Methimazole-Induced Antithyroid Arthritis Syndrome in Graves’ Disease Management: A Case Report

Abstract

Patient: Male, 29-year-old

Final Diagnosis: Antithyroid arthritis syndrome • Graves’ disease

Symptoms: Systemic migratory pain

Clinical Procedure: —

Specialty: Endocrinology and Metabolic

Objective: Rare disease

Background

Antithyroid arthritis syndrome (AAS) is a rare adverse reaction to antithyroid drugs (ATDs), characterized by fever, rash, myalgia, and migratory polyarthralgia. It mimics rheumatic disorders, complicating diagnosis.

Case Report

We present a case with unique symptoms presentation of a 29-year-old Chinese man with Graves’ disease who presented with fever, rash and myalgia following methimazole initiation, then developed systemic migratory pain in muscle and joints after stopping medication. Initial suspicion of ANCA-associated vasculitis (AAV) or drug-induced lupus arose due to elevated inflammatory markers and negative ANCA/autoimmune serology (except ANA+). Pharmacist-led assessment using the Naranjo scale and the inquiry during daily care confirmed the temporal association with methimazole. After excluding AAV and lupus via clinical and laboratory criteria, AAS was diagnosed. Corticosteroids and lithium carbonate was prescribed for the pain and Graves’ disease control at admission, then necessitating dosage adjustment for overall safety. Propylthiouracil was prescribed during a subsequent visit, but he then developed drug-induced liver injury manifested as jaundice, which finally required management with radioiodine therapy, which led to control of symptoms.

Conclusions

This case highlights the diagnostic complexity of AAS, particularly in male patients, and underscores the therapeutic role of lithium carbonate as a transitional agent for thionamide-intolerant Graves’ disease. Given the high cross-sensitivity between antithyroid drugs limiting pharmacological alternatives, propylthiouracil also carries a significant risk of adverse reactions. Pharmacist involvement in adverse drug reaction assessment and lithium dosing optimization was critical for successful management. Heightened clinical vigilance and experience are essential when encountering suspected AAS.

Introduction

Graves’ disease (GD) is an autoimmune thyroid disorder primarily managed with antithyroid drugs (ATD), including methimazole (MMI) and propylthiouracil (PTU). MMI has become the therapeutic mainstay due to its superior safety profile compared to PTU. However, the adverse reaction of MMI ranges from mild manifestation (eg, skin reaction) to severe complications (eg, hemophagocytic syndrome [1] and anti-neutrophil cytoplasmic antibody [ANCA]-associated vasculitis [AAV]). Notably, while AAV may present with polyarthritis, these articular manifestations are not pathognomonic and require differentiation from a distinct complication – antithyroid arthritis syndrome (AAS).

AAS is a rare adverse reaction caused by ATDs in GD management, characterized by fever, rash, and myalgia, with arthralgia in the joints of the lower limbs, and even in the wrists and forearms [2]. Epidemiological data remain limited, although a 1.6% incidence has been reported in patients exhibiting polyarthralgia [3]. AAS must be distinguished from ANCA-associated vasculitis (AAV), which shares articular manifestations but requires different management. Unlike AAV, AAS typically lacks ANCA seropositivity and systemic organ involvement. Autoimmune tests such as ANA, ANCA, and drug lymphocyte stimulation tests (DLST) can help distinguish AAS from other rheumatic condition, but the results are not definitive [2]. Furthermore, as with most adverse drug reactions, discontinuation of suspected medications and symptomatic treatment with NSAIDs and corticosteroids can be an effective approach to AAS, but use of colchicine was also reported as an new approach [4]. For MMI-intolerant patients, the 50% cross-reactivity between thionamide agents [5] severely limits pharmacological alternatives like lithium for thyroid hormone suppression, which adds to the difficulties of AAS management.

We report the case of a 29-year-old Chinese man with GD who developed MMI-induced polyarthritis. He was initially suspected to have methimazole-induced ANCA-associated vasculitis, given the migratory polyarthralgia and elevated inflammatory markers, but comprehensive evaluation confirmed a diagnosis of AAS. The use of lithium carbonate combined with corticosteroid therapy resulted in progressive clinical resolution. This case underscores 3 critical aspects: (1) the importance for differential diagnosis between AAS and AAV, (2) the therapeutic utility of lithium in thionamide-intolerant GD patients, and (3) the contribution of pharmacists in identifying suspected adverse reactions to medication.

