Arthritis Associated With Antithyroid Therapy in a 15-Year-Old Girl

Abstract

A 15-year-old white girl with autoimmune thyroiditis developed arthritis 3 weeks after starting therapy with the antithyroid drug thiamazole. Because an adverse drug reaction of thionamide therapy was suspected, thiamazole was withdrawn, and symptoms disappeared rapidly. Thionamide therapy is indicated for hyperthyroidism and has been widely used since 1948. Reported adverse drug reactions range from mild to potentially life threatening. Arthritis is an uncommon but serious side effect and can develop as a part of the antithyroid arthritis syndrome or as a part of antineutrophil cytoplasmic antibody-associated vasculitis that is induced by antithyroid drugs. Little is known about the exact pathogenesis. Therapy consists of prompt discontinuation of the drug, where upon symptoms rapidly disappear. Because of possible cross-reactivity with alternative thionamides, another form of treatment for hyperthyroidism is recommended. Clinical awareness is important, and prompt withdrawal of the antithyroid drug is necessary when serious side effects occur.

INTRODUCTION

Antithyroid drugs are widely used, along with radioactive iodine or surgery, in the treatment of hyperthyroidism, including before surgery or radiotherapy. These medications can be categorized as a thiouracilderivate (e.g., propylthiouracil [PTU]) or as a thio-imidazolderivate (e.g., carbimazole, methimazole, and thiamazole). Propylthiouracil and methimazole (Tapazole, AAI Pharma, Wilmington, NC) are used in the United States, while methimazole, known as thiamazole (Strumazol, Organon, Oss, Netherlands), is used in the Netherlands. A variety of adverse effects, ranging from mild to potentially life threatening, (Table) have been reported following treatment with antithyroid drugs.¹ Minor adverse effects, such as cutaneous reaction and arthralgias, occur relatively frequently (1%-6%), compared with major ones, such as agranulocytosis, hepatitis and polyarthritis (0.5%-2%).² Depending on the medication, the adverse reaction may be dose related.³ Although a number of case reports have described antithyroid drug-induced arthralgia and arthritis,^4–6 only a few have detailed the occurrence of arthritis in children treated with these agents.^7,8 We describe a child with Graves' disease who had oligoarticular arthritis during treatment with thiamazole.

CASE

A 15-year-old white girl was admitted to the hospital with a 4-day history of malaise, itching and arthralgias affecting the right ankle, shoulders and fingers. Three weeks before, she had received a diagnosis of hyperthyroidism due to Graves' disease (autoimmune thyroiditis). She was started on an antithyroid drug (thiamazole) with an initial daily dose of 30 mg. The dose was subsequently increased to a maximum of 90 mg daily. Propranolol was added at a dose of 80 mg daily because of tachycardia. The patient's medical history included an allergy for grass pollen and birch, for which she used 10 mg of cetirizine dihydrochloride (Zyrtec, UCB Pharma BV, Breda, Netherlands). Unfortunately, this treatment for allergic rhinitis was insufficient and she was started on sublingual immunotherapy with a grass pollen extract (Oralgen, Artu Biologicals, Lelystad, Netherlands) approximately 4 weeks before the onset of Graves' disease.

Upon physical examination, the patient was afebrile, had a blood pressure of 110/70 mm Hg and had a pulse rate of 80 beats per minute. Her weight was 58 kg. The thyroid gland was diffusely enlarged. She was unable to walk because of pain in her right ankle; her right ankle was erythematous, swollen and tender on examination, but the other joints were normal. She had urticaria on her right leg. Findings from further physical examination were unremarkable.

Laboratory results showed hemoglobin of 7.9 g/dL, total white blood cell count of 8.6 × 10³/μL and a platelet count of 261 × 10³/μL. The C-reactive protein was slightly elevated at 12 mg/L. The liver enzymes were within normal range. The free serum thyroxine (FT4) was markedly elevated at 4.23 ng/dL, while the thyroid stimulating hormone (0.005 mIU/L) was below the normal range.

Test results were negative for the presence of antineutrophil cytoplasmic antibodies (ANCAs) and rheumatoid factor. However, the tested specimen was positive for antinuclear antibodies (ANA). The total concentrations of immunoglobulins were within normal range. Serological tests for Borrelia burgdorferi, Epstein-Barr virus and parvovirus showed negative results. Tests were also negative for the presence of antistreptolysine titer and anti-DNAse B. The results of urinalysis were negative for the presence of protein and erythrocytes.

Radiographs of the right ankle showed no bone abnormalities. Ultrasonography of the right ankle revealed a synovial effusion. The consultant orthopaedic surgeon performed an ankle joint aspiration, since septic arthritis could not be ruled out. Blood and synovial fluid cultures were obtained, and the patient was subsequently treated with intravenous flucloxacillin 1500 mg, 4 times a day (Flucloxacillin, ACS Dobfar Generics, Luxembourg). Analysis of the synovial fluid showed an elevated leucocyte count, but no bacteria.

Due to the afebrile condition of the patient and since the laboratory tests were not suggestive of an infection, reactive arthritis or an adverse reaction to thiamazole was suspected. The antithyroid drug and the sublingual Oralgen immunotherapy were withdrawn. Propranolol was continued. The pain decreased after administration of diclofenac 50 mg one to three times a day (Diclofenacnatrium, Pharmachemie BV, Haarlem, Netherlands).

Two days later, antibiotic therapy was discontinued since blood and synovial fluid cultures remained sterile, and the concentration of C-reactive protein was on slightly elevated at 14 mg/L (133 nmol/L). The arthritis rapidly disappeared after discontinuation of the thiamazole and after 4 days the patient was discharged without any symptoms.

