PTU-associated cutaneous vasculitis with ANCA anti-MPO and anti-PR3 antibodies

A 36-year-old woman presented at our clinic with symmetrical, tender, palpable purpuric lesions on her lower legs and buttocks after restarting PTU therapy for relapsing Graves' disease. PTU-induced vasculitis was diagnosed with remarkable ANCA anti-MPO and anti-PR3 antibody positivity. The purpuric skin lesions resolved immediately after discontinuation of the drug and the ANCA titres lowered. In the presence of activated neutrophils, PTU could induce a high cytotoxity and injure the vessel walls. Treatment of choice is discontinuation of the drug. Sometimes more aggressive therapy as cyclophosphamide or plasmapheresis is warranted.     

Purpura chez une jeune femme hyperthyroïdienne

IntroductionPropylthiouracil (PTU) is a synthetic antithyroid drug that can induce ANCA-associated vasculitis.ObservationA 27-year-old woman diagnosed with Graves’ disease was on PTU for the past 10 years. She developed purpuric lesions of the legs and on the tip of the nose diagnosed as vasculitis. ANCAs were positive, with anti-MPO and anti-PR3 on blood ELISA. After discontinuation of PTU, she was able to fully recover.ConclusionAll synthetic antithyroid drugs can induce ANCA-associated vasculitis, more often PTU. In most cases, antibodies are directed against MPO. Dual anti-MPO and anti-PR3 positivity is possible, but rare. The mechanism could be through an accumulation of PTU in neutrophils, altering the structure of MPO and making it immunogenic. PTU can also induce ANCA-free or lupus vasculitis, maculopapular rashes or urticaria. Many other drugs can induce ANCA-associated vasculitis.     

丙基硫氧嘧啶导致的抗中性粒细胞胞质抗体阳性小血管炎及其靶抗原研究

目的 研究丙基硫氧嘧啶（PTU）引起的抗中性粒细胞胞质抗体（ANCA）阳性小血管炎的临床病理表现及其靶抗原。方法 对我院近年诊治的4例PTU引起的ANCA阳性小血管炎患者进行临床病理分析。以纯化的7种已知的ANCA靶抗原蛋白酶3（PR3）、髓过氧化物酶（MPO）、人白细胞弹力蛋白酶（HLE）、乳铁蛋白（LF）、组蛋白酶G（CG）、杀菌／通透性增高蛋白（BPI）和天青杀素（AZU）为固相抗原,采用ELISA法检测患者血清的靶抗原及治疗前后抗体滴度的变化。结果 4例病人中男女各2例,平均年龄30（11－57）岁,服PTU时间7－60个月。4例均有肾脏、肺脏、皮肤、关节肌肉和血液系统等受累,均为p-ANCA阳性,患者血清均识别MPO、LF和CG;3例识别HLE、AZU,2例识别PR3;无1例识别BPI。多数抗体滴度高,可大于1：25600;而服PTU无小血管炎临床表现的甲状腺功能亢进（甲亢）病人的30份血清均为阴性。肾活检2例为新月体性肾炎,2例为轻微病变,免疫荧光检查均为阴性。4例患者均立即停用PTU,3例应用免疫抑制剂,1例行血浆置换。4例小血管炎的临床症状均得以缓解,但1例晚期新月体肾炎患者发展为慢性肾衰竭而依赖透析。停药和治疗后各种抗体滴度均有所下降,但多未能短期阴转。结论 PTU可引起ANCA阳性小血管炎,其自身抗体可识别中性粒细胞胞质中多种已知的靶抗原;及时诊治,预后较好。     

The prevalence and target antigens of antithyroid drugs induced antineutrophil cytoplasmic antibodies (ANCA) in Chinese patients with hyperthyroidism

