Clinical Vasculitis Research Articles

Impact of [18F]FDG PET/CT in the Assessment of Immunotherapy-Induced Arterial Wall Inflammation in Melanoma Patients Receiving Immune Checkpoint Inhibitors.

We aimed to investigate the role of [18F]FDG positron emission tomography/computed tomography (PET/CT) in the early detection of arterial wall inflammation (AWI) in melanoma patients receiving immune checkpoint inhibitors (ICIs). Our retrospective study enrolled 95 melanoma patients who had received ICIs. Inclusion criteria were ICI therapy for at least six months and at least three [18F]FDG PET/CTs, including one pretreatment session plus two scans three and six months after treatment initiation. AWI was assessed using quantitative and qualitative methods in the subclavian artery, thoracic aorta, and abdominal aorta. We found three patients with AWI visual suspicion in the baseline scan, which increased to five in the second and twelve in the third session. Most of these patients' treatments were terminated due to either immune-related adverse events (irAEs) or disease progression. In the overall population, the ratio of arterial-wall maximum standardized uptake value (SUVmax)/liver-SUVmax was significantly higher three months after treatment than the pretreatment scan in the thoracic aorta (0.83 ± 0.12 vs. 0.79 ± 0.10; p-value = 0.01) and subclavian artery (0.67 ± 0.13 vs. 0.63 ± 0.12; p-value = 0.01), and it remained steady in the six-month follow-up. None of our patients were diagnosed with definite clinical vasculitis on the dermatology follow-up reports. To conclude, our study showed [18F]FDG PET/CT's potential to visualise immunotherapy-induced subclinical inflammation in large vessels. This may lead to more accurate prediction of irAEs and better patient management.

MO202: Pulmonary-Renal Syndrome in Patient with Chronic Hepatitis C And HIV Disease

Abstract BACKGROUND AND AIMS Pulmonary-renal syndrome (PRS) is characterized by rapidly progressive glomerulonephritis and lung vasculitis. Most common causes of PRS are Goodpasture's disease, antineutrophil cytoplasm antibody (ANCA) associated vasculitis and systemic lupus erythematosus; rarely it could be caused by cryoglobulinemic vasculitis. ANCA and cryoglobulins are present in a wide range of infectious, inflammatory and malignant conditions with or without evidence of clinical vasculitis. ANCA positivity has been described in patients with human immunodeficiency virus (HIV) or chronic hepatitis C (HCV), but only a negligible proportion of these patients developed true ANCA vasculitis. Cryoglobulinemia is seen in ∼50% of patients with HCV and ∼5% of these patients have symptomatic disease. According to previous studies, rapidly progressive glomerulonephritis and pulmonary involvement are rare manifestations of cryoglobulinemia. We describe a patient with HIV and HCV infection who presented with rapidly progressive glomerulonephritis and lung vasculitis. METHOD Case report presentation. RESULTS A 43-year-old male presented with fatigue, nausea and decreased urinary output of 3–4 days. Vital signs were stable and physical examination showed abdominal distention and peripheral oedema. His past medical history included heroin abuse. However, he denied any illicit drug use, and he had been on methadone maintenance treatment for 8 years. The patient was diagnosed with HIV 11 years previously. His antiretroviral therapy included abacavir, dolutegravir and lamivudine. CD4 count before admission was 180–200 cells/mm3. In addition to HIV infection, the patient had HCV diagnosed 20 years ago, but he has not received any treatment. The laboratory tests revealed pancytopenia (leukocytes 1.3 × 109/L, haemoglobin 66 g/L, platelets 66 × 109/L), kidney injury (proteinuria 0.8 g/24 h and haematuria) with renal insufficiency (creatinine 727 mcmol/L, urea 36.6 mmol/L). Ultrasound workup demonstrated diffuse changes in liver parenchyma with signs of portal hypertension, and normal-sized, non-obstructed kidneys with Grade 0 parenchymal echogenicity. Chest CT revealed wide areas of ground-glass opacity with patchy airspace consolidations, more severe in the left upper lobe. A serologic workup was positive for cryoglobulins, ANA, c-ANCA (high titre of anti-PR3 143 IU/mL), with decreased levels of C3 and C4. CRP level was slightly elevated (40 mg/L). Moreover patient had positive treponemal and non-treponemal syphilis serological tests. An ultrasound-guided renal biopsy showed crescentic glomerulonephritis with predominant IgM and focal C3, C1q deposition in glomerular capillary walls without any significant glomerular proliferative features. Changes could be interpreted as an immune complex and/or cryoglobulin-mediated glomerulonephritis, but overlapping pauci-immune glomerulonephritis could not be ruled out. Haemodialysis was initiated due to kidney failure and hyperhydration. The patient was treated with pulse methylprednisolone followed by a tapering course of oral prednisolone. Rituximab 1000 mg was prescribed after excluding HIV opportunistic infections, and treatment of syphilis with three doses of benzathine penicillin was used. Due to low GFR, HIV treatment was switched to Dolutegravir/Rilpivirine. The patient refused to initiate HCV therapy. The patient responded well to treatment and lung vasculitis and kidney function improved, therefore haemodialysis was discontinued. Serum creatinine level decreased to 130–120 mcmol/L and remained stable after 18 weeks since the treatment. CONCLUSION PRS in a patient with chronic infections, positive cryoglobulins and positive c-ANCA clinically seems more applicable to c-ANCA vasculitis than to cryoglobulinemic vasculitis. Still overlapping of both diseases could not be excluded.

