propylthiouracil and Anti-Neutrophil-Cytoplasmic-Antibody-Associated-Vasculitis

Propylthiouracil (PTU)-induced otitis media with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV) is an extremely rare adverse event associated with anti-thyroid drugs and is not well recognized. A 42-year-old woman with Graves' disease undergoing PTU therapy for 8 years visited our hospital because of earache and congested feeling in her left ear. Blood tests, a computed tomography scan and pure tone audiometry revealed otitis media and moderate mixed hearing impairment. Antibiotics, ear drops with antibiotics and painkillers were administered. However, her earache and hearing loss gradually got worse and symptoms of facial nerve palsy appeared. At several weeks after initiation of the treatment, a high serum level of myeloperoxidase (MPO)-ANCA, 75.6 U/mL, was revealed. After excluding other causes, she was diagnosed with OMAAV. PTU was suspected as the cause of her OMAAV and was immediately discontinued, and prednisolone was started. Hearing impairment in her left ear gradually got better and showed substantial improvement. Facial nerve palsy disappeared. Although PTU-induced OMAAV is an extremely rare disease, it is important to recognize the disease, as delayed treatment can lead to irreversible hearing loss, hypertrophic pachymeningitis, and subarachnoid hemorrhage. When patients taking anti-thyroid drugs, especially PTU, are diagnosed with refractory otitis media or hearing loss, it is possible that OMAAV might be the cause and thus serum ANCA levels should be evaluated.

Topics: Adult; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antithyroid Agents; Female; Graves Disease; Humans; Otitis Media; Propylthiouracil

The aim of this review was to delineate the characteristics of antineutrophil cytoplasmic antibody (ANCA)-associated small-vessel vasculitis associated with antithyroid drugs (ATD). A PubMed search was made for English language articles using the search terms antithyroid drugs AND ANCA OR ANCA-associated vasculitis.. The literature includes approximately 260 case reports of ANCA-associated small-vessel vasculitis related to ATD, with 75% of these associated with thiouracil derivatives (propylthiouracil [PTU]) and 25% with methyl-mercapto-imidazole derivatives (MMI/TMZ). The prevalence of ANCA-positive cases caused by ATD varied between 4% and 64% with PTU (median 30%), and 0% and 16% with MMI/TMZ (median 6%). Young age and the duration of ATD therapy were the main factors contributing to the emergence of ANCA positivity. Before ATD therapy initiation, the prevalence of ANCA-positive patients was 0-13%. During ATD administration, 20% of patients were found to be positive for ANCA. Only 15% of ANCA-positive patients treated with ATD exhibited clinical evidence of vasculitis, corresponding to 3% of all patients who received ATD. Clinical manifestations of ANCA-associated vasculitis related to ATD were extremely heterogeneous. When vasculitis occurred, ATD withdrawal was usually followed by rapid clinical improvement and a favorable prognosis.. ANCA screening is not systematically recommended for individuals on ATD therapy, particularly given the decreasing use of PTU in favor of TMZ/MMI. Particular attention should be given to the pediatric population with Graves' disease who receive ATD, as well as patients treated with thiouracil derivatives and those on long-term ATD therapy.

Topics: Age Factors; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antithyroid Agents; Humans; Hyperthyroidism; Methimazole; Prevalence; Propylthiouracil; Time Factors

Antineutrophil cytoplasmic autoantibody (ANCA) vasculitis is a systemic autoimmune disease resulting in small-vessel inflammation caused by pathogenic autoantibodies directed against proteinase 3 or myeloperoxidase. Legal drug culprits have been implicated as causative agents in secondary forms of disease, and a recent burst of reports also implicate levamisole-adulterated cocaine as a culprit.. Here, we briefly discuss all drug culprits associated with ANCA vasculitis and then focus on clinical, serologic, therapeutic and mechanistic aspects of four main drug culprits receiving attention of late, namely hydralazine, minocycline, propylthiouracil (PTU) and levamisole-adulterated cocaine.. Hydralazine, minocycline, propylthiouracil and levamisole-adulterated cocaine use should be closely considered in any patient where ANCA vasculitis is entertained given the wide use of these drugs in the community. Furthermore, medical practitioners should test urine for the presence of cocaine in any patient with presumed ANCA vasculitis, and if positive, then urine should also be tested for levamisole. Clinical features can be severe requiring not only drug cessation and supportive care, but also immunosuppression, plasma exchange in severe cases and dialysis as needed. Clinical trial investigators should strongly consider excluding patients with drug-induced forms of disease and mechanistic inroads are greatly needed in these secondary forms of disease to help elucidate the underlying cause and pathogenesis of ANCA vasculitis.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Cocaine; Cocaine-Related Disorders; Drug Contamination; Humans; Hydralazine; Levamisole; Minocycline; Propylthiouracil