Case Report

A 29-year-old Chinese man presented to the Emergency Department with a 2-week history of fever, rash, and muscle pain. Two weeks before admission, he received oral propranolol 10 mg QD and methimazole 10 mg BID for suspected Graves’ disease at another hospital. After 1 week, he developed swelling, rashes, and itching. Although his symptoms were temporarily relieved while stopping the medications, he developed systemic migratory pain and tightness in the limbs, joints, and muscles. He sought medical attention in a different hospital and was diagnosed with urticaria and Graves’ disease. He received symptomatic treatment, but his joint pain worsened after discontinuing medications. He had no significant history of alcohol and cigarette consumption, and had no family history of rheumatic disease.

The investigation revealed a fever of 38.0°C, elevated blood pressure (163/76 mmHg), and heart rate (101 beats/min), raised CRP (50.88 mg/L, reference range [RR]: 0–5 mg/L), ESR (25 mm/h, RR: 0–15 mm/h), and pain scores (Numeric Rating Scale: 3). The thyroid imaging by ^99mTcO₄⁻ single-photon emission computed tomography/computed tomography (SPECT/CT) showed diffuse enlargement (left lobe: 63×26 mm, volume: 34.4 cm³; right lobe: 85×33 mm, volume: 72.0 cm³) (Figure 1). He was diagnosed with Graves’ disease due to abnormal thyroid function (TSH <0.008 IU/mL, FT3 >20 pg/ml, FT4 8.47 ng/dL) and was suspected to have methimazole-induced ANCA-associated vasculitis (AAV) based on his symptoms.

Figure 1.

The thyroid SPECT/CT imaging of the patient.

The pharmacist identified a history of untreated Graves’ disease since 2018 and penicillin allergy during daily care. In 2019, he received methimazole and developed rash and itching. After stopping medications, he developed systemic migratory pain, exacerbated by daily activity. He reported the symptoms resolved after taking an unknown traditional Chinese medicine. It is suspected that his symptoms were an adverse reaction induced by methimazole, assessed using the Naranjo ADR probability scale (Table 1). The pharmacist advised the endocrinologist, and the advice was accepted.

Table 1.

Naranjo ADR Probability Scale.

Question	Yes	No	Unknown	Score
Are there previous conclusive reports on this reaction?	+1	0	0	+1
Did the adverse event appear after the suspected drug was administered?	+2	−1	0	+2
Did the adverse reaction improve when the drug was discontinued, or a specific antagonist was administered?	+1	0	0	+1
Did the adverse reaction reappear when the drug was readministered?	+2	−1	0	+2
Are there alternative causes (other than the drug) that could on their own have caused the reaction?	−1	+2	0	+2
Did the reaction reappear when a placebo was given?	−1	+1	0	0
Was the drug detected in the blood (or other fluids) in concentrations known to be toxic?	+1	0	0	0
Was the reaction more severe when the dose was increased or less severe when the dose was decreased?	+1	0	0	0
Did the patient have a similar reaction to the same or similar drug in any previous exposure?	+1	0	0	0
Was the adverse event confirmed by any objective evidence?	+1	0	0	+1
Total score				9 (Highly probable)

ADR – adverse drug reaction. Score interpretation: above 9=highly probable, 5–8=probable, 1–4=possible, and 0=doubtful.

After admission, the patient was treated with propranolol 10 mg PO TID, methylprednisolone 40 mg IVI QD, topical desonide cream, tramadol, and NSAIDs-containing patches and lithium carbonate 0.25 g PO TID. On day 2, he still had a fever (T_max 38.1°C), high blood pressure (142–163/72–76 mmHg), rash in the thoracic region, and migratory pain exacerbated by daily activity. The pharmacist suggested ANCA and autoimmune testing, which were negative except for ANA. Our literature search suggested ATDs-induced rheumatic diseases, including ANCA-associated vasculitis, drug-induced lupus, and arthritis syndrome, given the clinical presentation of rash, fever, multiple arthralgia, negative ANCA, and autoimmune testing. With the absence of systemic organ involvement and symptom exacerbation following methimazole discontinuation, ANCA-associated vasculitis and drug-induced lupus were excluded. AAS was then diagnosed. On day 3, the patient reported his pain (Numeric Rating Scale: 1), rash, and fever had improved, although his blood pressure remained elevated at 144/78 mmHg. Considering the pain from AAS was improved, methylprednisolone 40 mg IVI QD was discontinued and replaced with prednisone 30 mg PO QD. In addition, the symptoms of thyrotoxicosis were obvious, prompting the addition of lithium carbonate 0.5 g BID, as suggested by the pharmacist. On day 5, the patient reported the pain in his joints and rash were further relieved. By day 8, his symptoms had significantly improved, prompting discharge from the hospital on a tapering prednisone regimen to prevent withdrawal syndrome.