PULMONARY RENAL SYNDROME IN PROPYLTHIOURACIL INDUCED ANCA VASCULITIS

SESSION TITLE: Tuesday Fellows Case Report Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: 10/22/2019 01:00 PM - 02:00 PM INTRODUCTION: ANCA associated vasculitis (AAV) refers to a group of serious and sometimes fatal autoimmune diseases. While certain drugs may cause ANCA seropositivity, only a minority develop clinical vasculitis. Pulmonary-renal syndrome (PRS) occurs very rarely in drug induced vasculitis, but requires prompt recognition and treatment to avoid fatal complications. We present a case of PTU-induced small vessel vasculitis causing pulmonary-renal syndrome. CASE PRESENTATION: 59 year old female with past history of diabetes, hypertension and hyperthyroidism on propylthiouracil (PTU) was admitted with chest pain, dyspnea and hemoptysis of one month duration. She was febrile (101˚F) with physical exam significant for bilateral lower extremity pitting edema, bilateral rhonchi and bibasilar crackles. ABG showed hypoxemia with a PaO2:FiO2 ratio of 132. CT scan of the chest showed bilateral multilobar consolidations for which empiric antibiotics were given. She was intubated for worsening hypoxemia. Bronchoalveolar lavage showed Acinetobacter baumanii and Klebsiella pneumoniae. Endobronchial biopsies showed chronic inflammation. Her creatinine was elevated at 3.5 mg/dL on admission and worsened to 5.2 gm/dL during her hospital course. Urinalysis showed hematuria and proteinuria. Renal ultrasound showed increased echogenicity of kidneys consistent with medical renal disease. Autoimmune workup showed Myeloperoxidase antibody level of 25.8 (normal<1.0) and Proteinase-3 antibody level of 2.7 (normal <1.0). Renal biopsy showed focal crescenteric and sclerosing glomerulonephritis, pauci-immune type concerning for drug-induced vasculitis. She was found to have PTU induced AAV causing PRS. She was given IV Solumedrol 500 mg for three days, followed by a tapering course of steroids. Her renal and pulmonary function improved. DISCUSSION: PTU induced AAV was first reported in 1992 and has become increasingly recognized. It remains a diagnosis of exclusion in the right clinical setting with appropriate seropositivity and supporting biopsy results. Patients may test positive for either MPO or PR3 antibodies, and in rare circumstances have dual seropositivity. It carries a better prognosis than primary AAV, and in some cases stopping the offending agent may induce disease remission. PRS remains a rare, but serious complication, which requires corticosteroids and immunosuppressive therapy. It can be treated with a shorter duration of immunosuppressive therapy and may not require maintenance therapy. CONCLUSIONS: This case raises awareness of Pulmonary Renal Syndrome as a result of drug-induced vasculitis, and the variations in seropositivity that may be seen with this entity. Clinicians are urged to carefully consider risks and benefits of these medications, and closely monitor patients receiving them. Prompt recognition, treatment and cessation of the offending agent can help avoid serious and sometimes fatal organ failure. Reference #1: Chen, M., Gao, Y., Guo, X. and Zhao, M. (2012). Propylthiouracil-induced antineutrophil cytoplasmic antibody-associated vasculitis. Nature Reviews Nephrology, 8(8), pp.476-483. Reference #2: Gao, Y. and Zhao, M. (2009). Review article: Drug-induced anti-neutrophil cytoplasmic antibody-associated vasculitis. Nephrology, 14(1), pp.33-41. Reference #3: Pendergraft, W. and Niles, J. (2014). Trojan horses: drug culprits associated with antineutrophil cytoplasmic autoantibody (ANCA) vasculitis. Current Opinion in Rheumatology, 26(1), pp.42-49. DISCLOSURES: No relevant relationships by Jagadish Akella, source=Web Response No relevant relationships by Javed Iqbal, source=Web Response No relevant relationships by Dolly Patel, source=Web Response No relevant relationships by Rishi Patel, source=Web Response

