Propylthiouracil-induced vasculitis with alveolar hemorrhage after 31 years of treatment: a case report

Abstract

Background

Propylthiouracil is an antithyroid medication that is associated with ANCA positivity, often in the absence of clinically overt vasculitis. Propylthiouracil-induced ANCA-associated vasculitis (AAV) is characterized by multiple antigenicity and presents similarly to other forms of drug-induced vasculitis.

Case presentation

We report a case of a 49-year-old woman who developed propylthiouracil-induced AAV after 31 years of intermittent therapy. The patient presented with progressive respiratory and generalized symptoms. She was diagnosed with propylthiouracil-induced AAV with alveolar hemorrhage based on detection of ANCA and anti-MPO antibodies, exclusion of primary vasculitis, and symptom resolution following propylthiouracil withdrawal. The patient was treated with intravenous methylprednisolone, followed by oral prednisolone. Her symptoms resolved, and her laboratory and radiological tests improved within one week.

Conclusions

Research linking the duration of propylthiouracil use to the development of vasculitis is restricted by multiple methodological limitations. Maintaining a high index of clinical suspicion is a more reliable approach to detecting propylthiouracil-induced AAV than regular laboratory monitoring, given that patients with Graves’ disease may show ANCA positivity in the absence of medication use. Therefore, clinicians should remain vigilant for the varied presentations of propylthiouracil-induced AAV. Moreover, further research is recommended to investigate the possible link between the duration of PTU use and the onset of clinically overt vasculitis.

Background

Drug-induced anti-neutrophil cytoplasm antibodies (ANCA)-associated vasculitis (AAV) is a subtype of drug-induced vasculitis (DIV) characterized by inflammation and necrosis of blood vessels and caused by the use of a pharmaceutical agent and accompanied by the presence of ANCAs [1]. Although drug-induced AAV shares similar features with idiopathic vasculitis, it typically follows a milder course [1, 2]. It mostly presents with nonspecific symptoms such as skin rash, arthralgia, myalgia, and fever, but it may involve single organs, leading to rapidly progressive glomerulonephritis and pulmonary manifestations [1].

ANCAs are autoantibodies directed against cytoplasmic antigens, including primary azurophil granules in neutrophils and lysosomes in monocytes [3, 4]. The two main patterns of ANCAs are C-ANCAs, directed almost exclusively against proteinase 3 (PR3), and P-ANCAs, which target a range of antigens, such as myeloperoxidase (MPO), cathepsin G, and elastase [4, 5]. Drug-induced AAV is diagnosed clinically based on the development of vasculitis symptoms after initiating a pharmaceutical agent, while excluding other causes of primary vasculitis [1, 6]. Moreover, drug-induced AAV demonstrates a distinctive immunological profile, in which ANCAs are directed against multitarget antigens, contrary to primary AAV [2].

Propylthiouracil (PTU) is an antithyroid medication commonly used to treat hyperthyroidism [7]. The prevalence of ANCA positivity in PTU users is variable, with a reported pooled median prevalence of 30% [8]. AAV associated with PTU is characterized by multiple antigenicity, including antibodies against PR3, MPO, and lactoferrin [2]. Its presentation is similar to other forms of DIV and may affect the skin, kidneys, and lungs [2, 9]. Numerous cases with variable clinical presentations have been reported in the literature [8]. Here, we report a case of PTU-induced AAV following 31 years of intermittent therapy.

Case presentation

A 49-year-old woman with a 31-year history of Graves’ disease presented to the emergency department with a one-month history of fever, productive cough with yellowish sputum, hemoptysis, progressive exertional dyspnea, and left-sided chest pain. She also had night sweats, anorexia, weight loss, myalgia, and arthralgia. The patient was started on PTU (50 mg bid) after she had received the diagnosis of Graves’ disease 31 years ago. She continued to take the drug for 15 years with poor adherence and without regular follow-up. Consequently, she underwent subtotal thyroidectomy and discontinued PTU. Due to a recurrence of Graves’ disease, PTU was resumed for three years at the same dose.