Seven days after discharge, Iodine-131 treatment was administered for the hyperthyroidism. Although this treatment appeared to be effective, after 8 weeks the hypothyroidism returned and levothyroxine (Levothyroxine, Nycomed BV, Hoofddorp, Netherlands) was started. Thyroid function stabilized after the patient began receiving a daily dose of 125 mcg of levothyroxine. Immunotherapy for grass pollen and birch were resumed soon after discharge. During a 6 month follow-up, the patient reported no complaints and upon repeated physical examinations there were no signs of arthritis.

DISCUSSION

Arthritis is an uncommon side effect of drugs, especially in children. Polyarthritis in a child receiving antithyroid therapy was first reported in 1970.⁷ Only a small number of such cases in children have been reported since.⁸ The present case demonstrates the potential for this side effect to occur in pediatric patients and emphasises the need for clinical awareness, recognition and management.

With the exception of PTU, side effects of thionamides may be dose related; larger doses are associated with an increased frequency of all side effects, including polyarthritis.² Our patient was treated with a fairly large dose of thiamazole. The maximum dose of thiamazole registered in the Netherlands is 1 mg/kg for children and 90 mg/day for adults. Our patient was started on 30 mg daily, which was subsequently raised to 60 mg daily. As this dose was still ineffective, the consultant endocrinologist recommended adjusting the dose to 90 mg daily. This dose could be justified since the child had a body size comparable to that of an adult; however, the large dose may have contributed to the occurrence of the side effect.

To determine the causative agent for the adverse reaction, we evaluated each of the patient's medications. Initially, Oralgen was discontinued because, even though we were not aware of any reported cases of arthritis due to Oralgen, such an association could not be excluded. Also, cessation of this drug was unlikely to have had an immediate negative clinical consequence. A few weeks after the patient was discharged, Oralgen was restarted without any problem, so an adverse reaction of Oralgen seemed unlikely.

We did not discontinue propranolol and thiamazole simultaneously because we expected the patient to have tachycardiac rhythms again due to the elevated concentration of free thyroxine in her body. Furthermore, to the best of our knowledge, arthritis induced by propranolol is rare. In order to assess the probability of an association between arthritis and one of the prescribed drugs, we also used the Naranjo adverse drug reaction probability scale.⁹ The score indicated that the association between arthritis and thiamazole was probable and less likely for either propranolol and Oralgen.

Arthritis is a major adverse drug effect of thionamide therapy. In most cases, the first symptom is arthralgia, which is one of the minor side effects of antithyroid medication. Despite the classification of arthralgia as a minor adverse effect, its development should prompt drug discontinuation because it may progress to a severe transient migratory polyarthritis. Migratory polyarthritis secondary to antithyroid therapy itself is unusual. However, it is a serious side effect with an unpredictable course, also known as Antithyroid arthritis syndrome.^4,5

Little is known about the exact pathogenesis of Antithyroid arthritis syndrome. Several mechanisms have been proposed. A deficit in cellular copper-binding capacity in some predisposed individuals could allow free copper to bind to the antithyroid drug. If this complex affects glutathione metabolism, it may induce the release of interleukins, which cause synovial inflammation.⁶ Another theory describes bonding of the antithyroid drug with macromolecules. Subsequently, this complex can serve as a hapten to induce antibody production or modify proteins involved in the immune response,¹⁰ which could possibly explain the detection of circulating ANA in patients with antithyroid arthritis syndrome.¹ This has been reported in the medical literature and was also found in our patient. Nevertheless, the specificity of ANA is low as the prevalence in healthy persons is 10%.¹¹ In addition, an increased prevalence of positive ANA exists in patients who have Graves' disease. During follow-up, the results of the ANA analysis were negative for the patient described in this case report.

Symptoms of antithyroid arthritis syndrome usually occur within 2 months after starting antithyroid treatment. Polyarthritis can be migratory and can involve large, medium and small joints. After patients discontinue the antithyroid drug, symptoms disappear in a few weeks.

Antithyroid drug-induced arthritis can be part of antithyroid arthritis syndrome, as described above, or it can be associated with ANCA-associated vasculitis that is induced by antithyroid drugs. This is a potentially life-threatening side effect of antithyroid therapy, which can lead to renal and respiratory failure.¹² Arthralgia can be the first presenting symptom,^13,14 and, therefore, clinicians should consider laboratory investigation for ANCAs in case of suspected antithyroid drug-induced arthritis. However, routine laboratory investigation for ANCAs is not indicated since some patients with Graves' disease have positive findings for ANCAs before onset of antithyroid treatment.^15,16 In our patient, results for the ANCA analysis were negative.

Treatment of antithyroid arthritis syndrome consists of prompt withdrawal of the antithyroid drug. A non-steroidal anti-inflammatory drug can be administered to relieve symptoms. In some patients, corticosteroids might be effective, but they are not initially recommended.¹⁷ Alternative thionamides may be considered; however, cross-reactivity between the 2 agents may be as high as 50%.¹⁷ Therefore, other forms of treatment such as iodine-131 treatment or surgery should be considered.

CONCLUSION

This case report emphasizes the importance of recognizing arthritis as an uncommon side effect of thiamazole as antithyroid therapy, especially in children. Given the unpredictability and potentially life-threatening manifestations of antithyroid therapy, clinical awareness is essential. Prompt withdrawal of the drug generally results in disappearance of symptoms. Due to potential cross-reactivity with alternative thionamides, another form of treatment for hyperthyroidism, such as iodine-131 treatment or surgery, is recommended.

ABBREVIATIONS

ANA

antinuclear antibodies

ANCA

antineutrophil cytoplasmic antibody

PTU

propylthiouracil

Table.

Adverse Reactions of Antithyroid Drugs¹