Prevalence and Clinical Significance of Antineutrophil Cytoplasmic Antibodies in North American Patients With Idiopathic Pulmonary Fibrosis

Antineutrophil cytoplasmic antibodies (ANCAs) have been reported to occur in 7%to 10%of patients with idiopathic pulmonary fibrosis (IPF), but their clinical relevance remains unclear. The aim of this study was to estimate the prevalence of ANCAs in a North American population with IPF and evaluate their clinical significance. This was a retrospective study of two independent cohorts of patients diagnosed with IPF at the University of California San Francisco (discovery cohort) and the University of Chicago (replication cohort). Myeloperoxidase (MPO) and proteinase 3 (PR3) ANCAs were measured in all patients. Prevalence and associations of ANCAs with clinical characteristics and transplant-free survival were evaluated. A total of 14 of 353 (4.0%; 95%CI, 2.2-6.5) and 20 of 392 (5.1%; 95%CI, 3.1-7.8) patients with IPF were positive for ANCAs at the time of diagnosis in the discovery and replication cohorts, respectively. Among those positive for MPO antibodies, two of six (33%) in the discovery cohort and three of 12 (25%) in the replication cohort developed vasculitis. None of the patients who were PR3-positive developed vasculitis. Patients who were ANCA-positive were more likely to be women than patients who were ANCA-negative, and were more likely to have some ground-glass opacities on CT scan. In the combined cohort of 745 patients, median transplant-free survival was not significantly different in patients who were ANCA-positive vsANCA-negative (P= .57). ANCA positivity is uncommon in North American patients with IPF and not associated with baseline disease severity or transplant-free survival; however, a significant proportion of patients who are MPO-positive with IPF develop clinical vasculitis.

Caracterización clínica, serológica y patrón radiológico de una cohorte unicéntrica de pacientes con enfermedad pulmonar difusa

Diffuse Lung Disease (DLD) is an important cause of morbidity and mortality, however in Chile we are lacking of epidemiological data on this condition. Our aim is communicate the first report of a prospective registry of DLD patients treated at bronchopulmonary unit of DIPRECA hospital. Methods: Cross-sectional study in patients referred to our bronchopulmonary unit under suspicion of DLD. Diagnosis was confirmed by chest computed tomography and informed consent was approved by patients. Data regarding clinical, serological, pulmonary function tests and echocardiography were collected from 2014 up to date. Results: 30 patients were analysed, their median of age was 76.5 years-old (Interquartile Range 68-80), 56.7% were women, median duration of disease: 4 years (IQR 1-10.6) and 43% has smoking history Most frequent signs and symptoms were crackles (97%), dyspnoea (90%) and cough (57%). Comorbidities: 3% had asthma, 3% chronic obstructive pulmonary disease and 6.7% connective tissue diseases. Radiological findings: 20% had DLD with usual interstitial pneumonia pattern (UIP), 23% DLD possible UIP, 30% DLD inconsistent with UIP, 14% chronic hypersensitivity pneumonitis and 13% nonspecific interstitial pneumonia. Serology: 18% had positive rheumatoid factor of which only one case had rheumatoid arthritis, 67% had positive antinuclear antibodies (ANA), 17% ANCA positive of which only one case of clinical vasculitis. Spirometry was mainly normal (52%) or restrictive (45%). Echocardiography showed pulmonary hypertension mainly mild in 52% of patients. No significant association was found between titles of ANA ≥ 1/320 and gender, smoking or radiological pattern. Conclusions: Our demographic and radiological findings are similar to those reported in literature; however, the highlights in our cohort are the increased frequency of female gender and positive ANA without history or clinical manifestation of connective tissue diseases.