OBJECTIVE: Antithyroid drugs such as propylthiouracil (PTU) and methimazole (MMI) are common medications in Chinese patients with hyperthyroidism and PTU-induced antineutrophil cytoplasmic antibody (ANCA) positive vasculitis has been reported. The current cross-sectional study aimed to investigate the prevalence and the target antigens of ANCA in Chinese patients with hyperthyroidism pre- and post-antithyroid medication therapy. METHODS: Sera from 216 patients with hyperthyroidism in our hospital were collected from January to July in 2002. Patients were divided into four groups: untreated (n = 34); treated with PTU (n = 62); treated with MMI (n = 77); and treated with both PTU and MMI (n = 43). Indirect immunofluorescence (IIF) assay was used to detect ANCA and ANA. Antigen-specific ELISAs were used to detect antigen specificities. The known antigens included myeloperoxidase (MPO), proteinase 3 (PR3), human leukocyte elastase (HLE), lactoferrin, bactericidal/permeability-increasing protein (BPI), cathepsin G and azurocidin. RESULTS: 33/216 sera were IIF positive, 20 of the 33 samples were ANCA positive, 11 samples were ANA positive, and two samples were both P-ANCA and ANA positive. The prevalence of positive ANCA in patients receiving PTU (14/62, 22.6%) was significantly higher than that of untreated patients (1/34, 2.9%) and patients treated with MMI (0/77, 0), P < 0.017. Of the 22 IIF-ANCA positive samples, 12 (54.5%) sera recognized lactoferrin, seven (31.8%) sera recognized HLE, four sera recognized MPO and azurocidin respectively, three sera recognized PR3 and cathepsin G respectively, and one serum recognized BPI. Six of the 22 (27.3%) patients with ANCA positive had clinical evidence of vasculitis. All patients with MPO-ANCA and two of the three patients with PR3-ANCA had clinical vasculitis. CONCLUSION: PTU is associated with the production of ANCA in patients with hyperthyroidism. PTU-induced ANCA are due to polyclonal activation of B cells. Anti-MPO and anti-PR3 antibodies may associate the occurrence of clinical vasculitis.     

Anti-thyroid drug-induced ANCA-associated vasculitis: a case report and review of the literature

We report a case of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis induced by propylthiouracil (PTU), and review the literature concerning to anti-thyroid drug-induced ANCA-associated vasculitis. A 45-year-old man treated with PTU developed fever and arthralgia without pulmonary, skin or eye involvement. These symptoms persisted for a long period without specific symptom, sign or laboratory data of other arthritis. Laboratory findings of urine and blood were normal, except for positive MPO-ANCA (191EU) and PR3-ANCA (37EU) findings. After PTU was discontinued without steroids or immune modulating drugs, both symptoms disappeared. Our patient had a high titer of MPO-ANCA. Moreover, titers of ANCA fell in correlation with the course of symptoms after the cessation of PTU, and we diagnosed PTU-induced ANCA-associated vasculitis. Most patients with pulmonary renal syndrome receive anti-thyroid drugs over a prolonged period, but the duration of our case was shorter than those of these patients. It is suggested that our patient was diagnosed at an early stage of ANCA-associated vasculitis before the start of pulmonary or renal involvement.     

PTU-induced ANCA-positive vasculitis: an innocent or a life-threatening adverse effect?

Antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides are rare, but they can be triggered by chemicals, infections and drugs; among them, antithyroid drugs are common. Autoimmune disorders, such as vasculitis, are unusual, but serious complications of antithyroid therapy. Both propylthiouracil (PTU) and methimazole may induce ANCA-associated vasculitis. PTU-induced vasculitides may have different organ involvement patterns. Herein, we report four cases with ANCA-associated vasculitis with different clinical manifestations.     

Antineutrophil cytoplasmic antibody positive alveolar haemorrhage during propylthiouracil therapy for hyperthyroidism

Recently, propylthiouracil (PTU) has been thought to be one of the possible causes of antineutrophil cytoplasmic antibody (ANCA)-associated small vessel vasculitis syndrome, resulting in glomerulonephritis and, infrequently, diffuse alveolar haemorrhage (DAH). The mechanism of ANCA-positive vasculitis during PTU therapy is still unknown. Herein, we describe the case of a 59-year-old woman who developed myeloperoxidase (MPO)- and proteinase 3 (PR3)-ANCA positive DAH, without any other organ system involvement, during PTU therapy. Diminution and discontinuation of PTU resulted in a positive response. To our knowledge, this is the first documentation of both MPO- and PR3-ANCA-positive DAH, without systemic manifestations, developing during PTU therapy.     

Follow-up of avidity and titre of anti-myeloperoxidase antibodies in sera from patients with propylthiouracil-induced vasculitis

OBJECTIVE: Propylthiouracil (PTU) has been known to induce myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) positive vasculitis. Our previous study indicated that the increase of avidity of MPO-ANCA might be associated with the occurrence of clinical vasculitis in patients with PTU-induced ANCA. The current study aimed to follow-up the avidity and titre of anti-MPO antibodies in sequential sera from patients with PTU-induced ANCA-associated systemic vasculitis (AASV). METHODS: Six patients with PTU-induced vasculitis were enrolled in the current study. Serial sera in both active phase and in remission were collected. MPO-ANCA avidity was assessed by antigen-inhibition enzyme-linked immunosorbent assays (ELISAs), and avidity constant (aK) was determined as the reciprocal value of the MPO molar concentration in the liquid phase resulting in 50% inhibition of anti-MPO antibody binding to MPO in solid phase ELISA. Titres of MPO-ANCA were determined by using serial serum dilutions in MPO-ELISA. RESULTS: After cessation of PTU and initiation of immunosuppressive therapy, the avidity and titre of MPO-ANCA decreased significantly during follow-up in sera from all the patients, and the avidity decreased much more quickly than the titres. CONCLUSION: Our study indicates that avidity of anti-MPO antibodies might be more closely associated with clinical vasculitis than titre.     

