A case of renal limited myeloperoxidase anti-neutrophil cytoplasmic antibody-positive vasculitis treated with maintenance avacopan monotherapy.

A 76-year-old woman was admitted with progressive renal function decline. A kidney biopsy was performed because of myeloperoxidase anti-neutrophil cytoplasmic antibody (ANCA; 333 IU/mL), proteinuria (1.21 g/d), and urinary erythrocyte sediment (10-19/high-power field). Renal-limited ANCA-positive vasculitis with pauci-immune necrotizing crescentic glomerulonephritis (ANCA-associated vasculitis, AAV) was diagnosed. Glucocorticoid therapy was started, and the patient responded well. About 1 year later, avacopan treatment was started and glucocorticoid therapy was discontinued. Avacopan did not normalize ANCA levels and did not make urinary findings negative. However, further progression of renal function decline is prevented. Factors attributed to the development of AAV in this case were investigated; AAV developed after the second dose of the COVID-19 vaccine and ANCA levels re-elevated after the fifth dose. This suggests that the COVID-19 vaccine may have contributed to the development of AAV in this elderly patient. Avacopan monotherapy has been shown to be effective as maintenance therapy to control the progression of renal failure although not sufficient for complete remission of AAV.

Late-onset Neutropenia after Rituximab Treatment for MPO-ANCA-associated Vasculitis.

An underestimated side effect of rituximab is late-onset neutropenia (R-LON), which often resolves spontaneously and rarely results in a severe infection. We herein report a case of febrile neutropenia due to R-LON in a 91-year-old woman with renal failure who was treated with rituximab to induce remission of MPO-ANCA-associated vasculitis. Fifty-four days after the last rituximab administration, the patient was hospitalized for febrile neutropenia due to R-LON, which improved with granulocyte colony-stimulating factor and antibiotics. Although R-LON may resolve spontaneously and remain unnoticed, it can cause severe infections in the elderly and patients with renal failure.

ANCA-Positive Small-Vessel Vasculitis Following SARS-CoV-2 Vaccination-A Systematic Review.

As vaccinations against the SARS-CoV-2 virus have become a crucial tool in controlling the spread of the disease, reports of rare health complications have emerged, including new-onset antineutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitis (AAV). We systematically reviewed new-onset AAV following COVID-19 vaccination case reports and case series published in three databases before January 2024 following PRISMA guidelines to understand the characteristics of possible causal relationships or coincidences. In total, 404 articles were screened respectively by title, abstracts, and full-texts. Thirty-four papers fulfilled the inclusion criteria and have been analyzed, covering 44 patients with new-onset AAV after COVID-19 vaccination with no prior history of COVID-19 infection. Data regarding patients' metrics, comorbidities, vaccination characteristics, symptoms, diagnostics, treatment, and outcomes were investigated and summarized. The cohort consisted predominantly of females. AAV diagnosis was confirmed via biopsy, with renal dysfunction as a prevailing manifestation. In most cases, the first symptoms of AAV developed after the second dose; moreover, Pfizer-BioNTech was the most frequently administered vaccine among the analyzed cohort. Primary treatment involved glucocorticoid therapy, with a mostly favourable response. This systematic review aims to raise awareness among clinicians in the field regarding this rare but possible complication, to promote the prompt recognition and diagnosis of de novo ANCA-positive small-vessel vasculitis in timely association with SARS-CoV-2 vaccination.

Very Slowly Progressive Microscopic Polyangiitis: Comparative Analysis with Rapidly Progressive Forms.