A familial case of TRAPS in a Russian population

Tumor necrosis factor (TNF) receptor-1-associated periodic syndrome (TRAPS) is a classical autoinflammatory syndrome (AIS). The paper describes repeated cases of TRAPS in an ethnic Russian family. Molecular genetic examination of a 9-year-old boy, his mother and his grandmother has revealed the heterozygous mutation of c151C<T in exon 2 of the TNFRSF1 gene, which gives rise to amino acid substitution in pHis51Tyr protein sequencing. It is interesting that this mutation has been described in a North American population, but it has been encountered in only 2% of the patients with TRAPS in the European Registry (EuroTRAPS). This case alludes to the fact that in the Russian population there are families with TRAPS, which may have atypical mutations in the TNFRSF1A gene. Curiously, his mother and his grandmother were diagnosed with TRAPS only after its identification in the child (i. e. 34 and 45 years after the onset of the disease, respectively). Moreover, maternal blood tests permanently showed a pronounced increase in the acute-phase inflammatory markers missed by their local doctors. With each further generation, the family has exhibited an early onset of TRAPS and its progressively severer course with more time taken for its attacks. But if his mother and his grandmother had symptoms as erythema centrifugum, fasciitis, myalgias, and transient joint contractures, which are a distinguishing feature of this syndrome, the manifestations of the disease in the child were more non-specific. In the patient’s mother, the abovementioned characteristic symptoms of TRAPS occurred not at the onset of the disease, but just in adolescence. It is not inconceivable that if her son had not been adequately treated, he could also develop these symptoms with time. It is intriguing that the child was observed to have clinical hemorrhagic vasculitis, a condition associated with a number of AISs, primarily with familial Mediterranean fever. In this case, all the manifestations of the disease, including hemorrhagic vasculitis, were completely abolished in the child treated with the interleukin 1 inhibitor canakinumab.

Hydrophilic polymer embolism and associated vasculopathy of the lung: prevalence in a retrospective autopsy study

Hydrophilic polymers are commonly applied as surface coatings on vascular devices and have been shown to dissociate during endovascular use, causing hydrophilic polymer embolism (HPE). Adverse effects related to this phenomenon have been recognized and reported. The prevalence of this complication is unknown. We conducted a retrospective study to determine the prevalence of HPE among hospital autopsies over a 29-month period. Postmortem tissue was histologically evaluated for the presence, location(s) and extent of HPE. HPE findings were correlated with documented clinical and laboratory data and patient outcome. Of 136 hospital autopsies examined, 18 (13%) showed evidence of HPE involving the lungs (n = 18), heart (n = 1) or central nervous system (n = 1). Localized pulmonary HPE was seen in 12 patients (9%). Multifocal pulmonary HPE was found in 6 patients (4%) and was associated with clinical vasculitis (33%; P < .0001), suspected pulmonary ischemia (50%; P = .008), coagulopathy (67%; P = .002), and constitutional disease (83%; P = .01). Within affected lung, associated histopathologic changes included occlusive intravascular or perivascular inflammation (89%), intravascular fibrous response (56%), microthrombus formation (44%), vasculitis (28%), and/or pulmonary microinfarction (28%). Statistically significant differences in hospital days (P = .008) and number of vascular interventions (P = .01) were noted between affected and unaffected patients. We conclude that HPE is an underdiagnosed phenomenon with primary involvement of the lungs, where secondary vascular changes are common. Additional studies may be needed to clarify risks and to identify preventative strategies for this iatrogenic complication of catheterizations and "minimally invasive" endovascular techniques.

Epitope analysis of anti-myeloperoxidase antibodies in propylthiouracil-induced antineutrophil cytoplasmic antibody-associated vasculitis

IntroductionIncreasing 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.MethodsSix 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.ResultsCompared 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].ConclusionsLinear 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.