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antithyroid Agents; Autoimmunity; Bone Marrow Cells; Cytokines; Dendritic Cells; Deoxyribonuclease I; Humans; Inflammation Mediators; Microscopic Polyangiitis; Neutrophil Activation; Neutrophils; Peroxidase; Propylthiouracil; Rats

Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is a common autoimmune disease in China. AAVs in the majority of Chinese patients are microscopic polyangiitis with antigenicity to myeloperoxidase. Propylthiouracil is the leading cause of drug-induced AAV. The genetic background and immunological characteristics of ANCA, such as the epitope, IgG subclass and avidity, might contribute to various clinical phenotypes of AAV.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antithyroid Agents; Asian People; Biomarkers; China; Genetic Predisposition to Disease; Humans; Myeloblastin; Peroxidase; Phenotype; Prognosis; Propylthiouracil; Risk Factors

Neutrophil extracellular traps (NETs) are characterized by the presence of extracellular DNA fibers studded with antimicrobial proteins, including myeloperoxidase (MPO). Although NETs play an important role in the innate immune system, the scattered extracellular enzymes, such as MPO, pose risks to the host. Therefore, NETs are strictly regulated by DNase I in the serum, which prevents them from persisting. Recent studies have demonstrated that dysregulation of NETs could be involved in the pathogenesis of autoimmune diseases, including systemic lupus erythematosus. In this review, we interpret the association of disordered NETs with autoimmune diseases, especially propylthiouracil-induced MPO-ANCA-associated vasculitis.

Topics: alpha-Defensins; Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Deoxyribonuclease I; Disease Models, Animal; Humans; Neutrophils; Peroxidase; Propylthiouracil

A 71-year-old man with hyperthyroidism complained of headache lasting two months. He had been using propylthiouracil (PTU) for 14 years. Treatment intensification did not improve the symptoms. Blood tests detected a positive myeloperoxidase-anti-neutrophil cytoplasmic antibody (MPO-ANCA). Diffuse dural thickening was identified by magnetic resonance imaging. The patient was diagnosed with hypertrophic pachymeningitis (HP) due to ANCA-associated vasculitis (AAV). He received methylprednisolone pulse therapy followed by prednisolone and methotrexate, which improved his headache. PTU-induced AAV-related HP is a rare and indiscernible disease. Therefore, the possibility of the disease should be proactively considered when a PTU user experiences refractory headaches.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antithyroid Agents; Headache; Humans; Hypertrophy; Male; Meningitis; Peroxidase; Propylthiouracil

Propylthiouracil (PTU) is a synthetic antithyroid drug that can induce ANCA-associated vasculitis.. A 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.. All 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.

Topics: Adult; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antithyroid Agents; Female; Humans; Hyperthyroidism; Propylthiouracil; Purpura

A number of disease processes can culminate in rapidly progressive glomerulonephritis, including pauci-immune focal segmental necrotising glomerulonephritis, usually seen with positive serum antineutrophil cytoplasmic antibodies (ANCA). Propylthiouracil (PTU) has been associated with drug-induced ANCA-associated vasculitis (AAV), with antibodies against myeloperoxidase (MPO) and proteinase 3 (PR3) present individually and together having been recognised. 'Double-positive' vasculitis with ANCA and anti-glomerular basement membrane (GBM) antibodies has also been reported in association with PTU treatment. We present a case of PTU-induced anti-MPO and PR3 positive ANCA vasculitis with associated anti-GBM antibodies, IgA nephropathy and an IgG4 interstitial infiltrate.. A 51-year-old man presented 2 weeks after re-commencing propylthiouracil (PTU) treatment for Graves' disease, with a severe acute kidney injury and haemato-proteinuria. He demonstrated positive titres for autoantibodies to PR3 (76.9 IU/mL), MPO (28.8 IU/mL) and GBM (94 IU/mL). Renal biopsy demonstrated numerous glomerular crescents, widespread IgG4-positive lymphoplasmacytic infiltrate and mesangial positivity for IgA. PTU was stopped and he was treated with steroids, plasma exchange and cyclophosphamide with sustained improvement in his renal function.. This case of drug-induced AAV presented a unique and intriguing collection of serological and histological features. We propose that the PTU-induced AAV resulted in epiphenomena of anti-GBM antibody production and an IgG4-cell-rich tubulointerstitial infiltrate. It is uncertain whether the mesangial IgA deposition preceded or resulted from the AAV.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Glomerulonephritis, IGA; Humans; Immunoglobulin G; Male; Middle Aged; Myeloblastin; Peroxidase; Propylthiouracil

