Propylthiouracil-Induced Leucocytoclastic Vasculitis With Pulmonary Hemorrhage Treated With Plasmapheresis

Propylthiouracil (PTU) can effectuate antineutrophil cytoplasmic antibodies (ANCA)–positive vasculitis. We report a case of severe, PTU-induced leucocytoclastic vasculitis with diffuse pulmonary hemorrhage within a month of initiating PTU. Emergent plasmapheresis was initiated with excellent clinical response. A clinical suspicion for this potential side effect coupled with early cessation of the drug is generally adequate. Clinical manifestations, posited pathogenetic mechanisms, and therapeutic strategies, including the role of plasmapheresis, are discussed.     

Propylthiouracil-induced nonspecific interstitial pneumonia

Propylthiouracil (PTU) is a drug used to treat hyperthyroidism. A number of adverse effects have been reported with this drug, including fever, agranulocytosis, skin rash, and vasculitis. PTU-induced interstitial pneumonia is rare--only three cases have been reported--and PTU-induced nonspecific interstitial pneumonia (NSIP) has not been reported. We report a patient who developed NSIP after taking PTU for 1 year. She developed dyspnea, cough, and mild fever lasting 1 month, and a chest CT scan showed multifocal patchy consolidation in both lungs. She underwent a surgical lung biopsy, and NSIP was confirmed pathologically. The symptoms and abnormalities seen in the chest radiograph improved after withdrawal of PTU. To our knowledge, this is the first documented case of pathologically proven PTU-induced NSIP.     

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.     

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.     

丙硫氧嘧啶相关性小血管炎和原发性小血管炎血清髓过氧化物酶抗体抗原决定簇结合谱的比较

目的比较丙硫氧嘧啶(PTU)相关性小血管炎和原发性小血管炎髓过氧化物酶(MPO)抗体的抗原决定簇结合谱.方法以人MPO制备的MPO亲和层析柱,分别从1例PTU相关性小血管炎和1例显微镜下型多血管炎(MPA)患者的血浆置换液中分离纯化MPO抗体(Pab1和Pab2),并经辣根过氧化物酶标记(Pab1-HRP和Pab2-HRP). 以Pab1-HRP和Pab2-HRP以及两种鼠抗人MPO单克隆抗体(3D8和6B9)分别作为识别MPO分子上不同抗原决定簇的探针,应用竞争性ELISA对10例PTU引起的抗中性粒细胞胞浆抗体(ANCA)阳性小血管炎患者和10例MPA患者血清中MPO抗体的抗原决定簇结合谱进行比较研究.结果 PTU组10例标本均可抑制3D8,平均抑制率为44.7%, 9/10例标本可抑制6B9, 平均抑制率为35.6%; MPA组10例标本均可抑制3D8和6B9, 平均抑制率分别为68.4%和62.2%, 与PTU组相比差异具有显著性(P<0.01).两组标本对Pab1-HRP的平均抑制率均达80%以上,MPA组标本对Pab2-HRP的抑制率均值显著大于PTU组(76.3% 比 58.9%, P<0.01).结论丙硫氧嘧啶相关性小血管炎和MPA患者血清中的MPO抗体均可识别MPO分子上多个抗原决定簇,二者识别的抗原决定簇有一定程度的交叉,但PTU组识别的抗原决定簇可能较局限.抗原决定簇结合谱的不同可能与临床表现的不同有关.     

Propylthiouracyl-induced severe liver toxicity： An indication for alanine aminotransferase monitoring？

INTRODUCTION Propylthiouracil (PTU)-related severe hepatitis remains a relatively rare occurrence[1,2] even if a transient increase in liver function tests is observed following the initiation of treatment in 15% to 28% of cases[2-4]. Before 1998, only 25…     

Dose-dependent induction of anti-native DNA antibodies in cats by propylthiouracil

Cats receiving propylthiouracil (PTU) develop antinuclear antibodies (ANA) and an immune-mediated disease syndrome characterized by anorexia, lymphadenopathy, weight loss, and Coombs-positive hemolytic anemia. Investigation of the ANA specificity indicated that the predominant ANA activity consistent of anti-native DNA (nDNA) antibodies. The formation of anti-nDNA antibodies and immune-mediated disease syndrome appeared to be dose-dependent, even in cats in which a response had been induced on 4 prior occasions. These results supply further evidence that PTU-induced autoimmunity is not the result of a simple drug allergy. Rather, it appears that PTU induces a lupus-like syndrome, including the hallmark sign of systemic lupus erythematosus, anti-nDNA antibodies.     

