Propylthiouracil-induced myeloperoxidase antineutrophil cytoplasmic antibody-associated leukocytoclastic vasculitis

Abstract

Propylthiouracil (PTU), an antithyroid medication used in managing Graves disease, can rarely cause antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), a potentially serious complication. We report a case of a 54-year-old woman with Graves disease on long-term PTU therapy who developed a progressive purpuric rash and polyarthralgia. Laboratory tests showed elevated inflammatory markers and positive results for perinuclear ANCA (p-ANCA) and myeloperoxidase antibodies. A skin biopsy confirmed leukocytoclastic vasculitis. Symptoms improved after the discontinuation of PTU and initiation of corticosteroid therapy. The patient subsequently underwent total thyroidectomy for definitive treatment of Graves disease. This case highlights the importance of considering PTU-induced AAV in patients with vasculitic rashes, even after years of stable therapy. Early detection, prompt discontinuation of the medication, and multidisciplinary collaboration are essential to prevent disease progression and ensure favorable outcomes.

Introduction

Propylthiouracil (PTU) is a thionamide used to treat Graves disease and is rarely associated with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) [1]. The proposed mechanism involves drug-induced alterations in neutrophil antigens, particularly myeloperoxidase (MPO), leading to the formation of autoantibodies [2].

This case illustrates the diagnostic challenge of PTU-induced AAV, which may occur after years of uneventful therapy and mimic other drug reactions or autoimmune conditions. Early recognition and discontinuation of PTU are crucial to prevent disease progression. By sharing this case, we aim to increase clinician awareness of this uncommon but potentially severe complication and highlight the importance of considering PTU as a possible cause of unexplained vasculitic rashes in patients treated for Graves disease.

Case presentation

A 54-year-old woman with a 6-year history of Graves disease presented to the emergency department (ED) with a 1-month history of a progressive generalized rash involving the upper and lower extremities. A review of systems was otherwise negative, and family history was notable for systemic lupus erythematosus in her sister. At the time of her Graves disease diagnosis, she was treated with methimazole but developed a rash, prompting transition to PTU, maintained at 50 mg daily for 5 years. Notably, the onset of her current rash coincided with the recent initiation of pregabalin for neuropathic pain in her lower extremities.

Diagnostic assessment

Physical examination revealed a diffuse palpable, nonblanching purpuric rash over the upper and lower extremities bilaterally (Fig. 1). Laboratory results showed normal thyroid hormone levels, normal white blood cell count, normal liver enzymes, normal renal function, erythrocyte sedimentation rate (ESR) of 44 mm/h (reference range, 0-30 mm/h), and C-reactive protein (CRP) of 3.40 mg/dL (SI: 34 mg/L) (reference range, ≤0.50 mg/dL [SI: ≤5 mg/L]).

Figure 1.

Diffuse palpable purpuric rash over the bilateral lower extremities at presentation.

To evaluate internal vasculitic processes, the ED obtained computed tomography angiography of the head, neck, and chest, and computed tomography of the abdomen and pelvis, which were unremarkable.

The dermatology and rheumatology departments were involved in her care and agreed to pursue a skin biopsy and an autoimmune workup. A skin biopsy was obtained from the medial thigh at the junction of the rash and normal skin, and pathology confirmed leukocytoclastic vasculitis (Fig. 2). The autoimmune workup (Table 1) showed negative results for antinuclear antibody, anti-Sjögren syndrome-related antigen A (SS-A/Ro), anti-Sjögren syndrome-related antigen B (SS-B/La), and anti-Smith antibodies, with normal complement levels (C3 and C4). The perinuclear ANCA (p-ANCA) titer was 1:160 (reference range, <1:20), with MPO at 1.6 AI (reference range, <1.0 AI) and proteinase 3 (PR3) antibody at <1.0 AI (reference range, <1.0 AI).

Figure 2.

(A) Skin (2×, hematoxylin and eosin stain) shows superficial and deep dermal perivascular inflammation around small vessels. (B) Skin (40×, hematoxylin and eosin stain) showing a dense, mixed inflammatory perivascular infiltrate, with a prominent population of neutrophils. The neutrophils infiltrate the vessel wall and show nuclear cytoplasmosis (nuclear dust). Fibrinoid necrosis of the postcapillary venule is present, with a characteristic pink, “smudged” vessel wall (yellow arrow). Damage to the vessel wall causes red cell extravasation (teal arrow), leading to the nonblanching rash observed clinically.

Table 1.

Summary of inflammatory and autoimmune laboratory findings confirming MPO-positive ANCA-associated vasculitis

Test	Result	Reference range
ESR	44 mm/h	0-30 mm/h
CRP	3.4 mg/dL (34 mg/L)	≤0.5 mg/dL (≤5 mg/L)
p-ANCA	1:160 titer	<1:20 titer
MPO antibody	1.6 AI	<1.0 AI
PR3 antibody	<1.0 AI	<1.0 AI
SS-A antibody	<1.0 AI	<1.0 AI
SS-B antibody	<1.0 AI	<1.0 AI
Anti-Smith antibody	<1.0 AI	<1.0 AI
C3 Complement	162 mg/dL (1.62 g/L)	83-193 mg/dL (0.83-1.93 g/L)
C4 complement	22 mg/dL (0.22 g/L)	15-57 mg/dL (0.15-0.57 g/L)

Abbreviations: ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; p-ANCA, perinuclear antineutrophil cytoplasmic antibody; MPO, myeloperoxidase; PR3, proteinase 3; SS-A, Sjögren syndrome-related antigen A (anti-Ro); SS-B, Sjögren syndrome-related antigen B (anti-La); C3, complement component 3; C4, complement component 4; AI, antibody index.