BACKGROUND Drug-induced anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) should be suspected in patients on certain medications who present with inflammatory ocular, constitutional, pulmonary, and/or renal manifestations. Here, we present a case of propylthiouracil (PTU)-induced AAV presenting initially with red eye, and review important diagnostic and management considerations for this uncommon disorder. CASE REPORT A 34-year-old woman with hyperthyroidism taking PTU presented with red eye, later followed by fevers and hemoptysis. She was found to have episcleritis, diffuse alveolar hemorrhage, and microhematuria. The infectious diseases workup was unrevealing. Laboratory evaluations were notable for a high-titer perinuclear ANCA and elevated anti-myeloperoxidase antibodies. Renal function was normal. She was ultimately diagnosed with PTU-induced AAV. PTU was promptly discontinued and she was treated with pulse-dose methylprednisolone for 3 days, followed by prednisone 60 mg daily. A kidney biopsy revealed pauci-immune focal segmental necrotizing and crescentic glomerulonephritis. Given an allergy to methimazole, she underwent thyroidectomy and was ultimately treated with rituximab. Her steroid doses are progressively being tapered and she has complete resolution of symptoms. CONCLUSIONS PTU-induced AAV is a rare and serious condition. Our patient presented with ocular symptoms prior to more commonly recognized pulmonary and renal manifestations. Patients may have favorable outcomes if PTU is discontinued promptly, but patients with vital-organ involvement may require treatment with steroids and may need additional immunosuppression.

Topics: Adult; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antithyroid Agents; Female; Humans; Peroxidase; Propylthiouracil

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is rare in children and is characterised as necrotising vasculitis predominantly affecting small and medium-sized vessels. Propylthiouracil (PTU), an antithyroid drug, has been implicated in drug-induced AAV. In contrast, Kawasaki disease (KD) is a common systemic vasculitis, typically observed in children, which affects the medium-sized vessels, including the coronary arteries. An 11-year-old girl who developed AAV while receiving PTU therapy for Graves' disease is described. She was admitted to hospital following a 2-day history of fever, cervical adenopathy, cheilitis and papular rash, 3 weeks after an increase in the PTU dose. Despite discontinuation of PTU and the administration of intravenous antibiotic therapy, her clinical condition deteriorated and over the next 2 days she developed severe diarrhoea, conjunctival injection and swelling and redness of the right index finger. Additional findings included liver dysfunction, hydrops of the gallbladder, coagulopathy and urine abnormalities, suggesting glomerulonephritis. She met the diagnostic criteria for KD and received intravenous immunoglobulin (IVIG) combined with prednisolone, with rapid resolution of clinical and laboratory parameters. Peeling of the right index fingertip became evident on Day 12 of admission. Serial ultrasound cardiography demonstrated no evidence of cardiac involvement. A high titre of myeloperoxidase ANCA was detected in the patient's serum on admission, and the titre decreased during the convalescent stage. This case demonstrates that children with PTU-associated AAV may present with clinical features mimicking KD, and that IVIG along with corticosteroid therapy may be effective in treating patients with drug-induced severe systemic AAV.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antithyroid Agents; Blood Chemical Analysis; Child; Diagnosis, Differential; Female; Graves Disease; Humans; Mucocutaneous Lymph Node Syndrome; Propylthiouracil

Topics: Adult; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antithyroid Agents; Female; Graves Disease; Humans; Middle Aged; Propylthiouracil; Upper Extremity Deep Vein Thrombosis

