Abstract: The association of juvenile rheumatoid arthritis and type 1 diabetes mellitus is rare. These two diseases belong to different clusters of autoimmune diseases and it is uncommon for diseases belonging to different cluster occurring together. This is a case report of a fourteen-year-old girl having the above two disorders along with autoimmune thyroid disease.

Key words: Juvenile rheumatoid arthritis, Type 1 diabetes mellitus.

The association of type 1 diabetes mellitus (T1DM) and thyroid disorders such as Hashimoto’s thyroiditis in childhood and adolescence is well known, but juvenile diabetes mellitus with juvenile rheumatoid arthritis is infrequently reported.

We report a 14-year-old girl who had simultaneous occurrence of T1DM and seropositive polyarthritic type of juvenile rheumatoid arthritis as well as asymptomatic euthyroid autoimmune thyroid disease. The asociation of these immunologically mediated diseases is most likely not a matter of chance alone and may be more common than previously realized.

Case Report

A 14-year-old girl born of non-consanguineous Muslim parents was referred for poorly controlled diabetes and poly-arthritis. She developed polyuria, polydipsia and loss of weight over a period of few weeks and nearly six months back was diagnosed to have diabetes based on her fasting and postprandial blood sugar of 130 mg/dL and 360 mg/dL respectively along with glycosuria but no ketosis. Therapy was initiated with human insulin but her blood sugar was not under control. Soon thereafter, she also developed pain and swelling in her joints. Following the initial involvement of her right ankle joint, there was non-migratory asymmetric involvement of large as well as small joints with painful limitation of movements and morning stiffness. There was no history suggestive of thyroid dysfunction or symptoms involving any other system. There was no history of tubercular contact. None of the family members had any autoimmune disorder.

On examination, she was pale, thin built, underweight 26 kg (<5th pecentile), with a height of 154 cm (between 50th and 75th percentile). There was spindle shaped, tender swelling of small joints of hands and swelling and painful restriction of movements of elbows and left ankle. There were no skin lesions or subcutaneous rheumatoid nodules. Cardiovascular and systemic examinations were normal. Fundus and slit examination for iridocyclitis was normal. Thyroid gland was normal on palpation.

Investigations showed low hemoglobin of 8.5 g/dL with a total white cell count of 6100 µL, neutrophils 60% and ESR of 112 mm at end of one hour. Fasting blood sugar was high (326 mg/dL) inspite of insulin therapy. Glycosylated hemoglobin was 15.7% (normal 4.5-7%). There was no ketosis. Serological testing for ASO, ANA and LE cell was negative. RA factor was strongly positive in the dilution of 1:128. Serum immuno-globulins were elevated with IgG-1640 (normal 725-1085 mg/dL), IgA-270 (normal 70-230 g/dL), and IgM-105 (normal 35-70 mg/dL). The thyroid profile was normal with total serum T3 and T4 levels of 80 ng/dl (normal 70-220 ng/dL) and 11µ/dL (normal 4.4-11.6 µg/dL) respectively with a TSH of 0.4 µIU/mL (normal 0.22-6.8). Anti microsomal anti-bodies and antithyroglobulin antibodies by chemiluminescence technique were markedly elevated in titres of >1000 IU/mL and >3000 IU/mL respectively (normal <40 IU/mL for both). HLA typing by microlympho-cytotoxicity method showed A19, A28, B8, Cw7, DR3, and DQw2. X-rays of wrists and ankles showed osteoporotic changes and reduction in joint spaces. GAD antibodies were positive.

This patient therefore had simultaneous occurence of juvenile diabetes, juvenile rheumatoid arthritis and an euthyroid autoimmune thyroid disease. Her insulin dosage was gradually stepped up so as to normalize her blood sugar and therapy with salazopyrine and indomethacin was initiated for her rheumatoid arthritis.

Discussion

The association of type 1 diabetes mellitus with autoimmune thyroiditis is well documented but association with rheumatoid arthritis is infrequently reported in pediatric literature. In this case all the three disorders having an autoimmune basis were associated.

Conventionally, autoimmune disorders are divided into two group or clusters. One cluster includes disease like rheumatoid arthritis, systemic lupus erythematosus and scleroderma which have non-organ specific antibodies, such as anti nuclear antibodies and rheumatoid factor. The other group is the thyrogastric cluster, which includes organ specific disorders with organ specific autoantibodies like thyroiditis, pernicious anemia, and vitiligo. T1DM, although not clearly established as an auto immune disease, is considered one of the thyrogastric cluster by virtue of its common association with diseases in that group, in particular thyroid disease. Prevalence of autoimmune thyroid disease in children with type 1 diabetes mellitus has been estimated to be 4-16%(1).

It is uncommon for diseases in one cluster to be associated with disease from the other cluster. In the present case, T1DM was associated with juvenile rheumatoid arthritis. There have been few reported cases of this kind in pediatric literature(2-4). One study has reported a series of seven children with diabetes and rheumatoid arthritis, of which six had the polyarticular form of the disease(5). In another instance, a sixteen year old girl, earlier diagnosed as having celiac disease and IgA deficiency developed a cluster of autoimmune diseases which included T1DM, rheumatoid arthritis and euthyroid autoimmune thyroid-itis, which eventually resulted in a simul-taneous long term remission. However in another 7-year-old girl onset of T1DM occured five months after initiation of etanercept therapy for systemic onset juvenile rheumatoid arthritis(6). This raises the possi-bility of T1DM occurring as a complication of etanercept therapy probably due to modulation of tumour necrosis factor (TNF).

Certain HLA antigens occur with increased frequency in individuals with various autoimmune diseases. Inheritance of HLA-DR3 or DR4 antigens confers two to threefold increased risk for the development of T1DM. When both DR3 and DR4 are inherited, the relative risk for the development of diabetes mellitus is increased by seven to ten fold. Individuals with DR3 and DR4 also have an increased risk for developing rheumatoid arthritis, particularly the severe seropositive form(7,8). This implies that both DR3 and DR4 confer increased risk in both these conditions. However, the association of these two conditions is uncommon probably because there are different genomic markers for the HLA-DQ subregion, which discrimi-nates between the two diseases(9). HLA typing of our patient revealed the presence of B8, DR3 haplotype, similar to the one reported earlier(4).

The finding of these autoimmune diseases in genetically susceptible individuals suggests that the association could be more than chance alone. This case is reported for the rare association of three autoimmune disorders of different clusters occurring in a young female adolescent.

Acknowledgement

We would like to thank the Medical Director of Sir H. N. Hospital & Research Center for permitting us to publish this case. We would also like to specially thank the Medical Research Society for doing the GAD antibodies in our patient.

Contributors: MPD co-ordinated the case study and helped draft the paper. She will act as a guarantor for the paper. SA participated in the data collection and drafted the paper.

Funding: None.

Competing interests: None stated.

9. Nepom BS, Palmer J, Kim SJ, Hansen JA, Holbeck SL, Nepon GT. Specific genomic markers for the HLA-DQ subregion discri-minate between DR4 Insulin dependent diabetes mellitus and DR4 seropositive juvenile rheumatoid arthritis. J Exp Med 1986; 164: 345-350.