High prevalence of antineutrophil cytoplasmic antibody positivity in childhood onset Graves' disease treated with propylthiouracil

Propylthiouracil (PTU)-induced antineutrophil cytoplasmic antibody (ANCA)-related vasculitis and nephritis were recently reported in about 30 patients with hyperthyroidism. The objective of this study was to clarify the prevalence of ANCA and the relationship between ANCA and thyroid antibodies in children with Graves' disease. Titers of myeloperoxidase (MPO)-ANCA in sera of 51 patients with childhood onset Graves' disease (16 before treatment, 25 and 10 treated with PTU and methimazole, respectively) were measured by enzyme-linked immunosolvent assay. Antithyroglobulin antibodies (TGAbs) and antithyroperoxidase antibodies (TPOAbs) were also measured by RIA in 25 PTU-treated patients. No patients had clinical manifestations of vasculitis and nephritis. MPO-ANCA was positive in 6.7% of patients before treatment and in 64.0% of those treated with PTU and in none of those treated with methimazole. MPO-ANCA had a significantly positive correlation with TGAbs (P < 0.05) and no significant correlation with TPOAbs. These findings show the high prevalence of the MPO-ANCA positivity in PTU-treated childhood onset Graves' disease, suggesting that PTU may not be preferred as the first line for the treatment of children with Graves' disease. The significant correlation between MPO-ANCA and TGAbs indicates that the severity of Graves' disease may be a factor responsible for the MPO-ANCA positivity. The cross-reactivity between MPO-ANCA and TPOAbs may not play a role in the high prevalence of MPO-ANCA in the patients exposed to PTU.     

Frequency of appearance of myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) in Graves' disease patients treated with propylthiouracil and the relationship between MPO-ANCA and clinical manifestations

OBJECTIVE: Myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-positive vasculitis has been reported in patients with Graves' disease who were treated with propylthiouracil (PTU). The appearance of MPO-ANCA in these cases was suspected of being related to PTU because the titres of MPO-ANCA decreased when PTU was stopped. Nevertheless, there have been no studies on the temporal relationship between the appearance of MPO-ANCA and vasculitis during PTU therapy, or on the incidence of MPO-ANCA in untreated Graves' disease patients. Therefore, we sought to address these parameters in patients with Graves' disease. PATIENTS: We investigated 102 untreated patients with hyperthyroidism due to Graves' disease for the presence of MPO-ANCA, and for the development vasculitis after starting PTU therapy. Twenty-nine of them were later excluded because of adverse effects of PTU or because the observation period was less than 3 months. The remaining 73 patients (55 women and 18 men), all of whom were examined for more than 3 months, were adopted as the subjects of the investigation. The median observation period was 23.6 months (range: 3-37 months). MEASUREMENTS: MPO-ANCA was measured at intervals of 2-6 months. RESULTS: Before treatment, the MPO-ANCA titres of all 102 untreated Graves' disease patients were within the reference range (below 10 U/ml). Three (4.1%) of the 73 patients were positive for MPO-ANCA at 13, 16 and 17 months, respectively, after the start of PTU therapy. In two of them, the MPO-ANCA titres transiently increased to 12.8 and 15.0 U/ml, respectively, despite continued PTU therapy, but no vasculitic disorders developed. In the third patient, the MPO-ANCA titre increased to 204 U/ml and she developed a higher fever, oral ulcers and polyarthralgia, but the symptoms resolved 2 weeks after stopping PTU therapy, and the MPO-ANCA titre decreased to 20.7 U/ml by 4 months after discontinuing PTU. CONCLUSIONS: PTU therapy may be related to the appearance of MPO-ANCA, but MPO-ANCA does not appear to be closely related to vasculitis.     