Neutrophil extracellular traps (NETs) are immune defence systems that release extracellular chromatin and myeloid granules including myeloperoxidase (MPO) to kill pathogens. An experimental animal study recently demonstrated that disordered NETs induced by propylthiouracil (PTU) could contribute to the production of MPO anti-neutrophil cytoplasmic antibody (ANCA) and the development of ANCA-associated vasculitis (AAV). However, the role of dysregulated NETs in the pathogenesis of human AAV remains unclear.. We report a 19-year-old woman with Graves' disease on PTU presented fever, polyarthralgia, and lung hemorrhage with high titer of MPO-ANCA. This patient had a variety of atypical ANCAs and disordered NETs in vitro.. A diagnosis of PTU-induced AAV (PTU-AAV).. The PTU was discontinued and she was treated with immunosuppressants and plasmapheresis for reducing pathogenic autoantibodies.. Clinical manifestations including fever, polyarthralgia, and lung hemorrhage were on remission with a decrease of dysregulated NETs.. The clinical course of this PTU-AAV case indicated that dysregulated NETs would play a role in the development of ANCA and the pathogenesis of AAV.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antithyroid Agents; Extracellular Traps; Female; Graves Disease; Humans; Immunosuppressive Agents; Propylthiouracil; Young Adult

Antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) has been linked with thyroid disease as a result of antithyroid medications. We assessed the prevalence of thyroid disease in our patients with AAV.. Clinical records of 279 patients with AAV diagnosed between 1991 and 2014 were analyzed.. Thyroid disease was identified in 21.5% of patients, but only 2 had previously received propylthiouracil. There was a greater proportion of female patients, patients with antimyeloperoxidase antibodies, and patients with renal disease in the group with thyroid disease.. Our data show a higher prevalence of thyroid disease in patients with AAV than the general population. This was not attributable to antithyroid drugs.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies; Antithyroid Agents; Chi-Square Distribution; Female; Follow-Up Studies; Humans; Kidney Diseases; Logistic Models; Male; Multivariate Analysis; Peroxidase; Prevalence; Propylthiouracil; Retrospective Studies; Risk Factors; Sex Factors; Statistics, Nonparametric; Thyroid Diseases

We herein report a case of otitis media with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV) induced by propylthiouracil (PTU). A 30-year-old Japanese woman with Graves' disease, who was treated with PTU, reported with otitis media with sensorineural hearing loss bilaterally and trigeminal neuralgia on the left side, as well as elevated serum levels of myeloperoxidase-ANCA. Prior treatment with antibiotics was ineffective even after tympanostomy. However, clinical remission was immediately achieved after initiating prednisolone together with PTU withdrawal. These findings suggest that PTU therapy induces localized otological involvement as the concept of OMAAV.

Topics: Adult; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antithyroid Agents; Asian People; Female; Graves Disease; Humans; Otitis Media; Prednisolone; Propylthiouracil; Treatment Outcome

Topics: Adult; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antithyroid Agents; Biomarkers; Erythema; Female; Humans; Leg Dermatoses; Propylthiouracil

Topics: Adult; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antinuclear; Antithyroid Agents; Female; Graves Disease; Humans; Myeloblastin; Peroxidase; Propylthiouracil; Skin; Skin Diseases

This study sought to investigate the clinical characteristics and outcomes of propylthiouracil (PTU)-induced antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in patients with Graves' disease.. Sixteen patients diagnosed with PTU-induced ANCA-associated vasculitis at the authors' hospital from January 2010 to June 2017 were analyzed retrospectively.. All 16 patients with PTU-induced ANCA-associated vasculitis were female. The mean age ± standard deviation of the patients was 39.4 ± 15.3 years (range 19-69 years), and the median time of onset was 36 months (range 1-193 months) post-PTU initiation. The median dose at the onset of PTU-induced ANCA-associated vasculitis was 150 mg/day (range 50-300 mg/day). All patients had a positive serum perinuclear staining pattern (p-ANCA) and antibodies directed against myeloperoxidase (anti-MPO). Six patients tested positive for both anti-MPO antibodies and antibodies directed against proteinase-3. Seven (43.8%) patients presented with involvement of a single organ. The kidney was the organ most commonly affected, as 12 (75%) patients were found to have disease involving this organ. PTU was stopped in all patients, corticosteroids were administered to two patients, and immunosuppressive agents and corticosteroids were administered to five patients. Three patients were lost to follow-up. However, the remaining patients achieved remission after a median follow-up period of 38 months (range 6-76 months). Patients who were positive for pANCA and displayed cytoplasmic staining showed negative findings at rates of approximately 53.8% (7/13) and 100% (6/6), respectively, following treatment.. PTU-induced ANCA-positive vasculitis occurs at varying times and after exposure to various doses of PTU. The condition has a milder course and has a better prognosis after PTU cessation.