Microscopic polyangiitis (MPA) is predominantly characterized by rapidly progressive glomerulonephritis (RPGN) associated with myeloperoxidase anti-neutrophil cytoplasmic antibodies (MPO-ANCA). Nonetheless, up to 30% of cases of ANCA-associated vasculitis (AAV) may exhibit a more indolent progression toward renal failure, an aspect less frequently discussed and understood in medical literature. This study seeks to clarify the clinical and pathological distinctions between the slowly and rapidly progressive forms of MPA, thereby enhancing understanding of their distinct pathogeneses and treatment responses. We conducted a comparative analysis of two patients diagnosed with MPA under the 2022 American College of Rheumatology/the European Alliance of Associations for Rheumatology (ACR/EULAR) classification. Evaluations included laboratory tests such as serum creatinine levels, serology for MPO-ANCA, and renal biopsies. Patient 1 exhibited a mere 1.07% decrease in estimated glomerular filtration rate (eGFR) over 6 months, significantly below the RPGN threshold, and demonstrated sclerotic glomerular pathology without active inflammation. This patient also showed lower levels of MPO-ANCA, Birmingham Vasculitis Activity Score (BVAS), and C-reactive protein. Conversely, Patient 2 experienced an 89.9% reduction in eGFR over the same timeframe, accompanied by acute systemic inflammation. The comparative clinical analysis of these cases illuminates clear differences in disease activity. Slowly progressive MPA is marked by lesser disease activity that fosters chronic inflammation, leading to a more gradual decline in renal function. Early diagnosis, facilitated by initial measurements of MPO-ANCA, can enhance disease management and improve patient outcomes.

A Systematic Review of Perinuclear Antineutrophil Cytoplasmic Antibody-Associated Glomerulonephritis Following Coronavirus Disease 2019 Vaccination: A 2024 Update.

Antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (GN) is an immune-mediated kidney disease characterized by the inflammation of small blood vessels in the kidney, leading to renal impairment and potentially irreversible damage. Concerns have been raised over the reports of myeloperoxidase/perinuclear (MPO/p) ANCA GN following the coronavirus disease 2019 (COVID-19) vaccination. Our study provides a comprehensive insight into perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) GN after COVID-19 vaccination. We conducted a comprehensive literature search on PubMed, Cochrane Library, and EMBASE using the Medical Subject Headings (MeSH) terms related to "covid-19 vaccine," "glomerulonephritis," "p-ANCA," and "MPO-ANCA" up to March 5, 2024, to include cases of p-ANCA-associated GN following COVID-19 vaccination. Of the 4,102 articles, we included 29, reporting 35 patients demonstrating COVID-19 vaccine-induced p-ANCA GN, with 23 (65.7%) females and a median age of 69 years (mean ± SD = 63.22 ± 16). Twenty-six (74.28%) patients received the mRNA vaccine (Pfizer = 19, Moderna = 7). Seventeen (48.57%) patients presented with p-ANCA GN after the second dose of the COVID-19 vaccine, with a median gap of 19 days (1-84 days). Constitutional symptoms (54.28%) and acute kidney injury (42.85%) were the most reported initial presentations, and elevated serum creatinine (mean peak serum creatinine = 4.98 ± 5.02 mg/dL), hematuria, and proteinuria were the laboratory findings. MPO/p-ANCA was positive in 31 (88.6%) patients. All patients underwent renal biopsy, and crescentic GN was the most common finding among 27 (77.14%) patients. Management of p-ANCA GN included steroids in 30 (85.71%) patients, followed by rituximab (28.57%), and plasmapheresis (22.86%). Most patients responded well to treatment, with complete remission in 29 (82.86%) and relapse in four (11.42%) patients. Two patients did not achieve remission and became dialysis dependent. ANCA-associated GN is a rare and life-threatening complication of the COVID-19 vaccine, necessitating urgent evaluation and management. COVID-19 vaccine-induced p-ANCA GN should be included in the differential diagnoses of patients presenting with kidney injury after vaccination.

Avacopan's potential to decrease MPO-ANCA titres concurrent with ameliorated activity in ANCA-associated vasculitis.