A successful pregnancy and delivery case of Graves' disease with myeloperoxidase antineutrophil cytoplasmic antibody induced by propylthiouracil

A 30-year-old female patient, diagnosed as having Graves' disease in 1996, was treated with propylthiouracil (PTU) for 4 years. She developed a low-grade fever from December 1999. As myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) vasculitis is one of the adverse effects of PTU, we examined serum MPO-ANCA level and found it was positive, but cytoplasmic-ANCA (c-ANCA) was negative. There were no symptoms that indicated other diseases associated with MPO-ANCA. She was confirmed to be at 6 weeks gestation, and thyroid hormone levels were elevated at that time. We discontinued PTU and gave methyl-mercaptoimidazole (MMI), and the titer of MPO-ANCA fell along with fever. Therefore we estimated the case as probable MPO-ANCA positive vasculitis induced by PTU. MMI was also suspended because of the development of hepatic dysfunction. After thyroid function was normalized by administration of potassium iodide, she underwent subtotal thyroidectomy, and delivered a 2350 g infant at 38 weeks' gestation, which was less than the normal birth weight of 2400 g. MPO-ANCA is considered to be one reason of low birth weight infant including hyperthyroidism. It is necessary to consider the appearance of the possibility of MPO-ANCA positive vasculitis in patients who are treated with PTU.     

Eosinophilic Granulomatosis With Polyangiitis With Thrombotic Microangiopathy: Is Simultaneous Systemic Lupus Erythematosus Associated With Clinical Manifestations?: A Case Report and Review of the Literature

Eosinophilic granulomatosis with polyangiitis (EGPA) is one of the antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, which is characterized by vasculitis of the small to medium-sized vessels. On the contrary, thrombotic microangiopathy (TMA) is a life-threatening condition which can cause ischemic organ injury. Although several case reports have described patients with TMA associated with ANCA-associated vasculitis except for EGPA, there are no previous case reports of EGPA associated with TMA.A 71-year-old Japanese man was diagnosed with EGPA based on his asthma, eosinophilia, lung opacity, refractory sinusitis, and positive myeloperoxidase-ANCA. He was also diagnosed with TMA based on peripheral schizocytes and hemolytic anemia. We performed plasmapheresis and started high-dose corticosteroid therapy; thereafter, he improved promptly. His case also fulfilled the classification criteria of systemic lupus erythematosus (SLE) based on the pleural effusion, renal disorder, anemia, thrombocytopenia, positive antidouble-stranded DNA antibody, and low complement. Elements of SLE were thought to affect his clinical course.We reviewed 11 patients with EGPA or hypereosinophilic syndrome (HES) associated with SLE, including our case. Patients with EGPA or HES associated with SLE had more heart complications than patients with simple EGPA or simple HES did. Patients with EGPA or HES associated with SLE had more pleural effusion than patients with simple SLE did.Clinical manifestations of eosinophilia with SLE or SLE with eosinophilia may differ from simple SLE or simple eosinophilia.     

Diffuse alveolar hemorrhage and pulmonary capillaritis due to propylthiouracil

Propylthiouracil (PTU) has recently been observed to be associated with antineutrophil cytoplasmic antibody (ANCA)-positive small vessel vasculitis, resulting in crescentic glomerulonephritis and, infrequently, diffuse alveolar hemorrhage (DAH). We describe a case of a 23-year-old pregnant woman who developed a perinuclear ANCA and antimyeloperoxidase-positive small vessel vasculitis manifesting as DAH and crescentic glomerulonephritis after she began taking PTU. An open lung biopsy was consistent with pulmonary capillaritis. She responded to corticosteroid therapy and discontinuation of PTU. DAH can be caused by pulmonary capillaritis, bland hemorrhage, or diffuse alveolar damage. To our knowledge, this represents the first documentation of an underlying pulmonary capillaritis in a case of PTU-induced DAH.     

Propylthiouracil-induced autoimmune syndromes: 11 case report

The objective of this study was to report 11 cases of propylthiouracil (PTU)-induced autoimmune syndromes. We describe the clinical presentation, course, and outcome of 11 patients and compare clinical features between PTU-induced lupus and PTU-induced vasculitis. Of our 11 patients, 7 patients had vasculitis and 4 patients had lupus. Patients with vasculitis were olderand had a longer duration of treatment in comparison with lupus. P-ANCA were predominantly found in PTU-induced vasculitis, but also found in lupus, while ANA and anti-dsDNA were often found in lupus. Some difference of renal and pulmonary involvement was often found between PTU-induced vasculitis and lupus. Most of patients needed steroids or immunosuppressive drugs. Vasculitis in the cases of PTU-induced autoimmune phenomena is often found than lupus. P-ANCA in both PTU-induced lupus and vasculitis can all present, but there are differences in clinical and outcome features to diagnosis.     

Necrotizing glomerulonephritis and pulmonary hemorrhage associated with carbimazole therapy.

