INTRODUCTION
Thionamide drugs are widely used in the management of patients with hyperthyroidism. While radiactive iodine is currently the treatment of choice in United States, antithyroid drugs continue to be the first therapy in Europe1. These drugs (methimazole and propylthiouracil) are associated with side effects including: rash, urticaria, fever, transient leukopenia, agranulocytosis and most rarery arthralgias, either alone or as part of a lupus-like syndrome. Here, we describe a patient with Grave's disease, who developed polyarthritis following treatment with methimazole.
CASE REPORT
A 64-year-old woman was admitted with a 1 week history of generalized poly arthralgias. One month before admission, she presented anorexia and weight loss. Investigations showed Grave's disease: thyroid stimulating hormone (TSH) was below 0.01 mU/l (normal range 0.45-4.7 mU/ml), free thyroxine was 5.94 ng/dl (normal range: 0.7-1.85 ng/dl), and a thyroid scan showed increased diffuse activity. Thyroid stimulating immunoglobulins were positive (TSI) (37.9 U/l; normal range below 10 U/l), while anti-microsomal and anti-thyroglobulin antibodies were negative. Therapy was initiated with propranolol 20 mg bid and methimazole 10 mg tid.
Six weeks later, the patient developed sudden stiffness and pain in both hands, wrists, knees and ankles. Examination revealed a tired women with normal blood pressure (120/70 mmHg) and regular heart rate (70 beats per minute). Polyartrhalgias was generalized, symmetrical, without fever or rash. Temporal arteries were normal to palpation and muscle strength was normal, too.
Laboratory studies showed hemoglobin 115 mg/dl, leucocytes 5.3 * 109/l, and platelets 230 * 109/l. The erythrocyte sedimentation rate (ESR) was 59 mm/h. Antinuclear antibodies (ANA) and rheumatoid factor by nephelometry were negatives. Urinalysis, creatinine, liver tests, and haemostasia parameters were normal. A hand x-Ray showed on increased soft tissue without bone lessions. The patient denied a history of calcium pyrophosphate disease, trauma or occupational strain to her joints.
An adverse reaction to methimazole was suspected and the drug was whitdrawn. Indometacin 25 mg tid was begun with propylthiouracil 100 mg tid. Inflammation in metacarpophalangeal, proximal interphalangeal, and metatarsophalangeal joints, wrists, knees and ankles decreased and disappeared in one week. Twelve weeks later, the patient had normal thyroid function without arthralgias while receiving propylthiouracil 100 mg tid.
DISCUSSION
We have found a total of 25 cases of arthralgias secondary to antithyroid drugs reported in the literature. Most patients were women, which is likely secondary to the epidemiology of Graves' disease2-18. A common feature was the fact that polyarthralgias were migratory, and involved large and small joints. Polyarthralgias occurred within 1-2 months of starging antithyroid drugs, were associated with elevated ESR and ANA were usually negative. Symptoms disappeared within 2-4 weeks after stopping therapy. In our case, polyarthralgias disappeared with a short course of antiinflammatory drugs and changeover to propylthiouracil (PTU). Moreover, even when cross reactivity between propylthiouracil and methimazole has been documented to be 20%, our patient had no problems, three months after initiating PTU. There are 5 cases in the literature where corticoesteroids were used to treated arthralgias18, and the duration of symptoms did not appear to be shortened by the use of corticosteroid.
Some of the reported patients had additional features such as lymphadenopathy, serositis, rash and fever suggestive of a drug induced lupus-like syndrome (24%)3,8,10,12. Nephritis was rarely reported as part of the lupus like syndrome in these patients18.
Only two studies have recorded the frequency of this side-effect of antithyroid drugs. A study of 500 patients taking these drugs found a 1.6% prevalence of arthralgias5, and a second study reported 6 cases of arthralgia in 831 patients taking antithyroid medication. In these papers, rheumatic complaints did not appear to be dose-related.
The exact pathogenesis of antithyroid drug-induced ar thritis is unknown. Two mechanisms have been proposed. Most reports have postulated that antithyroid arthritis syndrome is an immunological phenomenon, with abnormal cellular and humoral immunologic activity19. In this hypothesis, the thiol group of these drugs may undergo covalent binding to cellular macromolecules behaving as a hapten to induce antibody production. Other authors20 have proposed a role of glutathione and cooper. Patients would be predisposed to this adverse effect if they had a deficit in cellular cooper binding capacity. The complex cooper-methimazole could then alter glutathione metabolism, enhancing release of interleukin 1 from mononuclear leukocytes, producing secondary synovial inflammation.
In conclusion, a high degree of clinical awareness of this side effect is essential to recognize this entity where drug discontinuation or change is necessary. If a cross reactivity with the second drug ensues, other forms of treatment for hyperhyroidism, such as radioablation of surgery, are recommended.