Avacopan, an orally administered C5a receptor antagonist, is effective in microscopic polyangiitis via the inhibition of neutrophil priming induced by C5a. However, the exact effect of avacopan on the production of myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) is yet to be clearly established. This report presents a microscopic polyangiitis patient without major organ damage where high levels of MPO-ANCA persisted with high-dose steroid therapy and azathioprine, but the addition of avacopan led to a reduction in MPO-ANCA titres. The present case implies that avacopan-mediated inhibition of C5a may lead to a reduction in MPO-ANCA levels, thereby potentially ameliorating the pathophysiology of ANCA-associated vasculitis. Nevertheless, the impact of avacopan on MPO-ANCA production cannot be asserted solely based on this report; therefore, further examination is necessary through subgroup analysis using data from larger-scale studies.

Presentation and progression of MPO-ANCA interstitial lung disease.

The association between MPO-ANCA-associated vasculitis (AAV) and interstitial lung disease (ILD) has been well established. Pulmonary fibrosis may coexist with, follow, or even precede the diagnosis of AAV, and its presence adversely affects the prognosis. The optimal approach to investigating ANCA in patients with ILD remains a subject of ongoing debate. Here we aim to describe presentation and progression of MPO-ANCA ILD. We conducted a retrospective evaluation of a cohort of individuals diagnosed with MPO-ANCA ILD, with or without accompanying renal impairment, at the Immunology and Cell Therapy Unit, Careggi University Hospital, Florence, Italy, between June 2016 and June 2022. Clinical records, imaging studies, pathologic examinations, and laboratory test results were collected. Among the 14 patients identified with MPO-ANCA ILD, we observed a significant association between MPO-ANCA titers assessed at the time of ILD diagnosis and renal involvement. Renal impairment in these cases often manifested as subclinical or slowly progressive kidney damage. Interestingly, complement C3 deposits were consistently found in all renal biopsy specimens, thereby suggesting the potential for novel therapeutic targets in managing renal complications associated with MPO-ANCA ILD. The presentation of MPO-ANCA vasculitis as ILD can be the first and only clinical manifestation. MPO-ANCA levels at ILD diagnosis could warn on the progression to renal involvement in patients with MPO-ANCA ILD, hence caution is needed because renal disease can be subclinical or smoldering.

An Unusual Presentation of Renal Failure: A Case of Myeloperoxidase-Antineutrophil Cytoplasmic Antibody (MPO-ANCA) Vasculitis.

Myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) vasculitis manifests as a neutrophilic inflammation impacting small vessels across multiple organs, notably the lungs, kidneys, and skin. We present a unique case of MPO-ANCA vasculitis in a 77-year-old female characterized by glomerulosclerosis, rapidly progressive renal failure necessitating hemodialysis (HD), bullous skin lesions, and hypoxic respiratory failure. The patient, who had a history of type 2 diabetes, presented with progressive dyspnea, hypoxia, and acute kidney injury superimposed on chronic kidney disease (CKD) progressing to renal failure requiring dialysis. A renal biopsy highlighted globally sclerosed glomeruli, interstitial fibrosis, and tubular atrophy, along with increased immunoglobulin M (IgM) deposits on immunofluorescence, differing from typical findings. Prompt initiation of prednisone led to respiratory and cutaneous improvement; however, despite therapy, extensive renal damage led to the permanent requirement of dialysis.  MPO vasculitis primarily targets small vessels, frequently affecting kidneys, with only a subset of patients progressing rapidly to end-stage renal failure necessitating HD, as observed in our case. Contrary to classical histopathological patterns, our patient exhibited augmented IgM deposits. Left untreated, MPO vasculitis with renal involvement poses a mortality risk of up to 90%, underscoring the significance of prompt detection and corticosteroid intervention to avert renal failure and improve patient outcomes. Early recognition and timely treatment are pivotal in mitigating the dire consequences of this condition, emphasizing the importance of considering MPO vasculitis in patients with rapidly deteriorating renal function.

A case of rapidly progressive glomerulonephritis with double-positive anti-GBM antibody and MPO-ANCA after SARS-CoV-2 vaccination and relapse during 1 year follow-up.