Topics: Adult; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antithyroid Agents; China; Female; Graves Disease; Humans; Middle Aged; Propylthiouracil; Retrospective Studies; Young Adult

Synthetic antithyroid drugs are often used in the treatment of hyperthyroidism, regardless of aetiology. They may cause various side effects, including the development of anti-neutrophil cytoplasmic antibodies (ANCA), ANCA-associated vasculitis, and neutrophilic dermatoses. Propylthiouracil (PTU) is the antithyroid drug most frequently implicated in ANCA-associated diseases specifically involving anti-myeloperoxidase ANCA (MPO-ANCA). To our knowledge, there are no clinical reports describing the association of pyoderma gangrenosum (PG) and anti-proteinase3-ANCA (PR3-ANCA) induced by PTU, with ANCA levels decreasing after antithyroid drug withdrawal.. A 68-year-old woman was treated with propylthiouracil (PTU) for toxic multinodular goitre. She presented necrotic ulceration of the lower abdomen. The patient's history, physical examination, and bacteriological and histological samples led to a diagnosis of pyoderma gangrenosum. This pyoderma involved ANCA with antigenic specificity for proteinase 3. Withdrawal of PTU and a short course of corticosteroids and cyclosporine resulted in rapid and complete resolution of the pyoderma gangrenosum as well as a decrease in ANCA. No relapse was observed one year after cessation of treatment.. We report a case of PG associated with PR3-ANCA induced by PTU, without any demonstrable vasculitis.

Topics: Abdomen; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antithyroid Agents; Biomarkers; Cyclosporine; Dermatologic Agents; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Hyperthyroidism; Propylthiouracil; Pyoderma Gangrenosum; Treatment Outcome

Propylthiouracil (PTU)-induced antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis presenting with renal failure, acute hepatic failure, and cerebral angiitis is a rare yet fatal disease. Early diagnosis and management may help in reducing mortality and morbidity. Plasmapheresis and induction with either cyclophosphamide or rituximab is indicated. Understanding the pathophysiology and complex management of this disease poses challenges to clinicians.. A 42-year-old woman presented with acute renal and hepatic failure. She had been on PTU for 11 months for Graves' disease. Initial urine microscopy showed red blood cell casts. Anti PR-3 antibodies were positive. Kidney biopsy revealed pauci-immune glomerulonephritis with crescent formation. Renal and hepatic failures were attributed to PTU-induced c-ANCA production as other serological workup was negative. Pulse steroids and plasmapheresis were initiated. Later she developed pneumonia. She was also given rituximab. After the first dose of rituximab, plasmapheresis was held for 3 days. The second dose of rituximab was given in 5 days owing to removal by plasmapheresis. She got 8 sessions of plasmapheresis. She also developed seizures and MRA of her head revealed cerebral infarct, with findings suggestive of cerebral angiitis. She did not recover and expired 20 days after presentation.. PTU can cause ANCAassociated vasculitis resulting in multiorgan failure. Plasmapheresis should be held for 3 days after rituximab infusion in order to allow maximum exposure. The second dose of rituximab may be given before the recommended 7-day interval in cases in which plasmapheresis is being performed to maximize therapeutic benefit.

Topics: Adult; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Murine-Derived; Antithyroid Agents; Biopsy; Combined Modality Therapy; Disease Progression; Fatal Outcome; Female; Glomerulonephritis; Graves Disease; Humans; Immunosuppressive Agents; Liver Failure, Acute; Magnetic Resonance Angiography; Microscopy, Electron; Multiple Organ Failure; Plasmapheresis; Propylthiouracil; Pulse Therapy, Drug; Rituximab; Steroids; Time Factors; Treatment Failure; Vasculitis, Central Nervous System

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antithyroid Agents; Ear, External; Female; Humans; Hyperthyroidism; Prednisone; Propylthiouracil; Purpura; Vasculitis, Leukocytoclastic, Cutaneous

Antineutrophil cytoplasmic antibodies (ANCAs) are the serologic hallmark of ANCA-associated primary small-vessel vasculitides (AAVs), but these antibodies have also been described in other autoimmune diseases such as inflammatory bowel diseases. Furthermore, different drugs are linked to the induction of ANCA, including propylthiouracil (PTU). However progression into clinical overt vasculitis is less common.. We describe the case of a young girl with Graves' disease presenting with fatigue, fever, episcleritis and arthritis. The unexpected double myeloperoxidase/proteinase 3-ANCA positivity triggered a multidisciplinary diagnostic work-up and resulted in the diagnosis of a clinically overt PTU-induced AAV. After PTU-withdrawal and treatment with high-dose corticosteroids, a favorable clinical and biochemical evolution was obtained.. The use of PTU in the management of hyperthyroidism is not considered first-line treatment in Europe and is even less commonly used in children. Nevertheless, pediatricians should be aware of the possibility of PTU-induced AAV, especially in the presence of multiple ANCA reactivities. Therefore, the use of this drug should be weighed carefully in children.