Cutaneous simulants of infectious disease

Many cutaneous conditions can mimic infection. If these lesions are not accurately recognized, they may be treated with antimicrobial agents, which adds cost, potential risk, and inconvenience to the patient and the healthcare system. The presenting signs and symptoms of many ulcerating, pustular, morbilliform, bullous, neoplastic, granulomatous, autoimmune, and neutrophilic conditions, as well as clinical vasculitis, cellulitis, folliculitis, and panniculitis, have been mistaken for infection. This review emphasizes the clinical presentation, physical exam, and diagnostic workup of many of these conditions to assist the clinician in ascertaining the correct diagnosis. In addition, general treatment options are provided for each disease category.

Peroxiredoxin 2 is a novel autoantigen for anti-endothelial cell antibodies in systemic vasculitis

Anti-endothelial cell antibodies (AECA) have been frequently detected in systemic vasculitis, which affects blood vessels of various sizes. To understand the pathogenic roles of AECA in systemic vasculitis, we attempted to identify target antigens for AECA comprehensively by a proteomic approach. Proteins extracted from human umbilical vein endothelial cells (HUVEC) were separated by two-dimensional electrophoresis, and Western blotting was subsequently conducted using sera from patients with systemic vasculitis. As a result, 53 autoantigenic protein spots for AECA were detected, nine of which were identified by mass spectrometry. One of the identified proteins was peroxiredoxin 2 (Prx2), an anti-oxidant enzyme. Frequency of anti-Prx2 autoantibodies, measured by enzyme-linked immunosorbent assay (ELISA), was significantly higher in systemic vasculitis (60%) compared to those in collagen diseases without clinical vasculitis (7%, P < 0·01) and healthy individuals (0%, P < 0·01). Further, the titres changed in parallel with the disease activity during time-courses. The presence of anti-Prx2 autoantibodies correlated significantly with elevation of serum d-dimers and thrombin-antithrombin complex (P < 0·05). Immunocytochemical analysis revealed that live endothelial cells expressed Prx2 on their surface. Interestingly, stimulation of HUVEC with rabbit anti-Prx2 antibodies increased secretion of interleukin (IL)-6, IL-1β, IL-1ra, growth regulated oncogene (GRO)-α, granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), IL-8 and monocyte chemoattractant protein (MCP)-1 more than twofold compared to that of with rabbit immunoglobulin (Ig)G. Taken together, our data suggest that anti-Prx2 autoantibodies would be a useful marker for systemic vasculitis and would be involved in the inflammatory processes of systemic vasculitis.

Correlations between plasma levels of a fibronectin isoform subpopulation and C-reactive protein in patients with systemic inflammatory disease

Surrogate markers to detect vasculitic processes prior to organ compromise are lacking. To determine if specific populations among the fibronectin (FN) family of alternatively spliced proteins correlate with parameters of vasculitis in at-risk patients, we retrospectively evaluated the association of plasma levels of total FN (TFN) and FN bearing the alternatively spliced EIIIA segment (A+FN) with clinical vasculitis status and with levels of two putative vasculitis markers (C-reactive protein (CRP) and von Willebrand factor) in a previously studied cohort of 27 patients with systemic inflammatory disease. We found that the percentage of TFN composed by A+FN (%A+) and A+FN, but not TFN, correlated with plasma levels of CRP, the prototypic inflammation biomarker used to detect vasculitis. These findings suggest that different FNs may confer distinct clinical information, and that their simultaneous measurement merits further investigation in our efforts to identify soluble biomarker systems to detect vasculitis.

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

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). 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. 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. Our study indicates that avidity of anti-MPO antibodies might be more closely associated with clinical vasculitis than titre.

The target antigens of antineutrophil cytoplasmic antibodies (ANCA) induced by propylthiouracil