Dose-dependent induction of anti–native dna antibodies in cats by propylthiouracil

Cats receiving propylthiouracil (PTU) develop antinuclear antibodies (ANA) and an immune-mediated disease syndrome characterized by anorexia, lymphadenopathy, weight loss, and Coombs-positive hemolytic anemia. Investigation of the ANA specificity indicated that the predominant ANA activity consisted of anti–native DNA (nDNA) antibodies. The formation of anti-nDNA antibodies and immune-mediated disease syndrome appeared to be dose-dependent, even in cats in which a response had been induced on 4 prior occasions. These results supply further evidence that PTU-induced autoimmunity is not the result of a simple drug allergy. Rather, it appears that PTU induces a lupus-like syndrome, including the hallmark sign of systemic lupus erythematosus, anti-nDNA antibodies.     

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.     

A man with interstitial pneumonia due to propylthiouracil

A 50-year-old Japanese man with Grave's disease had been taking propylthiouracil (PTU) for 10 years prior to the diagnosis of pneumonia. He noticed dyspnea on exertion and had a dry cough for at least 2 years and then suddenly developed high fever and dyspnea at rest. Clinical symptoms, chest radiographs, chest computed tomography and lung function revealed interstitial pneumonia. The symptoms were completely resolved after withdrawal of PTU, and consequently he was diagnosed with PTU-induced interstitial pneumonia. He also showed moderate myeloperoxidase (MPO)- antineutrophil cytoplasmic antibody (ANCA) positivity without any signs of vasculitis before as well as after PTU withdrawal. Although PTU-induced interstitial pneumonia is quite rare, with only 3 cases, including the present patient, so far reported, respiratory involvement should be considered in patients treated with PTU.     

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 reduces xenograft tumor growth in an athymic nude mouse prostate cancer model

METHODS: Several anecdotal reports indicate that cancer may occasionally remain in a dormant state for prolonged periods in patients with hypothyroidism. Once the hypothyroid state is recognized and supplementation therapy with thyroid hormones is initiated, disease progression occurs. In this experiment, 6-n-propyl-2-thiouracil (PTU) was added to the water of athymic nude mice. The animals were subsequently inoculated with cells from a human prostate cancer cell line. RESULTS: The growth rate of subcutaneously implanted prostate xenografts was significantly slower in mice treated with PTU compared with mice that did not receive PTU. In a separate experiment, tritiated thymidine incorporation assays were performed in DU145 and PC3 human prostate cancer cells with and without PTU. No significant differences were observed, indicating that PTU did not exert any antitumor effect in vitro. CONCLUSIONS: Our study demonstrates that PTU inhibits the growth of human prostate tumors in nude mice via an indirect effect. This antitumor effect may be caused by hypothyroidism. This is the first in vivo study suggesting potential therapeutic applications for thyroid hormone manipulations in human cancer of the prostate. Further studies will determine growth kinetics of xenotransplanted prostate cancer in vitro and in vivo. PTU-induced hypothyroidism may be further explored in conjunction with other antineoplastic therapy.     

Abnormal conformation and impaired degradation of propylthiouracil‐induced neutrophil extracellular traps: Implications of disordered neutrophil extracellular traps in a rat model of myeloperoxidase antineutrophil cytoplasmic antibody–associated vasculitis

Objective

Neutrophil extracellular traps (NETs) are composed of DNA and antimicrobial proteins, including myeloperoxidase (MPO). Recent studies have demonstrated that impaired regulation of NETs could trigger an autoimmune response. Propylthiouracil (PTU), an antithyroid drug, is associated with a risk of MPO antineutrophil cytoplasmic antibody (ANCA) production and MPO ANCA–associated vasculitis (MPO AAV). This study was undertaken to clarify the mechanism of MPO ANCA production, using the PTU‐induced model of MPO AAV.

Methods

NETs were induced by treating human neutrophils with phorbol myristate acetate (PMA) in vitro. We examined whether the addition of PTU influenced the NET formation induced by PMA and the degradation of NETs by DNase I, which is regarded as a regulator of NETs. Furthermore, we examined whether NETs generated by the combination of PMA and PTU induced MPO ANCA and MPO AAV in vivo in rats.

Results

When NETs were induced by PMA with PTU using human neutrophils in vitro, abnormal conformation of NETs was observed. Interestingly, the abnormal NETs were hardly digested by DNase I. Moreover, rats immunized with the abnormal NETs, which had been induced by PMA with PTU using rat neutrophils, produced MPO ANCA and developed pulmonary capillaritis. When rats were given oral PTU with intraperitoneal injection of PMA, pauci‐immune glomerulonephritis and pulmonary capillaritis occurred with MPO ANCA production in the serum.