Topics: Adolescent; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Female; Graves Disease; Humans; Propylthiouracil

The side effects of propylthiouracil, including cytopenia and vasculitis, are well established.  We present an interesting case in which cytopenia and cutaneous vasculopathy occurred concomitantly in a critically ill patient.  The patient was initially treated for suspected infection until dermatologic and rheumatologic workup revealed ANCA-positivity and vasculopathy on histopathology, most consistent with an atypical presentation of ANCA-positive vasculitis.  Upon initiation of immunosuppressive therapy, the patient's condition rapidly improved emphasizing the importance of early recognition of this condition.

Topics: Adult; Anorexia; Anti-Inflammatory Agents; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antithyroid Agents; Blister; Eyelid Diseases; Fatigue; Female; Graves Disease; Hemorrhage; Humans; Immunosuppressive Agents; Methylprednisolone; Pancytopenia; Pharyngitis; Prednisone; Propylthiouracil; Respiratory Insufficiency

To retrospectively investigate clinico-pathological features and outcomes of patients with renal involvement in propylthiouracil (PTU)-associated antineutrophil cytoplasmic autoantibody (ANCA) vasculitis (PTU-AAV).. Clinico-pathological features and outcomes of 12 patients (female 11, average age 32.4 ± 13.8 years) who developed AAV after treatment with PTU were collected and analyzed. ANCA was detected by both immunofluorescence (IF) and enzyme linked immunosorbent assay (ELISA). All patients had renal biopsy.. Twelve patients received PTU for 2-264 months (median 42 months) when PTUAAV was diagnosed. All patients had positive serum P-ANCA, 11 of them were MPO-ANCA, 1 was MPO and PR3-ANCA double positive. All patients presented with hematuria and proteinuria, 5 of them had gross hematuria, urine protein was 1.9 ± 1.6 g/24 h, 7 of 12 (58.3%) patients had renal dysfunction, among them 3 needed initial renal replacement therapy. Renal biopsy showed pauci-immune segmental necrotizing crescentic glomerulonephritis in ten patients, segmental necrotizing glomerulonephritis superimposed on membranous nephropathy in two patients. All patients withdrew PTU and received steroid and immunosuppressive therapy. After a median follow-up of 42 months (range 21-86), 3 patients developed to ESRD, 7 patients entered complete renal remission. Serum ANCA turned negative only in 2 patients, 10 patients had persistent positive serum ANCA. Three patients relapsed with the elevation of serum ANCA level.. Renal damage of PTU-AAV could be pauci-immune necrotizing crescentic glomerulonephritis, and necrotizing glomerulonephritis coexisted with membranous nephropathy. Most patients had persistent positive serum ANCA and had a risk of relapse and progression to ESRD even after PTU withdrawal and immunosuppressive therapy.

Topics: Adolescent; Adult; Anti-Inflammatory Agents; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antithyroid Agents; Child; Cyclophosphamide; Disease Progression; Hematuria; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Glomerulus; Kidney Tubules; Male; Middle Aged; Mycophenolic Acid; Prednisone; Propylthiouracil; Proteinuria; Recurrence; Remission Induction; Renal Replacement Therapy; Retrospective Studies; Thyroid Diseases; Young Adult

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antithyroid Agents; Diagnosis, Differential; Glomerulonephritis, IGA; Humans; Hyperthyroidism; Male; Middle Aged; Peroxidase; Propylthiouracil

Antineutrophilic cytoplasmic antibody (ANCA) associated vasculitis is one of the rare complications of propylthiouracil treatment. Having a variable clinical spectrum, it may be presented with both skin limited vasculitis and life-threatening systemic vasculitis. In this study, we present a case that developed ANCA-positive vasculitis with skin and kidney involvement (hematuria and proteinuria) six months after propylthiouracil treatment was initiated for toxic nodular goiter. Proteinuria recovered dramatically subsequent to radioactive iodine treatment following ceasing the drug.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antithyroid Agents; Female; Humans; Iodine Radioisotopes; Middle Aged; Propylthiouracil; Remission Induction