ObjectiveAntineutrophil cytoplasmic antibody (ANCA) has been well documented in association with propylthiouracil (PTU), and some patients with PTU-induced ANCA also develop clinical vasculitis. The aim of the current study was to detect ANCA specificities in sera from patients with PTU-induced ANCA with and without clinical vasculitis. MethodsSera from 65 patients with PTU-induced ANCA were collected, and 27 of these patients were diagnosed with PTU-induced ANCA associated systemic vasculitis (AASV). Indirect immunofluorescence assay and antigen-specific ELISAs were used to detect ANCA and their antigen specificities. The seven known target antigens included myeloperoxidase (MPO), proteinase 3, human leukocyte elastase, lactoferrin, cathepsin G, azurocidin and bactericidal/permeability-increasing protein (BPI). ResultsIn IIF assay, P-ANCA was found in 58/65 (89.2%) sera, C-ANCA in two, both P-ANCA and C-ANCA in five, respectively. MPO (60%) and lactoferrin (63.1%) were the two most common target antigens detected in sera from all the patients. 25/27 sera from patients with PTU-induced AASV recognized multiple target antigens, which was significantly higher than those (13/38) from patients without (P<0.001). Except anti-BPI antibodies, the prevalence of antibodies against the other six target antigens was significantly higher in patients with clinical vasculitis than that in patients without (P<0.05, respectively). ConclusionAntibodies against multiple ANCA specific antigens, especially the antigens rather than MPO and PR3, might be the characteristic of PTU-induced ANCA. Patients with antibodies against more ANCA specific antigens might be at increased risk of developing overt clinical vasculitis. The mechanism of ANCA production in PTU-induced cases was different from that in primary AASV.

Titre and affinity of propylthiouracil-induced anti-myeloperoxidase antibodies are closely associated with the development of clinical vasculitis

Substantial evidences suggested that propylthiouracil (PTU) could induced anti-myeloperoxidase (MPO) antibodies in sera from patients with hyperthyroidism, however, only a subgroup of the PTU-induced anti-MPO antibody positive patients developed clinical evident vasculitis. The aim of this study is to compare the titres and affinities of PTU induced anti-MPO antibodies in sera from patients with hyperthyroidism with and without clinical vasculitis. Anti-MPO antibody positive sera from patients diagnosed hyperthyroidism with (n = 13) and without (n = 14) clinical evident vasculitis were collected. The titre was determined by MPO-ELISA and expressed as logarithm value (lgT). The affinity constant (aK) of anti-MPO IgG was measured by antigen inhibition assay. The titre and aK values were compared between patients with and without vasculitis. In patients with vasculitis, the mean lgT of anti-MPO antibodies was 3.62 +/- 0.66; the median aK was 4.47 x 10(7)M(-1). In patients without vasculitis, the mean lgT was 2.54 +/- 0.29; the median aK was 0.14 x 10(7)M(-1), and both were significant lower than those in patients with vasculitis (t = 5.464; P = 0.000 & z = -4.373; P = 0.000, respectively). We concluded that the titre and affinity of anti-MPO antibodies might be associated with the development of clinical vasculitis in patients with PTU-induced ANCA.

Epitope analysis of myeloperoxidase-specific antineutrophil cytoplasmic autoantibodies (MPO-ANCA) in childhood onset Graves’ disease treated with propylthiouracil

This study aimed to elucidate the relationship between epitope profiles and clinical manifestations of patients with myeloperoxidase antineutrophil cytoplasmic autoantibodies-(MPO-ANCA) positive childhood onset Graves' disease treated with propylthiouracil (PTU). Sixteen patients were studied. The patients were grouped into ten without clinical vasculitis and nephritis (non-vasculitis group) and six with biopsy-proven pauci-immune necrotizing crescentic glomerulonephritis (vasculitis group). Epitope analysis was performed on serum samples by an enzyme-linked immunosorbent assay (ELISA) using a panel of recombinant deletion mutants of MPO. The high frequency sites were region upstream of Met341 (Ha region) near the N-terminus of the heavy chain, and regions downstream of Gly598 (Hf and Hg regions) near the C-terminus. Most patients in the non-vasculitis group had polyclonal MPO-ANCA recognizing both the above linear sites and other epitope sites of the heavy chain of MPO. Only one of ten patients in the non-vasculitis group, and four of six patients in the vasculitis group had MPO-ANCA recognizing only the linear sites of the heavy chain of the MPO molecule (Ha, Hf and/or Hg). Of the four patients in the vasculitis group, two had nephritis, like rapidly progressive glomerulonephritis and one had alveolar hemorrhage. These findings suggest that most patients with childhood onset Graves' disease treated with PTU who manifest no vasculitis have polyclonal MPO-ANCA recognizing both the linear and other epitope sites of the heavy chain of MPO. However, some patients who develop nephritis have MPO-ANCA recognizing only the linear sites of the heavy chain of MPO. This clonality of MPO-ANCA may be a risk factor that induces clinical vasculitis and nephritis in patients treated with PTU. Therefore, patients exposed to PTU should be monitored for MPO-ANCA level and epitopes.

