Propylthiouracil-induced lupus-like or vasculitis syndrome
© Tetikkurt et al.; licensee BioMed Central Ltd. 2012
Received: 25 June 2012
Accepted: 25 June 2012
Published: 17 July 2012
A 27 year old female with Graves’ disease presented with fever, exertional dyspnea and polyarthralgia. Erythema nodosum had occured three months earlier. The patient declared irregular use of propylthiouracil (PTU) for the last 8 months. Neutropenia and microscopic hematuria developed in the second week of admission. Chest X-ray showed inhomogenous pulmonary opacities, left pleural effusion and cardiomegaly. Computed tomography (CT) revealed multiple subpleural nodules, left pleural effusion, pericardial effusion, enlarged mediastinal and axillary lymph nodes. Bronchoalveolar lavage (BAL) cytology demonstrated hemosiderin laden macrophages. Histopathologic examination of the transbronchial biopsy specimen revealed a nonspecific inflammation. Serum was positive for ANA, P-ANCA, MPO-ANCA, PR3-ANCA and negative for anti-ds-DNA, C-ANCA, C3, C4 and anti-histone antibody. All symptoms resolved in two months after PTU withdrawal and starting steroid treatment. The same clinical manifestations recurred when the patient used PTU erronously one month after discharge.
This is a case of PTU induced-autoimmune disease in whom the accurate distinction between drug-induced-lupus (DIL) and vasculitis was not possible due to the significant overlap of clinical and laboratory findings causing a significant diagnostic challenge for the chest physician.
PTU can cause adverse reactions including fever, rash, leucopenia, arthiritis, vasculitis and lupus-like syndrome . However, pulmonary complications like interstitial pneumonia, adult respiratory distress-like syndrome and pleural effusion are extremely rare [2, 3] The mortality rate is low and related to systemic manifestations. PTU-induced lupus is now well established and many other autoimmune disorders including vasculitis have been reported. Most of the cases of PTU-induced autoimmune phenomena are due to vasculitis.
We present the case of a patient who developed erythema nodosum, pericardial and pleural effusion, subpleural nodules, microhematuria, alveolar hemorrhage, mediastinal and axillary lymph node enlargement due to PTU treatment. Although there are significant differences in the clinical features of drug-induced lupus (DIL) and vasculitis that allow an accurate diagnosis, the distinction was not possible in our case because of substantial overlap of clinical findings.
A 27 year old woman with a history of Graves’ disease was admitted for fever, exertional dyspnea and polyarthralgia. She had started on PTU (150 mg p.oqd) for Graves’ disease which she had used irregularly during the last 8 months. There was no other past medical history of interest.
It has long been known that PTU can induce an adverse autoimmune response with DIL or vasculitis . Cases can be classified into DIL or vasculitis according to the accepted definitions, clinical and serological features. Here we describe the case of a patient who presented with a clinical picture of vasculitis during PTU treatment for Graves’ disease. Our patient had both findings of DIL, in relation to the regular long-term medication use, and vasculitis . After PTU withdrawal, an excellent outcome took place with resolution of all symptoms, clinical, laboratory, and radiologic findings, however the same clinical picture occurred again when the patient inadvertently used PTU again. The patient was a diagnostic dilemma for the clinician because the risk of developing DIL with using PTU is less than 1% of the treated patients . Moreover the distinction between DIL and ANCA-associated vasculitis was not possible because of the significant overlap between these two entities in our case. Finally the patient did not fit into any collagen disease profile.
Aloush and coworkers have provided clear distinction between the DIL and ANCA-associated vasculitis reviewing their similarities and differences. Patients with PTU-induced DIL have more musculoskeletal complaints, more serositis and gastrointestinal involvement. On the contrary, the ANCA-associated vasculitis more frequently presents upper airways, pulmonary and renal involvement. ANA, anti-DNA, and anti-histone antibodies are predominantly found in DIL, whereas p-ANCA are found in a similar proportion of patients in both groups. c-ANCA are detected only in patients with vasculitis. All DIL patients recovered completely after withdrawal of PTU, while about 50% of PTU-induced vasculitis need steroids or immunosuppressive drugs . Nearly every feature of both entities was identified in our patient with a significant overlap of serologic markers. DIL includes various manifestations like arthralgia, pericarditis, pleuritis, and fever, which were all present in this patient. Antinuclear antibodies are positive in over 50% of cases and native anti-DNA are reported . These markers were negative in our case. Resolution of symptoms and radiologic findings after drug withdrawal suggested strongly the DIL associated with PTU treatment, while negative serum anti-histone antibody with positive C-ANCA, and the need for steroid immunosupression indicated PTU-induced-vasculitis.