Treatment

Initially, pregabalin-induced vasculitis was suspected by the primary team, and pregabalin was discontinued. She was discharged with instructions to follow-up with outpatient rheumatology in 3 months.

Outcome and follow-up

Two weeks later, she was readmitted with a persistent rash and new onset polyarthralgia. Rheumatology evaluated the patient; physical examination showed no synovitis, joint effusion, warmth, or deformity, and the overlying skin had the previously described nonblanching rash. Due to concerns about a possible drug-induced process, a thorough medication review was conducted, and PTU was discontinued because of a suspicion of PTU-induced AAV.

She was started on prednisone 30 mg daily. Endocrinology then evaluated the patient, and management options, including PTU discontinuation with monitoring vs definitive therapy, were discussed. After shared decision-making, the patient chose to proceed with thyroidectomy. Preoperative thyroid function tests showed thyroid-stimulating hormone at 3.94 mIU/mL (reference range, 0.55-4.78 mIU/mL), free thyroxine (fT4) at 1.18 ng/dL (SI: 15.19 pmol/L) (reference range, 0.89-1.76 ng/dL [SI: 11.46-22.65 pmol/L]), thyroid-stimulating immunoglobulin (TSI) < 89% baseline (reference range, <140% baseline), and thyrotropin receptor antibody < 1.00 IU/L (reference range, <2.00 IU/L). She underwent thyroidectomy 3 days into her admission. Pathology revealed a 16.5 g thyroid gland with hyperplastic changes and no evidence of malignancy. Following total thyroidectomy, levothyroxine was started. She was discharged on a prednisone taper over 3 weeks: 30 mg for 1 week, then 20 mg for 1 week, and 10 mg for 1 week.

At her 4-week endocrinology follow-up, the rash had significantly improved with only residual hyperpigmentation (Fig. 3), and her joint pains had resolved.

Figure 3.

improvement in vasculitic rash 4 weeks after discontinuation of propylthiouracil and initiation of a corticosteroid taper.

Discussion

This case describes PTU-induced AAV in a patient treated with PTU for Graves disease. Although sporadically reported, several case series and reviews describe consistent clinical patterns that parallel our patient's presentation.

Most reported cases involve women with 1 retrospective review suggesting a female-to-male ratio of about 9:1 [3], which likely reflects the higher prevalence of autoimmune thyroid disease in this population. Cases typically occur in the third to sixth decades of life [4, 5].

Cutaneous involvement, most often affecting the lower extremities, is the most commonly reported initial symptom [3, 6]. Systemic manifestations affecting the kidneys, lungs, and joints have also been observed, with multisystem disease representing a subset of more severe cases [5]. When organs are involved, the kidneys are the most frequently affected [4, 7]. Even with systemic organ involvement, symptoms are usually milder compared to primary ANCA-associated vasculitis [8, 9].

The time between PTU initiation and vasculitis onset varies, ranging from months to many years. Larger reviews indicate a median delay of about 3 to 4 years [4], although cases can still occur much later during treatment, as seen in a severe MPO-vasculitis case that happened 31 years after PTU treatment [10]. PTU-induced AAV also appears to be dose-independent [4].

A proposed pathophysiology for the association is that PTU can alter the structure and oxidation activity of MPO, creating neoantigens and immunogenic metabolites that trigger T-cell and B-cell activation, leading to ANCA production [11]. These drug-modified MPO interactions, along with PTU-derived reactive metabolites, are thought to drive the distinct pathogenesis of PTU-induced ANCA-associated vasculitis [11].

In most cases, the p-ANCA pattern with MPO specificity predominates, while PR3 antibodies are less common [3]. MPO titers do not correlate reliably with disease severity, emphasizing the importance of clinical judgment in diagnosis and management [5].

The cornerstone of treatment involves promptly stopping PTU. Corticosteroids are generally used for mild to moderate cases, while severe or multisystem involvement may require immunosuppressive therapy, such as cyclophosphamide [11]. Reported outcomes are usually positive, with most patients achieving remission after early intervention, although 10-15% may still face significant morbidity or mortality [3, 11].

Our case highlights several diagnostic and systemic challenges. The initial attribution of symptoms to another medication delayed the recognition of PTU-induced vasculitis, reflecting the condition's broad differential diagnosis. Additionally, limited access to subspecialty care can contribute to delays in diagnosis and management.

This case emphasizes the importance of clinicians staying vigilant for PTU-induced AAV, even after long-term, stable treatment. Early teamwork and prompt removal of the causative drug are crucial to lower morbidity and enhance outcomes.

Learning points

• PTU can cause ANCA-associated vasculitis even after years of stable therapy, making late-onset presentations an important diagnostic consideration.

• Cutaneous leukocytoclastic vasculitis may be the first clue to PTU-induced AAV and should prompt evaluation for MPO-ANCA positivity.

• Early recognition and prompt discontinuation of PTU are essential to prevent progression to systemic vasculitis and reduce morbidity.

• A thorough medication review is important in the diagnosis and management of all patients.

• Multidisciplinary teams are necessary when drug-induced vasculitis is suspected.

Contributors

H.Q., C.S., V.S., and G.E. contributed to the patient's diagnosis, clinical management, and follow-up. K.B. performed the histopathologic evaluation and prepared the histology images. O.O. acquired and interpreted the clinical data, conducted the literature review, and was involved in the scientific revision of the paper. All authors critically reviewed the manuscript for important intellectual content, approved the final version for publication, and agree to be accountable for all aspects of the work.

Funding

No public or commercial funding.

Disclosures

The authors have no relevant financial or nonfinancial interests to disclose. The authors declare that there are no conflicts of interest regarding the publication of this case report. No funding was received for the preparation of this manuscript.

Informed patient consent for publication

Signed informed consent was obtained directly from the patient.

Data availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.