Methimazole, carbimazole, and propylthiouracil (PTU) are the mainstays of antithyroid drug therapy. Adverse effects of these drugs have been documented in less than 15% of patients undergoing treatment for hyperthyroidism. Common problems include fever, skin rash, urticaria, arthralgias, and arthritis. Vasculitis associated with antineutrophil anticytoplasmic antibodies (ANCA) has been reported on several occasions following treatment with PTU. However, vasculitis rarely appears to be associated with carbimazole. We report the clinical history of a woman with a necrotizing glomerulonephritis and pulmonary hemorrhage associated with carbimazole therapy.     

Propylthiouracil-induced anti-neutrophil cytoplasmic antibodies and agranulocytosis together with granulocyte colony-stimulating factor induced Sweet's syndrome in a patient with Graves' disease

Propylthiouracil (PTU) is an antithyroid drug which is known to cause drug-induced vasculitis. PTU is implicated in 80-90% of cases of anti-neutrophil cytoplasm circulating antibody (ANCA)-associated vasculitis caused by anti-thyroid drugs which induce ANCA production. Sweet's syndrome is characterized by fever, leucocytosis, neutrophilia and the sudden onset of painful skin lesions. The pathology of the disease is still unclear. Cytokine dysregulation including interleukin-6 and endogenous granulocyte colony-stimulating factor (G-CSF) are thought to play a role in the pathogenesis of Sweet's syndrome. PTU and G-CSF are known to cause Sweet's syndrome and other neutrophilic dermatosis. The presence of ANCA can have a diagnostic value in Sweet's syndrome. Systemic corticosteroids are the first-line therapy for both diseases. Here we report a female patient with Graves' disease who developed ANCA and Sweet's syndrome after using PTU and G-CSF.     

抗甲状腺药物诱导的抗中性粒细胞胞质抗体相关性小血管炎

以丙基硫氧嘧啶(Propylthiouracil,PTU)、他巴唑(Thiamazole,MMI)等为代表的抗甲状腺药物(Antithyroid drugs,ATD)广泛应用于临床甲状腺功能亢进的治疗,同时也是导致药物相关性血管炎最常见的原因之一,其临床特点与原发性小血管炎相比有其特殊之处。本文回顾性分析国内外相关文献,对本病临床特点加以综述,总结其诊治进展,以期指导临床。     

Antineutrophil cytoplasmic antibody (Anca)-associated autoimmune disease induced by propylthiouracil

Antithyroid drugs sometimes cause severe complications. Propylthiouracil (PTU) can be associated to ANCA positive vasculitis, most often related to myeloperoxidase subtype (ANCA-MPO). Our objective is to describe a female patient with Graves' disease, who developed PTU induced-autoimmune disease, with cutaneous, pulmonary, and renal lesions, associated with ANCA. Histopathological examination revealed diffuse pulmonary hemorrhage, and focal segmental glomerulosclerosis at the kidney biopsy. She was treated with systemic corticosteroid therapy and cyclophosphamide, with clinical improvement. This case highlights the need for greater awareness of this relatively rare adverse effect of propylthiouracil.     

Myeloperoxidase-antineutrophil cytoplasmic antibody positive alveolar hemorrhage during propylthiouracil therapy for hyperthyroidism]

A 62-year-old woman had been treated with propylthiouracil(PTU) for hyperthyroidism. Because bloody sputum, dyspnea, and severe hypoxemia developed, the patient was admitted to our hospital. Chest X-ray and chest computed tomographic (CT) films disclosed diffuse infiltrative shadows in both lung fields. Bronchoalveolar lavage revealed abundant hemosiderin-laden macrophages. Alveolar hemorrhage associated with myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) positive vasculitis syndrome was diagnosed because of the high serum level of MPO-ANCA. After the initiation of steroid therapy and termination of PTU, the infiltrative shadows in both lung fields disappeared, PaO2 improved, and MPO-ANCA decreased. There have been some reports of MPO-ANCA positive vasculitis syndrome developing during PTU therapy, but most were concerned with renal disease. We concluded that PTU and similar agents should be given consideration as one of the possible causes of MPO-ANCA-induced alveolar hemorrhage.     

Anticorps anticytoplasme des polynucléaires neutrophiles multispécifiques induits par le propylthiouracile

We report the case of a 28-year-old woman who presented with arthralgia during a treatment with propylthiouracil (PTU) for hyperthyroidism. Detection of antineutrophil cytoplasmic antibodies (ANCA) against myeloperoxidase, proteinase 3 and elastase led to suspect PTU induced vasculitis.