 6.52 133 247 – 
34 17.4 Polyarticular 1.33 4.88 2.93 – – + 
35 17.6 Polyarticular 1.17 3.16 1.95 316 – – 
Number Sex Age (yr) JIA onset FT4 (ng/dl) FT3 (pg/ml) TSH (μIU/ml) TgA TPOA Coeliac disease 
2.0 Polyarticular 1.38 5.0 3.29 358 369 – 
2.3 Polyarticular 1.32 3.84 5.14 – – – 
2.5 Polyarticular 1.61 3.82 2.26 161 123 – 
3.2 Oligoarticular 1.20 3.91 1.57 250 – + 
3.3 Polyarticular 1.36 4.17 2.12 167 – – 
3.9 Oligoarticular 1.49 5.15 3.37 – – + 
3.9 Oligoarticular 1.22 3.40 2.83 – 100 – 
4.2 Oligoarticular 1.84 1.66 4.75 – – – 
4.6 Oligoarticular 1.34 3.36 6.14 – – – 
10 4.9 Oligoarticular 1.53 4.43 4.65 – – – 
11 6.3 Oligoarticular 1.32 3.61 4.28 – – – 
12 6.5 Oligoarticular 1.10 4.12 4.91 – – – 
13 6.8 Oligoarticular 1.37 3.34 4.71 – – – 
14 7.6 Oligoarticular 1.53 3.91 4.37 – – – 
15 7.6 Polyarticular 1.52 5.84 2.03 – 572 + 
16 7.9 Oligoarticular 1.49 4.10 5.10 – – – 
17 8.4 Oligoarticular 1.42 1.90 1.51 214 – + 
18 8.6 Polyarticular 1.11 3.71 1.54 – – + 
19 8.9 Oligoarticular 1.35 5.00 6.68 – – – 
20 9.4 Oligoarticular 1.47 4.59 2.89 445 117 – 
21 10.2 Oligoarticular 1.25 4.04 4.27 – – – 
22 10.3 Polyarticular 1.31 2.75 1.18 156 102 – 
23 11.0 Polyarticular 1.30 2.70 1.69 – – + 
24 11.2 Polyarticular 1.14 4.63 1.79 – 148 – 
25 11.8 Polyarticular 1.10 3.40 1.44 – – + 
26 12.0 Polyarticular 1.17 4.32 2.72 108 214 – 
27 12.0 Oligoarticular 1.32 3.54 2.58 – – + 
28 12.3 Oligoarticular 1.47 4.30 3.78 – 276 – 
29 12.4 Oligoarticular 1.37 5.00 5.39 – – + 
30 12.7 Oligoarticular 1.09 4.73 1.95 1000 2614 – 
31 13.2 Oligoarticular 1.11 3.88 4.27 1000 101 – 
32 13.3 Oligoarticular 1.00 2.13 2.20 – 174 – 
33 14.9 Oligoarticular 0.86 3.86 6.52 133 247 – 
34 17.4 Polyarticular 1.33 4.88 2.93 – – + 
35 17.6 Polyarticular 1.17 3.16 1.95 316 – – 

Normal range: free T4 (FT4) 0.8–1.9 ng/dl; free T3 (FT3) 1.9–4.8 pg/ml; u-TSH 0.4–4.0 μIU/ml.

Normal value: antithyroglobulin (TgA) antibodies <50 IU/ml; antiperoxidase (TPOA) antibodies <100 IU/ml.

Diagnosis of coeliac disease was confirmed by small intestine biopsy in all patients with specific positive autoantibody profile, namely 10 (6.7%) patients (nine females, one male, median age 9.1 yr, range 3.2–12.4 yr). Of these, three patients presented autoimmune thyroiditis.

JIA patients vs controls

We observed a significant increased prevalence of subclinical hypothyroidism (P<0.01), autoimmune thyroiditis (P<0.0001) and coeliac disease (P<0.005), in JIA patients, compared with controls. Subclinical hypothyroidism was more frequently detected in JIA patients with oligoarticular onset than in those with polyarticular onset (P<0.04) or systemic onset (P<0.01).

Discussion

In a large cohort of Italian children with JIA, our data showed a significantly increased prevalence of subclinical hypothyroidism, thyroid autoantibodies and coeliac disease.

Mihailova et al. [6] previously reported that among 27 JIA children, 44.4% had autoimmune thyroiditis; among these patients, 85.2% were euthyroid, 11.1% had a subclinical hypothyroidism and 3.7% had Hashi toxicosis. Alpigiani et al. [5], evaluating 66 JIA patients, showed just nine (14%) patients with antithyroid antibodies and all children showed a normal thyroid function.

In contrast to data reported by Alpigiani et al. [5], but in agreement with Mihailova et al. [6], our JIA patients frequently presented a subclinical hypothyroidism. Of note, conversely to Mihailova et al. [6], the majority (12/14) of children with subclinical hypothyroidism reported in our study did not show findings suggestive of autoimmune thyroiditis. These results might suggest that thyroid function in JIA could also be impaired in children without an associated autoimmune thyroiditis.

Interestingly, oligoarticular JIA patients seem more frequently to develop subclinical hypothyroidism in comparison with those with polyarticular and systemic onset; whilst no significant differences were found with regard to autoimmune thyroiditis and coeliac disease.

Adult rheumatoid arthritis commonly shows high association with autoimmune thyroid disease [2–4]. Positive thyroid autoantibodies have been detected in about 11% of rheumatoid arthritis patients [9], with a wide difference in most series, ranging from 2 [10] to 16% [4]. Conversely, the relationship between coeliac disease and rheumatoid arthritis is still controversial [11–14]. In our cohort, coeliac disease was quite commonly diagnosed, with about a 7-fold higher prevalence than in controls. This observation confirms and supports data from a previous study [15], in which the prevalence of coeliac disease in patients with JIA appeared higher (2.5%) than in controls.

Coeliac disease and autoimmune thyroid disease coexisted in three children, addressing the issue of additional autoimmune disease in the same subject.

Rheumatoid arthritis, psoriasis and autoimmune thyroiditis were the most frequent autoimmune disorders reported among the relatives of our patients. As previously described [16], relatives of JIA patients showed a higher frequency of autoimmune disorders than those of controls, although in our study second-degree relatives rather than first-degree relatives were principally affected.

In conclusion, our data confirmed the higher prevalence of thyroid disorders and coeliac disease, coupled with an increased prevalence of familial autoimmunity, among JIA patients. In order to minimize the risk of delayed and/or undiagnosed thyroid and coeliac diseases, this retrospective study seems to suggest the need for careful monitoring of possible associated autoimmunity during the course of JIA. Prospective studies or longer follow-up might be useful to clarify this issue.

The authors have declared no conflicts of interest.

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