Increasing evidence has suggested that linear epitopes of antineutrophil cytoplasmic antibody (ANCA) directed to myeloperoxidase (MPO) might provide clues to the pathogenesis of propylthiouracil (PTU)-induced ANCA-associated vasculitis (AAV). This study mapped epitopes of MPO-ANCA in sera from patients with PTU-induced MPO-ANCA (with or without vasculitis) and primary AAV, aiming to analyze certain epitopes associated with the development of PTU-induced AAV.. Six recombinant linear fragments, covering the whole amino acid sequence of a single chain of MPO, were produced from Escherichia coli. Sera from 17 patients with PTU-induced AAV, 17 patients with PTU-induced MPO-ANCA but without clinical evidence of vasculitis, and 64 patients with primary AAV were collected at presentation. Of the 17 patients with PTU-induced AAV, 12 also had sera at remission. The epitope specificities were detected by enzyme-linked immunosorbent assay by using the recombinant fragments as solid-phase ligands.. Compared with patients with PTU-induced MPO-ANCA but without clinical vasculitis, sera from PTU-induced AAV patients showed significantly higher reactivity against the H1 fragment of MPO (optical density values: 0.17 (0.10 to 0.35) versus 0.10 (0.04 to 0.21), P = 0.038) and could recognize a significantly higher number of fragments (two (none to four) versus one (none to two), P = 0.026). Compared with sera from primary AAV patients, sera from PTU-induced AAV patients had significantly higher reactivity to the P fragment and the H4 fragment (47.1% versus 14.1% P < 0.001; 41.2% versus 14.1%, P = 0.034, respectively), and could recognize a significantly higher number of fragments (two (none to four) versus one (none to two), P = 0.013]. Among the 12 PTU-induced AAV patients with sequential samples, the number of fragments recognized in remission was significantly less than that in initial onset (two (none to four) versus none (none to 0.75), P < 0.001].. Linear epitopes of MPO molecules might be associated closely with PTU-induced AAV. In particular, the P and H4 fragments may be important epitopes in PTU-induced AAV.

Topics: Adolescent; Adult; Amino Acid Sequence; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antithyroid Agents; Autoantibodies; Autoantigens; Child; Enzyme-Linked Immunosorbent Assay; Epitope Mapping; Epitopes, B-Lymphocyte; Female; Humans; Male; Middle Aged; Molecular Sequence Data; Peroxidase; Propylthiouracil; Young Adult

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.

Topics: Adult; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antithyroid Agents; Female; Goiter; Humans; Hyperthyroidism; Immunosuppressive Agents; Male; Middle Aged; Propylthiouracil; Withholding Treatment; Young Adult

Propylthiouracil (PTU) is recommended as a first-line antithyroid drug (ATD) during first trimester organogenesis in pregnancy because recent evidence suggests that methimazole (MMI) may be associated with congenital anomalies. However, PTU more commonly causes myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, which usually occurs during prolonged treatment, compared with MMI. We report a case of MPO-ANCA-associated vasculitis in a 35-year-old woman with Graves'disease. Although her thyroid function could be maintained euthyroid by MMI, her ATD was switched to PTU because she wished to become pregnant. The patient presented with flu-like symptoms 8 days after starting PTU and developed hemoptysis and dyspnea at 22 days. Her MPO-ANCA titer was 21 ELISA units (EUs) before PTU treatment but increased to 259 EUs at 22 days after PTU treatment. Her clinical condition improved with the discontinuation of PTU and with immunosuppressive therapy. This case indicated that MPO-ANCA vasculitis occurred within several weeks after the initiation of PTU and that this side effect could be caused by the change from MMI to PTU. Thus, our clinical observation suggests that patients treated with PTU should be carefully monitored for MPO-ANCA titers and variable manifestations of MPO-ANCA-associated vasculitis regardless of the period of administration.

Topics: Abnormalities, Drug-Induced; Adult; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antithyroid Agents; Female; Graves Disease; Humans; Methimazole; Peroxidase; Pregnancy; Pregnancy Complications; Propylthiouracil

Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) in patients with Graves' disease (GD) is linked with the use of anti-thyroid drugs (ATDs). We report the co-occurrence of AAV and GD in a patient that was independent of ATD therapy. A 38-year-old white male presented with systemic symptoms, palpitations, tremors, purpuric skin lesions, and digital pain. Physical examination and biological tests confirmed GD. He quickly developed multiple digital gangrenes and testicular pain/mass. Skin and testicular biopsies showed granulomatous vasculitis of the small- and medium-sized vessels, while his serum contained anti-proteinase-3 antibody.