Some patients receiving PTU develop a different and a more serious kind of adverse autoimmune response characterized by high titres of antibodies to MPO with clinical manifestations including pauci-immune necrotizing and crescentic glomeruloneprithis, upper respiratory tract disease, and pulmonary hemorrhage with negative or low titres of ANA [9, 10]. Our patient had microhematuria and alveolar hemorrhage that were diagnosed during the clinical investigation of a possible autoimmune disorder. Detection of MPO-ANCA with alveolar hemorrhage and microhematuria supports the presence of alveolar and glomerular vasculitis as Bosch has suggested .
PTU-induced vasculitis often occurs in a few weeks of treatment but may develop after months or years. The disorder is not usually dose dependent and may improve after discontinuation of the drug . The patient was not compliant and declared very irregular use of PTU in the previous 8 months when the use of PTU had started. Antibodies to double-stranded DNA were absent and complement levels were normal. The high levels of PR3-ANCA and MPO-ANCA, which is thought to be a specific marker of anti-thyroid drug-induced vasculitis, decreased in correlation with the course of symptoms and the resolution of radiologic findings after PTU withdrawal.
The mechanism responsible for ANCA and vasculitis in patients on PTU is not well understood. ANCA production may occur as a result of the interaction between PTU and neutrophils or neutrophil MPO. MPO and hydrogen peroxide produced by neutrophils can metabolize the drug leading to the reactive intermediates that are immunogenic for T-cells and stimulate the immune system [12, 13]. The metabolites which have a cytotoxic activity determine the cell death and production of autoantibodies . Because human MPO and thyroid peroxidase (TPO) are the members of the same gene family, patients with thyroid disease and TPO antibodies may develop cross-reactivity to MPO. TPO and MPO antibodies are often both present in these patients  as may be the case for our patient. Serious adverse effects required corticosteroid treatment. Complete recovery of clinical and laboratory findings occured following the cessation of PTU and starting of the steroid treatment. The same clinical picture recurred after the erroneous use of PTU by the patient.
Regardless of the mechanism, the association between PTU treatment and ANCA-associated vasculitis or DIL is rare but well described. Substantial differences in clinical, serologic and outcome of these syndromes provide an accurate diagnosis . The systemic adverse effects of PTU may also be difficult to distinguish from the manifestations of Graves’ disease or from other vasculitides. Antineutrophil cytoplasmic antibodies and especially high levels of anti-histone antibodies are useful for the diagnosis of PTU associated lupus-like syndrome. It is important to be aware of this complication because early withdrawal of the drug results in clinical recovery and may prevent a fatal outcome.
Our patient had severe respiratory problems with erythema nodosum as the initial sign. Neither the clinical manifestations and nor the serologic markers of our patient indicated DIL, ANCA-associated vasculitis or collagen disease accurately. Presence and resolution of enlarged mediastinal and axillary lymph nodes after drug withdrawal would also strongly suggest drug induced autoimmune disease in this case. Different presentations, overlap syndromes associated with PTU-induced disease, various clinical and laboratory findings may represent a diagnostic challenge for the pulmonary clinician. The current case did not fit into any of the two previously described classifications.
In addition to the negligible incidence of PTU-induced disease, the overlapping symptoms and laboratory findings may lead to a diagnostic conflict. Consequently, putting such patients into the PTU-induced autoimmune disease classification as opposed to the DIL or ANCA-associated vasculitis would better describe the clinical features.