The patient continued PTU therapy for an additional 13 years with dose adjustments based on thyroid function tests. One month before the current admission, the patient presented to the emergency department with fever, exertional dyspnea, and left-sided chest pain, and she was treated with oral moxifloxacin (400mg qd) based on a diagnosis of pneumonia. During the following month, she developed additional symptoms, for which she sought medical advice several times and was prescribed multiple antibiotics with progressive worsening of symptoms until her last presentation. The patient had no family history of thyroid diseases, vasculitis, or other autoimmune diseases.

On her last presentation, her vital signs were as follows: blood pressure 118/80, heart rate 112 bpm, temperature 38.5 °C, and O₂ saturation 89% on room air. The patient was clinically euthyroid. A lung examination revealed bilateral bronchial breathing without added sounds. No skin lesions, mouth ulcers, or lower limb edema were observed, and the remainder of the physical examination was unremarkable.

Initial laboratory tests showed a low hematocrit (35.5%), normal hemoglobin, white blood cell, platelet counts, and D-dimer (shown in Table 1). Inflammatory markers were elevated (CRP 169 mg/L; ESR 100 mm/h). The biochemistry panel and kidney and liver function tests were normal. Thyroid function tests showed a low TSH level (0.1748 mIU/mL) with normal free T₃ and total T₄. Blood and urine cultures and rapid COVID-19 antigen test were negative. Arterial blood gases (ABG) showed respiratory alkalosis mixed with metabolic acidosis (pH: 7.52; pCO₂ 24.4; pHCO₃ 19.7), with hypoxemia (pO₂ 67) resolved on 2 L of O₂. CXR showed bilateral diffuse alveolar infiltrates with interstitial septal thickening (shown in Fig. 1), and chest CT showed diffuse bilateral ground-glass appearance and alveolar consolidation with superimposed interlobular septal thickening (shown in Fig. 2).

Fig. 1

Posterior anterior chest radiograph on admission. Posterior anterior CXR performed at admission showing bilateral diffuse consolidative opacities associated with interstitial septal thickening, more prominent centrally and without pleural effusion

Fig. 2

Axial chest CT on admission. Axial chest CT performed at admission revealing diffuse bilateral alveolar consolidation and ground-glass opacification with superimposed interlobular septal thickening, predominantly in the middle and lower lung fields, consistent with pulmonary hemorrhage

Table 1 Ordered laboratory tests on admission, during admission, and at follow up

The patient was managed with antibiotics as a case of atypical pneumonia. Pulmonary embolism was ruled out based on a low Wells’ score. Immunology tests showed antibodies against MPO (35.3 U/ml), positive ANA, and negative anti-PR3 and anti-ENA antibodies. Based on these results, the patient was diagnosed with PTU-induced AAV with alveolar hemorrhage. PTU was discontinued and methylprednisolone (60 mg IV, < Emphasis Type="Italic”> qd</Emphasis> ) was started, in addition to ceftriaxone (1 g IV, < Emphasis Type="Italic”> bid</Emphasis> ) and moxifloxacin (400 mg IV, < Emphasis Type="Italic”> qd</Emphasis> ). Her fever, hemoptysis, dyspnea, and cough resolved by the second third, fifth, and sixth days of admission, respectively.

The patient was discharged after nine days with oral propranolol (10mg < Emphasis Type="Italic”> tid</Emphasis> ) and oral prednisolone (60mg < Emphasis Type="Italic”> qd</Emphasis> ), which was gradually tapered over 1–2 months. Repeat CXR (shown in Fig. 3) and chest CT (shown in Fig. 4) performed at discharge demonstrated resolution of previous abnormalities. A thyroid scan showed normal uptake, and the patient was considered for radiotherapy. Two months after her discharge, anti-MPO titer remained high, anti-PR3 remained negative, and other blood tests were within the normal ranges. She did not report additional symptoms.