At subsequent follow-up, the patient elected to trial propylthiouracil (PTU) over radioiodine due to concerns regarding lifelong levothyroxine dependence. A dosage of PTU 10 mg PO TID was prescribed, but he developed liver dysfunction characterized by jaundice after 1 month. After discontinuing PTU, he underwent radioactive iodine therapy and received 15 mCi of oral iodine-131 solution. He then experienced gradual improvement in thyroid function over the next 2 months. Hypothyroidism returned in May 2023, prompting a levothyroxine prescription. After that, the thyroid function gradually stabilized in July 2023, without recurrence of Graves’ disease symptoms (Table 2).

Table 2.

The laboratory test results of patient.

Indicators	Value	Reference range
Before admission
FT3	5.24 pg/mL ↑	2.3–4.2
FT4	4.21 ng/dL ↑	0.89–1.76
TSH	<0.008 IU/mL ↑	0.55–4.78
Anti-CPP	(−)	(−)
RF	(−)	(−)
Admission, before lithium and corticosteroid use
FT3	> 20 pg/ml ↑	2.3–4.2
FT4	8.47 ng/dL ↑	0.89–1.76
TSH	< 0.008 IU/mL ↑	0.55–4.78
CRP	50.88 mg/L ↑	<5
After lithium and corticosteroid use
ESR	25 mm/h ↑	0–15
MPO(p)-ANCA	(−)	(−)
PR3(c)-ANCA	(−)	(−)
ANA	(+)	(−)
IL-6	2.8 pg/ml	<7
IgM	0.75 g/L	0.4–2.3
IgA	2.20 g/L	0.7–4
IgG	12.47 g/L	7–16
Ferritin	607.5 ng/ml ↑	23.9–336.2
Anti-U1-nRNP/Sm	(−)	(−)
Anti-Sm	(−)	(−)
Anti-SS-A	(−)	(−)
Anti-Ro-52	(−)	(−)
Anti-SS-B	(−)	(−)
Anti-Scl-70	(−)	(−)
Anti-Jo-1	(−)	(−)
Anti-CENP B	(−)	(−)
Anti-dsDNA	(−)	(−)
Anti-Nukleosomen	(−)	(−)
Anti-Histone	(−)	(−)
Anti-Rib.P-Prot	(−)	(−)
The last visit
FT3	2.81 pg/mL	2.3–4.2
FT4	1.47 ng/dL ↑	0.89–1.76
TSH	0.855 IU/mL ↑	0.55–4.78

ANA – antinuclear antibody; anti-CCP – anti-cyclic citrullinated peptide antibody; anti-CENP B – anti-centromere protein B antibody; anti-dsDNA – anti-double stranded DNA antibody; anti-histone – anti-Histone antibody; anti-Jo-1 – anti-histidyl-tRNA synthetase antibody; anti-nukleosomen – anti-nucleosome antibody; anti-Rib.P-Prot –anti-ribosomal P protein antibody; anti-Ro-52 – anti-Ro52 (TRIM21) antibody; anti-Scl-70 – anti-Topoisomerase I antibody; anti-Sm – anti-Smith antibody; anti-SS-A – anti-Sjögren’s-syndrome-related antigen A antibody; anti-SS-B – anti-Sjögren’s-syndrome-related antigen B antibody; anti-U1-nRNP/Sm – anti-U1 small nuclear ribonucleoprotein/Smith antibody complex; CRP – C-reactive protein; ESR – erythrocyte sedimentation rate; FT3 – free triiodothyronine; FT4 – free thyroxine; IgA – immunoglobulin A; IgG – immunoglobulin G; IgM – immunoglobulin M; IL-6 – interleukin-6; MPO(p)-ANCA – myeloperoxidase (perinuclear) anti-neutrophil cytoplasmic antibody; PR3(c)-ANCA – proteinase 3 (cytoplasmic) anti-neutrophil cytoplasmic antibody; RF – rheumatoid factor; TSH – thyroid stimulating hormone.

Discussion

This case report highlights the diagnostic challenges and management complexities of antithyroid arthritis syndrome (AAS) in a 29-year-old Chinese man with Graves’ disease following methimazole administration. Notably, AAS management remains unstandardized due to the absence of established clinical guidelines. Current therapeutic approaches recommend primary discontinuation of suspected antithyroid agents, supplemented by NSAIDs and antihistamines for mild-to-moderate symptom control. In this case, empirical corticosteroid therapy demonstrated partial efficacy: methylprednisolone (40 mg/day) achieved initial symptom stabilization, followed by successful transition to prednisone (30 mg/day) as the pain was improved. The patient’s Graves’ disease management presented additional therapeutic dilemmas. Propylthiouracil (PTU) was initiated following refusal of radioactive iodine therapy due to concerns regarding lifelong levothyroxine replacement. However, subsequent PTU-induced hepatotoxicity necessitated radioactive iodine therapy implementation. This clinical trajectory underscores the intricate balance required in managing concurrent AAS and Graves’ disease.

