Gruber, Conor N.*; Finzel, Kathleen MD†; Gruber, Barry L. MD‡
From the *Cornell University, Ithaca, †ProHealth Care Associates, Lake Success, and ‡Mt Sinai School of Medicine, New York, NY.
The authors declare no conflict of interest.
Correspondence: Barry Gruber, MD, Mt Sinai School of Medicine, New York, NY. E-mail: firstname.lastname@example.org.
We describe a 40-year-old woman with a diagnosis of seronegative rheumatoid arthritis after presenting with frank arthritis that had become persistent and progressively severe over 7 years, during which time she was receiving treatment with methimazole (Tapazole; AAI Pharma, Wilmington, NC) for Graves disease. Upon withdrawal of methimazole, there was dramatic and prompt resolution of the synovitis despite its long-standing presence and severity. A vast array of drugs has been implicated in inducing rheumatologic conditions.1,2 Early recognition of drug-induced diseases is important to avert misdiagnosis, prevent unnecessary investigations, and avoid otherwise unwarranted and potentially hazardous treatments. Clinicians will often contemplate the possibility of an iatrogenic etiology of musculoskeletal symptoms when these occur shortly after initiation of a medication and abate upon withdrawal of the offending agent. In addition, specific symptom complexes such as new-onset generalized arthralgias, myalgias, or systemic disorders such as vasculitis or lupus will often prompt consideration of drugs as inciting these rheumatologic syndromes. In contrast, an iatrogenic origin for long-standing chronic arthritis is frequently overlooked. The case presented in this report highlights this concept.
A 40-year-old woman presented to our facility with a long-standing history of right-elbow pain and swelling dating back approximately 5 years, along with intermittent swelling and pain involving bilateral knees dating back 7 years. Further history revealed the onset of Graves disease 8 years before presentation, diagnosed shortly after an uneventful full-term pregnancy when she experienced palpitations, sweating, weight loss, fatigue, tremors, and exophthalmos. Laboratory testing confirmed the diagnosis, and treatment was begun with methimazole 10 mg initially twice a day and then tapered after several months to 10 mg every day. After a few months of therapy, she began to experience intermittent arthralgias in the right elbow and both knees; methimazole dose was further reduced to 5 mg daily. However, the pain became persistent, occurring on a daily basis. In particular, over the past 5 years, right-elbow swelling became chronic, persistent, and progressively severe. A prior rheumatology consultation, 3 years after initial symptoms began, led to a diagnosis of seronegative rheumatoid arthritis. At that time, synovial fluid obtained from right knee aspiration revealed 26,000 leukocytes per milliliter. Treatment with sulfasalazine was initiated, and subsequently methotrexate was recommended. In addition, orthopedic specialists involved with management over the course of several years treated her with repetitive intra-articular corticosteroid injections and eventually recommended a right-elbow synovectomy and arthroscopic debridement of the right knee.
Examination revealed a thin white woman with normal vital signs including blood pressure of 108/70 mm Hg, heart rate of 72 beats/min, weight 124 lb, and height 63 in (body mass index 22 kg/m2). Mild exophthalmos was noted, but no thyromegaly or nodules were detected. The remainder of the general examination was unremarkable. Musculoskeletal examination revealed moderately swollen, warm, and markedly tender right elbow with limited range of motion as well as bilateral knee effusions. No other joint abnormalities were detected.
Laboratory studies revealed positive antinuclear antibody 1:80 titer with homogeneous pattern, negative Sm/ribonucleoprotein antibodies, negative histone antibodies, negative rheumatoid factor and cyclic citrullinated peptide antibodies, negative Lyme serology, and negative HLA-B27, with normal erythrocyte sedimentation rate, C-reactive protein, C3, C4, and angiotensin-converting enzyme levels. In addition, antineutrophil cytoplasmic antibody, antiproteinase 3, and antimyeloperoxidase antibodies were absent. Thyroid function tests were within the reference range. Arthrocentesis of the right elbow was attempted with ultrasound guidance, but no synovial fluid could be aspirated. At that time, ultrasound revealed synovial thickening distending the capsule of the radial capitellar articulation, with increased power Doppler signal suggesting inflammation (Figure, A). Magnetic resonance imaging (MRI) of the right elbow 5 years after methimazole was initiated revealed exuberant proliferative synovitis with reactive marrow edema and lack of full extension (Figure, B).
FIGURE. A, Long-axis...Image Tools
Based on the temporal course of symptoms, with onset after initiating methimazole, discontinuation of methimazole was advised with close monitoring of subsequent thyroid function and overall clinical course. Within 2 weeks of discontinuation of methimazole, her elbow symptoms diminished with progressive and complete reduction of swelling. In addition, no further knee pain or swelling was noted. By 6 weeks following discontinuation, at follow-up evaluation, the elbow appeared normal on examination with full range of motion, and both knees were entirely normal. Repeat antinuclear antibody was 1:80. A repeat MRI revealed significant reduction in the volume of synovitis and resolution of the reactive marrow edema pattern with full elbow extension (Figure, C). Subsequent ultrasound showed no color Doppler activity. At this stage, the patient remains totally asymptomatic, and thyroid function testing to date has remained normal.