Topics: Adult; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antithyroid Agents; Azathioprine; Biomarkers; Drug Therapy, Combination; Glucocorticoids; Graves Disease; Humans; Immunosuppressive Agents; Male; Methylprednisolone; Myeloblastin; Propylthiouracil; Remission Induction; Skin; Testis; Treatment Outcome

Renal involvement is frequently present in primary antineutrophil cytoplasmic antibody-associated small-vessel vasculitis (AAV) as well as propylthiouracil (PTU)-induced AAV. We analyzed the characteristics of patients with PTU-induced AAV with renal involvement and investigated the differences of the 2 diseases.. Thirty-six patients with PTU-induced AAV, diagnosed from 1997 to 2010, were enrolled for study. Their data were compared with those of 174 patients with primary AAV diagnosed at the same time. Renal involvement was present in all patients.. There was a prominent proportion of young women with PTU-induced AAV (p < 0.01). They had lower levels of proteinuria and serum creatinine and higher estimated glomerular filtration rate (p < 0.01, p < 0.01, and p < 0.01, respectively). Clinical immunological abnormalities were less severe in patients with PTU-induced AAV. Patients with PTU-induced AAV had less organ involvement and lower Birmingham Vasculitis Assessment Score than patients with primary AAV (p < 0.01). Renal biopsies showed a lower proportion of glomeruli with crescents (p < 0.01). Interstitial inflammation was less severe in patients with PTU-induced AAV (p < 0.05). Similarly, interstitial fibrosis and tubular atrophy were less severe in patients with PTU-induced AAV (p < 0.01, p < 0.05, respectively). Renal survival and total survival were better in patients with PTU-associated vasculitis (p < 0.05, p = 0.01).. Clinical and histopathological abnormalities were less severe in patients with PTU-induced AAV and most of them had a good prognosis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antithyroid Agents; Creatinine; Female; Fibrosis; Glomerular Filtration Rate; Humans; Incidence; Kidney; Male; Middle Aged; Propylthiouracil; Retrospective Studies; Survival Rate; Thyroid Diseases; Young Adult

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Humans; Neutrophils; Peroxidase; Propylthiouracil

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.. 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.. 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.. 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.

Topics: alpha-Defensins; Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antimetabolites; Carcinogens; Deoxyribonuclease I; Disease Models, Animal; DNA; Humans; Neutrophils; Nucleic Acid Conformation; Peroxidase; Propylthiouracil; Rats; Rats, Inbred WKY; Tetradecanoylphorbol Acetate

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Emergency Service, Hospital; Female; Graves Disease; Humans; IgA Vasculitis; Middle Aged; Pain; Propylthiouracil; Skin

Propylthiouracil, a drug commonly used to treat hyperthyroidism, is known to cause antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis as a rare complication. The wide clinical spectrum of propylthiouracil-induced vasculitis ranges from mild forms with rash and/or arthralgia to severe forms with renal or pulmonary involvement, which can be critical and life-threatening if left unrecognized and untreated. Given its rarity and exceedingly variable clinical presentations, diagnosis may be challenging, and delayed diagnosis is not uncommon without a high index of suspicion, as illustrated by this report of a 17-year-old girl with Graves' disease who developed occult pulmonary hemorrhage as an overlooked rare presentation of ANCA-associated vasculitis after administration of propylthiouracil. Associated clinical features included fever, fatigue, palpable purpura, polyarthritis, and nephritis. Positive findings on chest radiography prompted the bronchoalveolar lavage procedure, which led to the identification of pulmonary hemorrhage. Skin biopsy showed leukocytoclastic vasculitis. Serologic test results were positive for perinuclear ANCA, cytoplasmic ANCA, myeloperoxidase-ANCA, proteinase 3-ANCA, and cryoglobulins but negative for antinuclear antibody, anti-double-stranded DNA, rheumatoid factor, and anti-hepatitis C virus antibody. The symptoms resolved after discontinuation of propylthiouracil and a few months of corticosteroids and azathioprine. This report highlights the necessity for physicians to keep alert for the protean manifestations of propylthiouracil-induced vasculitis.

Topics: Adolescent; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antithyroid Agents; Female; Hemorrhage; Humans; Lung Diseases; Propylthiouracil