According to our literature search, the predisposing factors of AAS have not been fully elucidated but may associated with duration of treatment initiation, sex, dosage, and certain autoimmune markers. The clinical manifestations of AAS mostly occur in the first 2 months after the initiation of treatment. Its clinical manifestations are paroxysmal, migratory joint pain, which can affect multiple joints in the body, nearly 50% of patients have skin rash with itching or fever symptoms, and most patients have elevated erythrocyte sedimentation rate and C-reactive protein [6,7]. Takaya et al found that males have a lower incidence rate (2 in 23 patients), and AAS can develop at any age [8]. Unfortunately, there are no published studies explaining the sex difference in AAS susceptibility, as no mechanistic studies have systematically investigated potential contributing factors. As illustrated in Table 3, reported male AAS cases (n=7) show consistent timing/dosing patterns despite its rarity. The adverse effects of methimazole (MMI) are reported to be dose-dependent [5], with AAS most commonly occurring at doses exceeding 30 mg/d [9], but have also been reported to occur at a dose of 10 mg/d [10]. Notably, AAS poses diagnostic challenges due to the similarity of its symptoms to other rheumatic conditions, and the laboratory tests were usually non-specific. The results of autoimmune tests such as ANA, ANCA, and drug lymphocyte stimulation tests (DLST) may help distinguish AAS from other rheumatic condition, but are not definitive [2]. High levels of IgG, IgA deficiency, and other histocompatibility haplotypes were reported to be associated with drug-induced autoimmune conditions [11,12], but the levels of IgG and IgA were within the reference range in our case. Magnetic resonance imaging (MRI) was reported to be a useful diagnostic tool [2].

Table 3.

Reported male patients with antithyroid arthritis syndrome.

Reference/Published years	Age	Drug	Other drugs	Duration of treatment initiation	Dosage (mg/d)	Symptoms	Laboratory test	Treatment
[23]/1954	50	MMI	None specified	5.5 weeks	60	Rash, fever, arthralgia	ESR↑, Agranulocytosis	Drug withdrawal
[23]/1954	55	MMI	Digitalis, ephedrine	4 weeks	60	Pain, swelling, anorexia, nausea, vomiting and polyarthritis	Albuminuria, hemoglobin↑	3 weeks of corticosteroid therapy, ending in sudden death
[24]/1999	50	CBZ	Cetirizine, ranitidine, coproxamol, fluoxetine	5 days	60	Fever, pain, swelling, migratory polyarthritis	CRP↑, ESR↑	Drug withdrawal + PTU 600 mg/d +Atenolol 100 mg/d + morphine + corticosteroid for 2 weeks
[25]/2012	64	CBZ	Propranolol 30–60 mg/d	5 weeks	20→30	Fever, rash, intermittent and migratory arthralgia	ALT↑, AST↑, CRP↑, ESR↑, ANCA (−), C4(−), IgE 664 U/ml	Drug withdrawal + NSAIDs + antihistamines for 13 days
[26]/2020	30	MMI	Propranolol 30 mg/d	4 weeks	20	Pain, swelling, tachycardia, polyarthritis	ANA (+), ANCA (−)	Drug withdrawal + PTU 100 mg/d + corticosteriod for 4 weeks → dose tapered & stopped
[6]/2021	42	MMI	Metoprolol 100 mg/d → Propranolol 30 mg/d	5 weeks	20→40	Asymmetric polyarthritis, fever	CRP↑, ANCA (−)	PTU + corticosteriod resolved in 2 weeks
[27]/2021	50	CBZ	None specified	2 weeks	30	Fever, tachycardia, asymmetric polyarthritis	Total leukocyte count↑, CRP↑, ESR↑	Drug withdrawal, levothyroxine 37.5 mcg/day for 6 weeks → dose tapered & stopped

ALT – alanine aminotransferase; ANA – antinuclear antibody; ANCA – anti-neutrophil cytoplasmic antibody; AST – aspartate aminotransferase; CBZ – carbimazole; CRP – C-reactive protein; ESR – erythrocyte sedimentation rate; IgE – immunoglobulin E; MMI – methimazole; NSAIDs – non-steroidal anti-inflammatory drugs; PTU – propylthiouracil.