Although mRNA vaccines for COVID-19 are highly beneficial and are recommended for patients with kidney disease, adverse reactions in some patients after vaccination have been problematic. Various vasculitis and renal disorders have been reported after vaccination; however, a causal relationship has not yet been identified. In this report, we describe a case of rapidly progressive glomerulonephritis that developed after SARS-CoV-2 vaccination, in which both anti-glomerular basement membrane (anti-GBM) and myeloperoxidase antineutrophil cytoplasmic antibodies (MPO-ANCA) were present. The patient's renal biopsy showed that of the 48 glomeruli in total, four showed global sclerosis and none showed segmental sclerosis. The biopsy showed 11 cellular glomerular crescents and 5 fibrocellular glomerular crescents. Renal function improved with steroids, rituximab, and plasma exchange. Approximately 9 months later, MPO-ANCA was again elevated, and the pulmonary lesions worsened, again requiring multidisciplinary treatment. This case suggests that caution should be exercised in the development of double-positive disease after vaccination, and that long-term observation may be necessary because of the possibility of relapse.

A case of subarachnoid haemorrhage associated with MPO-ANCA-positive eosinophilic granulomatosis with polyangiitis, successfully treated with glucocorticoid, cyclophosphamide, and mepolizumab.

Subarachnoid haemorrhage (SAH) is a quite rare but serious central nervous system complication of eosinophilic granulomatosis with polyangiitis (EGPA). We report a case of myeloperoxidase antineutrophil cytoplasmic antibody-positive EGPA in which SAH developed during glucocorticoid induction pulse therapy for skin purpura, peripheral neuropathy, and rapidly progressive glomerulonephritis. In addition to high-dose glucocorticoid and intravenous cyclophosphamide, we administered mepolizumab, a humanised anti-interleukin-5 monoclonal antibody, and this resulted in remission of the SAH. Although the pathogenesis of SAH in EGPA is not fully understood, both necrotising vasculitis and eosinophilic inflammation are thought to be involved. In addition to prompt intensive immunosuppressive therapy, mepolizumab should be considered for SAH associated with EGPA.

Early transition to avacopan from glucocorticoids applied during induction therapy for microscopic polyangiitis with rapidly progressive glomerulonephritis.

Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is a systemic autoimmune disease characterized by necrotizing inflammation of small blood vessels. Glucocorticoids (GC) in combination with rituximab or cyclophosphamide can reduce AAV-related mortality and rescue renal function. However, several side effects associated with these agents, including GC toxicity, are concerning. Avacopan, an inhibitor of the C5a receptor, is now available for AAV treatment and is expected to mitigate GC toxicity. We present a case of myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)-positive microscopic polyangiitis (MPA) with rapidly progressive glomerulonephritis treated with an early switch from GC to avacopan in combination with rituximab during induction therapy. Over a 6-month treatment period, clinical remission was achieved and maintained without infection or elevated liver enzyme levels. Efficacy and safety data regarding avacopan for AAV induction therapy remain limited. Therefore, more case reports are required to clarify the role of avacopan in AAV induction and maintenance therapy. Since the MPO-ANCA titer remained elevated despite the clinical remission of AAV in this case, the ANCA titer may not necessarily be a reliable biomarker for predicting AAV relapse when avacopan is applied as an induction therapy for AAV.

Proteinase 3 Antibody and Anti-Double-Stranded DNA in a Patient With Immunoglobin Light Chain Amyloidosis.

Proteinase 3 (PR3) anti-neutrophil cytoplasmic antibodies (ANCA) and anti-double-stranded DNA (anti-dsDNA) antibodies have been associated with a variety of nephritic diseases, most recognizably granulomatosis with polyangiitis and systemic lupus erythematosus (SLE) glomerulonephritis, respectively. We report the first clinical case of positive PR3 and dsDNA in a patient with renal Immunoglobin light chain (AL) amyloidosis. A 75-year-old man presented to the hospital with chronic fatigue, weight loss, and a recent diagnosis of left ventricular infiltrative cardiomyopathy secondary to AL amyloidosis. Autoimmune serology was significant for PR3-ANCA and anti-dsDNA antibodies. A renal biopsy confirmed AL amyloidosis with diffuse Congo red stain. This case report is the first of its kind, showing atypical antibody presentation in the setting of amyloidosis.