How to induce remission in primary systemic vasculitis

Systemic vasculitis is treatable but not curable. Combination therapy with corticosteroids and immune suppressives induces remission in approximately 90% of cases, and therapeutic regimens have been standardised by randomised controlled trials. Patient subgrouping at presentation reflects prognosis and influences the design of induction regimens. Ongoing problems are therapeutic toxicity, especially in the elderly, the quality of remission obtained and the need for long-term therapy to prevent relapse. Cyclophosphamide remains the most effective immune suppressive, and more recent protocols have minimised its toxicity. An increasing range of newer immune suppressives, and therapeutic recombinant proteins aimed at cytokine blockade or lymphocyte depletion, is emerging. Their correct evaluation and integration with current regimens to improve long-term outcome is the major challenge in clinical vasculitis research today.

Anti-endothelial cell antibodies (AECA) in patients with propylthiouracil (PTU)-induced ANCA positive vasculitis are associated with disease activity.

Increasing evidence has demonstrated that propylthiouracil (PTU) could induce ANCA positive vasculitis. However, our previous work has suggested that only one-fifth of the PTU-induced ANCA positive patients had clinical vasculitis and so the mechanism is not clear. Anti-endothelial cell antibodies (AECA) have been implicated in the pathogenesis of various vasculitides, including primary ANCA positive systemic vasculitis. The purpose of this study is to investigate the prevalence of AECA and their possible role in the pathogenesis of patients with PTU-induced ANCA positive vasculitis. Sera from 11 patients with PTU-induced ANCA positive vasculitis at both active and quiescent phases, and sera from 10 patients with PTU-induced ANCA but without clinical vasculitis, were studied. Sera from 30 healthy blood donors were collected as normal controls. Soluble proteins from 1% Triton-100 extracted in vitro cultured human umbilical vein endothelial cells were used as antigens and an immunoblotting technique was performed to determine the presence of AECA, and their specific target antigens were identified. In patients with PTU-induced ANCA positive vasculitis, 10 of the 11 patients in an active phase of disease were serum IgG-AECA positive and six protein bands of endothelial antigens could be blotted (61 kD, 69 kD, 77 kD, 85 kD, 91 kD and 97 kD). However, in the quiescent phase, seven of the 10 positive sera turned negative. None of the ANCA positive but vasculitis negative patients or normal controls were AECA positive. In conclusion, AECA could be found in sera from patients with PTU-induced ANCA positive vasculitis and were associated more closely with vasculitic disease activity.

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.

The clinical value of septal perforation biopsy.

Biopsy from the edge of a septal perforation is performed to diagnose potentially significant aetiological conditions, including malignant pathology and Wegener's granulomatosis. However, it is common for the histological result to be undiagnostic and unhelpful in planning an individual patient's management. To clarify the role of septal perforation biopsy, we reviewed all biopsies performed on our patients over a 13-year period. Of the 65 biopsies performed, in 63 patients, none had a histological result which changed the clinical diagnosis made before biopsy. Forty-three patients had clinically benign perforations biopsied, and no histology other than chronic inflammation was obtained. In 16 patients with a clinical vasculitis, none had this diagnosis confirmed histologically. One positive biopsy was obtained from two patients with clinically malignant perforations yet both were treated for T-cell lymphoma. The subsequent management of all patients was based on their clinical diagnosis rather than their biopsy results. We suggest only clinically malignant perforations are worthwhile biopsying.

Autoimmune vasculitis in MRL/Mp-lpr/lpr mice: orthochromatic basophils participate in the development of delayed-type hypersensitivity angiitis.

The pathogenesis of autoimmune vasculitis is poorly understood. Understanding the immunologic mechanisms governing this disease requires precise identification of the cells which comprise the lesion. In this report, we have evaluated tissue sections from MRL/lpr mice from 16 to 45 weeks of age, representing all stages of clinical vasculitis. We demonstrate that basophil myelocytes participate in the evolution of the delayed-type hypersensitivity (DTH) response which initiates and perpetuates autoimmune vasculitis in these mice. These findings raise questions regarding the immunologic mechanisms by which basophils develop in this lesion and the interaction of basophils. VSMCs and lymphocytes in vasculitic angiodestruction.