Fig. 3

Posterior anterior chest radiograph on discharge. Posterior anterior CXR performed at discharge showing near-complete resolution of the bilateral lung opacities

Fig. 4

Axial chest CT at discharge. Axial chest CT performed at discharge showing residual bilateral fibrotic bands with resolution of the alveolar infiltrates and ground-glass opacities

Discussion and conclusions

We reported a case of PTU-induced vasculitis with alveolar hemorrhage in a patient with a 31-year history of PTU therapy for Graves’ disease. PTU is one of the most frequently reported drugs associated with AAV [6]. A review conducted in 2015 reported that over 260 case reports of AAV related to antithyroid medications were published in the literature, with PTU accounting for 75% of these reports [8]. Our patient received PTU for 15 years, discontinued it for 3 years following subtotal thyroidectomy, and resumed PTU for an additional 13 years after a recurrence of Graves’ disease.

Research has shown that the duration of PTU use before developing vasculitis is variable. A study by Gao Y et al. included 15 patients with PTU-induced vasculitis and reported an average PTU use of 48 months (SD ± 25.8) before disease onset. Of note, 14 out of 15 patients received PTU for more than 24 months before developing clinical vasculitis [9]. While a longer duration of PTU use has been suggested as a risk factor for vasculitis, the evidence for this association is unsubstantiated and largely based on ANCA positivity rather than clinically evident AAV. Schmiedeberg et al. reported that PTU-sulfonate, a reactive metabolite of PTU, was shown to be immunogenic to T-cells in vitro. T-cell sensitization activates B-cell to produce IgG antibodies that lead to vasculitis. Long-term exposure to PTU is associated with greater conversion of PTU to PTU-sulfonate, which enhances T-cell sensitization to these reactive metabolites [10, 11]. Another prospective study of 30 patients who received antithyroid medications reported that ANCA-positive patients used PTU for significantly longer durations (7.9 years, SD ± 10.2) than ANCA-negative patients (0.8 years, SD ± 2.2). However, the study was limited by a small sample size, including only six ANCA-positive PTU users [12]. Additionally, a review of 14 studies reported a trend between the duration of antithyroid medication use and the onset of ANCA positivity. This trend was reported without using a statistical test and was limited to 5 out of the 14 included studies [8], which highlights the need for further studies to explore a potential link between the duration of PTU use and the development of clinically overt vasculitis. Therefore, a high index of clinical suspicion should be maintained to detect the variable symptomatology associated with PTU-induced AAV, especially in patients with chronic use of the drug. Clinical observation and follow-up seem to be more reliable than regular laboratory monitoring, given that patients with Graves’ disease who do not use antithyroid medications may also demonstrate ANCA positivity for long periods without developing clinical vasculitis [13].

Our patient presented with fever, exertional dyspnea, chest pain, productive cough with yellowish sputum, hemoptysis, anorexia, weight loss, myalgia, and arthralgia. The diagnosis of AAV was confirmed by detecting anti-MPO antibodies and ANCA, excluding other vasculitis and vasculitis-mimicking conditions, and observing symptom resolution following PTU withdrawal. Her respiratory symptoms were suggestive of alveolar hemorrhage, which was confirmed by the CT findings [14]. Cases involving major organs, including those with alveolar hemorrhage, have been reported in the literature, although PTU-induced vasculitis mostly presents with nonspecific, constitutional symptoms [1, 2]. This is in addition to a wide range of other presentations, such as pyoderma gangrenosum and hearing loss [15, 16].

PTU-induced vasculitis tends to follow a milder course, with less organ involvement, fewer relapses, and a better prognosis than primary AAV [2, 17, 18]. While patients typically improve upon cessation of PTU, those with alveolar hemorrhage should receive IV methylprednisolone, to which our patient responded well [19, 20]. Because a shorter duration of glucocorticoid therapy has been recommended for cases of DIV compared to primary AAV [6], our patient received IV methylprednisolone for five days and was discharged on oral prednisolone tapered over two months. Moreover, although plasmapheresis has been suggested for severe ANCA-AAV, it was not used for our patient as studies have not shown a benefit in reducing mortality or preventing chronic kidney failure [21]. For long-term management, patients with PTU-induced AAV may shift to other antithyroid medications that are less associated with AAV [22], or resort to other treatment methods, as was the case with our patient who was eligible for radiotherapy.