Compared with other reported male cases, this case is distinctive as a male presentation of AAS with symptom progression after drug cessation, necessitating use of lithium carbonate alongside corticosteroids. In this case, the symptoms of AAS presented atypically, with swelling, rash, itching (all grade 1 with Common Terminology Criteria for Adverse Events [CTCAE] 5.0), and myalgia (grade 2 with CTCAE 5.0) appearing after methimazole administration, followed by relief upon medication withdrawal and subsequent development of fever (grade 1 with CTCAE 5.0) and systemic migratory pain (grade 3 with CTCAE 5.0). This unique presentation may indicate that structural changes occurred in the joints, since there was a reported case [13], and can confuse healthcare teams in determining an accurate diagnosis. Therefore, as no standard diagnostic criteria of AAS have been published, and the laboratory tests can only provide a reference for diagnosis, the diagnosis of AAS strongly relies on the clinical manifestations and the awareness and experience of the clinical care team. In this case, after research by the pharmacist, AAV and drug-induced lupus were excluded based on the clinical manifestations, the result of autoimmune tests, and the recurrence after medication discontinuation. Such a decision-making process may provide a reference for differentiation and diagnosis of AAS.

Our patient’s Graves’ disease necessitated alternative therapy due to the high cross-sensitivity between ATDs. Lithium carbonate guided by the pharmacist is a better option, while thionamides are contraindicated since lithium inhibits thyroid hormone synthesis via iodine uptake blockade, providing antithyroid benefits [14,15]. This approach is supported by international guidelines, which recommend lithium as a therapeutic option for patients intolerant of thionamides, particularly when radioactive iodine therapy is delayed [16–18]. Treatment with 900 mg/day LiCO3 for 7 days prevents transient worsening of hyperthyroidism after radioactive iodine therapy and shows no toxicity [19,20]. In our patient, the level of FT4 was 3 times higher than the upper limit of normal (8.47 ng/dL, RR: 0.89–1.76 ng/dL). Under this condition, the direct use of radioactive iodine may induce thyroid storm; thus, we applied lithium as a transitional therapy. However, our dosage selection was relatively conservative compared with the guidelines – 0.25 g TID of lithium was initiated and then adjusted to 0.5 g BID was suggested, followed by the package insert (0.5–1.0 g/d) due to the concerns about the narrow therapeutic window. Notably, caution is needed when prescribing NSAIDs with lithium due to potential drug interactions affecting lithium excretion via renal prostaglandins. Regular blood lithium monitoring should be emphasized in clinical practice.

Although lithium may have contributed to joint symptom resolution via inhibition of pro-inflammatory cytokines (eg, IL-1β, TNF-α) and metalloproteinases (MMPs) [21,22], its primary role here was thyroid suppression in a thionamide-intolerant patient. Given lithium’s narrow therapeutic index, our dosing strategy (0.75–1.0 g/d) aligned with Graves’ disease guidelines, while avoiding NSAID co-administration prevented renal lithium excretion interference. The rapid symptom improvement likely reflects corticosteroid’s efficacy rather than lithium’s articular effects. Therefore, although the lithium use was unintentional, our case might be a rare reference to the application of lithium for arthritis in clinical practice.

This case underscores pharmacists’ pivotal role in adverse drug reaction mitigation through 3 critical interventions: 1) Identifying suspected medication and establishing temporal medication-symptom correlation (symptoms occurred in 2019 after taking MMI, and symptoms re-appeared after taking MMI 2 weeks before admission) via Naranjo assessment; 2) Differentiating AAS from ANCA-associated vasculitis through targeted testing; and 3) Optimizing lithium dosing and NSAID alternatives (topical NSAIDs) to ensure the overall safety. Unfortunately, we did not identify the traditional Chinese medicine that the patient reported taking. This case report emphasizes the importance of pharmacist involvement in managing rare adverse reactions to medications. This case report represents a novel presentation of AAS for 2 key reasons. First, the patient’s male sex contrasts with the predominantly female demographic reported in the literature, while his unique clinical manifestations necessitated an unconventional therapeutic approach that required steroid therapy. Second, the initiation and dosage adjustment of lithium carbonate and steroid guided by the pharmacist to treat Graves’ disease demonstrates a novel pharmacological management approach and the importance of clinical team collaboration.

Conclusions

This case illustrates a unique manifestation and the diagnostic complexity of methimazole-induced AAS in a 29-old man with Graves’ disease and emphasizes the need for vigilant monitoring of atypical inflammatory reactions during antithyroid therapy. Successful management required differentiation from autoimmune conditions and implementation of lithium as a transitional agent prior to definitive radioiodine treatment. The collaborative efforts of the clinical team ensured timely intervention, demonstrating the value of integrated care in optimizing patient safety and therapeutic efficacy.