Conclusion

Our findings indicate that abnormal conformation and impaired degradation of NETs induced by PTU are involved in the pathogenesis of PTU‐induced MPO ANCA production and MPO AAV. These findings suggest that disordered NETs can be critically implicated in the pathogenesis of MPO AAV.

     

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.     

药物治疗甲状腺功能亢进症患者不良反应的临床研究

目的探讨两种常见药物治疗甲状腺功能亢进症（甲亢）不良反应发生率,特别是出现抗中性粒细胞胞浆抗体（ANCA）阳性血管炎发生率和临床特点。方法将227例确诊的甲亢患者随机分为两组,分别给予硫脲类（121例）和咪唑类（106例）治疗。随访两组患者药物不良反应发生事件。采用间接免疫荧光法测定患者血清ANCA浓度,ELISA法测定血清抗蛋白酶3和髓过氧化物酶浓度。化学放光法测定甲状腺激素水平。结果硫脲类组患者不良反应为药物性皮疹8例（6．61％）,粒细胞减少4例（3．30％）,肝功能损害3例（2．48％）,ANCA阳性血管炎5例（4．13％）。咪唑类治疗甲亢不良反应药物性皮疹7例（6．60％）,粒细胞减少6例（5．66％）,肝功能损害3例（2．83％）,ANCA阳性血管炎0例。结论服用硫脲类和咪唑类两种药物治疗甲亢患者,药物性皮疹、肝功能受损和粒细胞减少发生率无显著性差异,但硫脲类组发生ANCA阳性血管炎比率明显高于咪唑类组。     

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.     

Propylthiouracil (PTU)-induced vasculitis associated with antineutrophil antibody against myeloperoxidase (MPO-ANCA)

A 54-year-old woman had been administered propylthiouracil (PTU) for Graves' disease for 4 years. Recently, she complained of hemoptysis due to pulmonary alveolar hemorrhage causing anemia, and also had microhematuria. Antineutrophil cytoplasmic antibody against myeloperoxidase (MPO-ANCA) was positive, and she was diagnosed with PTU-induced vasculitis. Cessation of PTU and the administration of corticosteroids ameliorated these manifestations.     

丙硫氧嘧啶导致症状性肝损伤的临床特征及相关因素分析

目的　探讨丙硫氧嘧啶 (PTU)治疗甲状腺功能亢进症 (甲亢 )过程中导致症状性肝损伤的临床特点及相关因素。方法　对PTU导致症状性肝损伤的临床及实验室特征、肝损伤恢复特点和相关因素进行回顾性分析。结果　PTU导致症状性肝损伤 12例 ,占同期因甲亢住院患者的 1 3%(12 /914 ) ,男 1例 ,女 11例 ,年龄 (30± 9)岁 ,肝损伤出现在服药后 (36± 18)d ,临床表现为腹胀、乏力、恶心、尿色黄等 ,肝功异常的峰值分别为 :ALT (5 31 7± 35 2 0 ) 11314 2 5U/L、血清碱性磷酸酶 (183±97) 84 35 4U/L、总胆红素 [(中位数 )范围 ]6 7 6 (17 15 6 7 7) μmol/L、直接胆红素 4 7 9(5 6 2 71 0 ) μmol/L ;损伤类型中肝细胞性占 6 6 7%、混合性占 2 5 0 %、胆汁淤积性占 8 3% ,肝损伤时PTU服用剂量为15 0～ 30 0mg/d ;停用PTU及治疗后 ,肝功能恢复正常时间 14～ 14 0d。症状性肝损伤、亚临床性肝损伤和无肝损伤 3组比较 ,既往有抗甲状腺药不良反应史者 ,损伤组显著多于无肝损伤发生组 ,PTU的起始剂量也显著低于无肝损伤组 ,治疗前ALT异常者亚临床性肝损伤组显著高于其他 2组。结论　PTU引起症状性肝损伤多发生于治疗初始阶段 ,以肝细胞性肝损伤多见 ,临床过程相对良性 ,停药、保肝和糖皮质激素治疗后 ,肝功能可恢     

丙基硫氧嘧啶诱导的ANCA相关性系统性小血管炎与IgA肾病

抗甲状腺药物丙基硫氧嘧啶(PTU)可引起针对多种靶抗原的抗中性粒细胞胞浆抗体(ANCA)阳性,进而导致系统性小血管炎(AASV),最常累及肾脏,多表现为寡免疫复合物型急进性肾小球肾炎.IgA肾病以肾小球系膜区IgA沉积为特点,ANCA阳性可能是其预后不良的一个指标,但目前尚无证据表明PTU致ANCA阳性可引起IgA肾病,多数学者仍认为两者是并存的关系.     

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.