Methimazole and propylthiouracil (PTU), collectively classified as thioureas (thioureylenes), have achieved widespread use over decades for the treatment of hyperthyroidism. Hypersensitivity reactions to thioureas (eg, methimazole and PTU) have been recognized for quite some time and include cutaneous, hepatic, musculoskeletal, and rarely hematologic adverse events.3 These agents have also been implicated as inciting vasculitis, occasionally with positive antineutrophil cytoplasmic antibody serology, or lupus-like syndromes.1,2,4 It is now widely recognized that this class of drugs may be etiologic in these systemic vasculitic disorders, which at times may be life threatening as a result of severe renal and respiratory deterioration.1,2,4 In contrast, “antithyroid arthritis syndrome” is less well appreciated and is distinguished from these more widespread systemic antithyroid drug–induced reactions.5,6 Nonetheless, arthralgia can be the first presenting symptom of a systemic vasculitic disorder,1,2,4 and therefore, clinicians should be alert to recognize the entire gamut of rheumatologic disorders linked to antithyroid drugs.
Arthritic symptoms linked to antithyroid drugs have been recognized for more than 4 decades and have been referred to alternatively as “antithyroid arthritis syndrome” or “collagen like syndrome.”5–8 In a series of more than 500 patients treated with antithyroid drugs,6 rheumatic symptoms were the second most common noted adverse effect (1.6%), whereas in a more recent report of 100 children with Graves disease treated with methimazole, musculoskeletal symptoms were noted in ∼5%.9 The description of the rheumatic manifestations varies considerably in these reports, from arthralgias with an absence of objective inflammation6 to monoarthritis as reported in an adolescent with an inflammatory effusion documented both on ultrasound and arthrocentesis.10 In reviewing the available literature after searching MEDLINE database (Table), it is evident that clinical presentations may range from arthralgias to inflammatory arthropathies manifesting as monoarthritis, episodic migratory polyarthritis, or most commonly polyarthritis—with onset usually within weeks, but up to 36 months after initiating antithyroid drug therapy.3,5–8,10,12–16 In addition, as indicated in the Table, the duration of the clinical syndrome (when data were available) was generally short-lived (weeks to several months, with few notable exceptions) before the drug was withdrawn. Prompt resolution was then almost universally observed, lending further support to the drug as the inciting etiologic agent.
TABLE Current Case a...Image Tools
Although previous publications have depicted this phenomenon in some detail, essentially all describe relatively short-term manifestations before recognition and removal of the etiologic agent (as depicted in the Table). Our case is unique and worthy of discussion in this regard, having experienced persistent arthritis that progressed over many years while continuing to use methimazole to treat hyperthyroidism. Indeed, several musculoskeletal specialists rendered a diagnosis of seronegative rheumatoid arthritis. Consequently, disease-modifying antirheumatic drugs were recommended, and surgical intervention advised. After many years elapsed, a possible iatrogenic etiology was recognized, and fortuitously, simple withdrawal of methimazole resulted in dramatic rapid resolution of symptoms and signs of disease. This case is unique in both its chronicity and yet remarkable reversibility and emphasizes the need to appreciate the entire spectrum of rheumatologic manifestations potentially induced by antithyroid drugs. Lastly, this case highlights the importance of diligently searching for etiologic agents, especially with what is often termed “seronegative rheumatoid arthritis.”
1. Mor A, Pillinger MH, Wortmann RL, et al. Drug-induced arthritic and connective tissue disorders. Semin Arthritis Rheum
. 2008; 38: 249–264.
2. Brenner J, Solitar BM, Golden BD. Rheumatic manifestations of current pharmacopeia. Curr Rheum Rep
. 2000; 2: 151–155.
3. Farbman K, Wheeler MF, Glich SM. Arthritis induced by antithyroid medication. N Y State J Med
. l969; 69: 826–831.
4. Aloush V, Litinsky I, Caspi D, et al. Propylthiouracil-induced autoimmune syndromes: two distinct clinical presentations with different course and management. Semin Arthritis Rheum
. 2006, 36: 4–9.
5. Bajaj S, Bell MJ, Shumak S, et al. Antithyroid arthritis syndrome. J Rheumatol
. 1998; 25: 1235–1239.
6. Shabtai R, Shapiro MS, Orenstein D, et al. The antithyroid arthritis syndromes reviewed. Arthritis Rheum
. 1984; 27: 227–229.
7. Hung W, August GP. A ‘collagen-like’ syndrome associated with antithyroid therapy. J Pediatr
. 1973; 82: 852–854.
8. Librik L, Sussman L, Bejar R, et al. Thyrotoxicosis and collagen-like disease in three sisters of American Indian extraction. J Pediatr
. 1970; 76: 64–68.
9. Rivkees SA, Stephenson K, Dinauer C. Adverse events associated with methimazole therapy in children. Int J Pediatr Endocrinol
. 2010; 2010: 1769–1770.
10. Ploegstra WM, Boontje RP, Kamps AW. Arthritis associated with antithyroid therapy in a 15-year-old girl. J Pediatr Pharmacol Ther
. 2011; 16: 98–101.
11. Hietarinta M, Merilahti PR. Methimazole-induced arthritis. Scand J Rheumatol
. 1989; 18: 61–62.
12. Tan F, Nam TQ, Lee KO, et al. Recurrent episodes of arthritis in a hyperthyroid patient. Singapore Med J
. 2006; 47: 163–165.
13. Caballero Mora FJ, Muñez Calvo MT, López Robledillo JC, et al. Poliartritis severa asociada al tratamiento con metimazol en paciente con enfermedad de Graves. An Pediatr
. 2011; 75: 74–75.
14. Martn MA, Boquet ED. Syndrome of arthritis by antithyroid drugs. Med Clin (Barc)
. 2003; 120: 436–437.
15. Oh BK, Van Overeld G, McFarlane JD. Polyarthritis induced by propylthiouracil. Br J Rheumatol
. 1983; 22: 106–108.
16. Tosun M, Güler M, Erem C, et al. Intermittent polyarthritis due to propylthiouracil. Clin Rheumatol
. 1995; 14: 574–575.
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