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
- Vasily DB, Tyler WB: Propylthiouracil-induced cutaneous vasculitis. Case presentation and review of the literature. JAMA. 1980, 243: 458-461. 10.1001/jama.1980.03300310046021.View ArticlePubMedGoogle Scholar
- Miyazono K, Okazaki T, Uchida S, Totsuka Y, Matsumoto T, Ogata E, Terakawa K, Kurihara N, Takeda T: Propylthiouracil-induced diffuse interstitial pneumonitis. Arch Intern Med. 1984, 144: 1764-1765. 10.1001/archinte.1984.00350210076013.View ArticlePubMedGoogle Scholar
- Chevrolet JC, Guelpa G, Schifferli JA: Recurrent adult respiratory distress–like syndrome associated with propylthiouracil therapy. EurRespir J. 1991, 4: 899-901.Google Scholar
- Yung RL, Richardson BC: Drug-induced lupus. Rheum Dis Clin North Am. 1994, 20: 61-86.PubMedGoogle Scholar
- Rubin RL: Drug induced lupus. Toxicology. 2005, 209: 135-147. 10.1016/j.tox.2004.12.025.View ArticlePubMedGoogle Scholar
- Rubin RL: Etiology and mechanisms of drug-induced lupus. Curr Opin Rheumatol. 1999, 11: 357-363. 10.1097/00002281-199909000-00006.View ArticlePubMedGoogle Scholar
- Aloush V, Litinsky I, Caspi D, Elkayam O: Propylthiouracil-induced autoimmune syndromes: two distinct clinical presentations with different course and management. Semin Arthirits Rheum. 2006, 36: 4-9. 10.1016/j.semarthrit.2006.03.003.View ArticleGoogle Scholar
- Mathieu E, Fain O, Sitbon M, Thomas M: Systemic adverse effects of antithyroid drugs. Clin Rheumatol. 1999, 18: 66-68. 10.1007/s100670050057.View ArticlePubMedGoogle Scholar
- Dolman KM, Gans RO, Vervaat TJ, Zevenbergen G, Maingay D, Nikkels RE, Donker AJ, von dem Borne AE, Goldschmeding R: Vasculitis and antineutrophil cytoplasmic autoantibodies associated with prophylthiouracil therapy. Lancet. 1993, 342: 651-652. 10.1016/0140-6736(93)91761-A.View ArticlePubMedGoogle Scholar
- D’Cruz D, Chesser AM, Lightowler C, Comer M, Hurst MJ, Baker LR, Raine AE: Antineutrophil cytoplasmic antibody-positive crescentic glomerulonephritis associated with anti-thyroid drug treatment. Br J Rheumatol. 1995, 34: 1090-1091. 10.1093/rheumatology/34.11.1090.View ArticlePubMedGoogle Scholar
- Bosch X, López-Soto A, Mirapeix E, Font J, Ingelmo M, Urbano-Márquez A: Anti-neutrophil cytoplasmic autoantibody-associated alveolar capillaritis in patients presenting with pulmonary hemorrhage. Arch Pathol Lab Med. 1994, 118: 517-522.PubMedGoogle Scholar
- Ohtsuka M, Yamashita Y, Doi M, Hasegawa S: Propylthiouracil-induced alveolar hemorrhage associated with antineutrophil cytoplasmic antibody. Eur Respir J. 1997, 10: 1405-1407.PubMedGoogle Scholar
- von Schmiedeberg S, Goebel C, Gleichmann E, Uetrecht J: Neutrophils and drug metabolism. Science. 1995, 268: 585-586.View ArticlePubMedGoogle Scholar
- Cambridge G, Wallace H, Bernstein RM, Leaker B: Autoantibodies to myeloperoxidase in idiopathic and drug-induced systemic lupus erithematosus and vasculitis. Br J Rheumatol. 1994, 33: 109-114. 10.1093/rheumatology/33.2.109.View ArticlePubMedGoogle Scholar
- Kimura S, Ikeda-Saito M: Human myeloperoxidase and thyroid peroxidase, two enzymes with separate and distinct physiological functions, are evolutionary related members of the same gene family. Proteins. 1998, 3: 113-120.View ArticleGoogle Scholar
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