Bruton's tyrosine kinase is a possible therapeutic target in microscopic polyangiitis.

BACKGROUND: Bruton's tyrosine kinase (Btk) is an enzyme expressed in leukocytes other than T lymphocytes and plasma cells and involved in B-cell receptor- and Fcγ receptor (FcγR)-mediated signal transduction. Btk inhibitors potentially suppress autoantibody production due to the expected inhibitory ability of B lymphocyte differentiation into antibody-producing plasma cells and reduce FcγR-mediated neutrophil activation, including the release of neutrophil extracellular traps (NETs). Microscopic polyangiitis (MPA) is a systemic small-vessel vasculitis characterized by the pathogenic autoantibody, antineutrophil cytoplasmic antibody (ANCA) that reacts with myeloperoxidase (MPO). MPO and MPO-ANCA immune complex (IC)-induced FcγR-mediated NETs are critically involved in MPA pathogenesis. This study aimed to demonstrate the therapeutic efficacy of the Btk inhibitor tirabrutinib on MPA. METHODS: Various doses of tirabrutinib or vehicle were orally administered to Sprague-Dawley rats daily. Four weeks later, the number of peripheral B lymphocytes was counted, and Btk phosphorylation in B lymphocytes was evaluated by flow cytometry. Human peripheral blood neutrophils were stimulated by MPO and anti-MPO antibody ICs (MPO and anti-MPO-ICs), and Btk and its downstream Vav phosphorylation were assessed by western blotting. The effects of tirabrutinib on MPO and anti-MPO-IC-induced NET formation were examined in vitro. Wistar Kyoto rats were immunized with human MPO to induce experimental MPA and given drug-free or tirabrutinib-containing feed (0.0037% or 0.012%) from day 0 or 28. All rats were euthanized on day 42 for serological and histological evaluation. RESULTS: Tirabrutinib inhibited Btk phosphorylation without decreasing B lymphocytes in vivo. Neutrophil Btk and Vav were phosphorylated when stimulated with MPO and anti-MPO-ICs. Tirabrutinib suppressed MPO and anti-MPO-IC-induced NET formation in vitro and ameliorated experimental MPA in a dose-dependent manner in vivo. Although MPO-ANCA production was not affected, NET-forming neutrophils in the blood were significantly reduced by tirabrutinib. CONCLUSIONS: The Btk inhibitor tirabrutinib suppressed MPO and anti-MPO-IC-induced NET formation in vitro and ameliorated experimental MPA by reducing NET-forming neutrophils but not decreasing MPO-ANCA titer in vivo. This study suggests that Btk is a possible therapeutic target in MPA.

Newly diagnosed ANCA-associated vasculitis after COVID-19 infection: a case report.

BACKGROUND: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a systemic autoimmune disease characterized by mononuclear cell infiltration and small and medium-sized blood vessel destruction leading to renal failure. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been shown to have the potential to induce the presentation or exacerbation of autoimmune disease. This report describes the clinical features of a case of newly diagnosed ANCA-associated vasculitis after COVID-19 Infection. CASE PRESENTATION: During the COVID-19 pandemic, a 67- year-old female Japanese was undergoing treatment for interstitial pneumonia, diabetes mellitus, and hypertension at her local doctor. About 2 months ago, she was diagnosed with COVID-19 and went to a hotel for treatment, and her condition improved. But a month later, after her COVID-19 infection, she presented with a fever and cough and visited Yodogawa Christian Hospital in Osaka, Japan. The reverse transcription-polymerase chain reaction was negative. She underwent extensive radiological and laboratory investigations. Serologies revealed a high perinuclear-ANCA titer with a specific anti-myeloperoxidase antibody titer of 31.7 units/mL. We suspected ANCA-associated vasculitis and performed a renal biopsy. Renal biopsy showed evidence of crescentic glomerulonephritis, which was consistent with ANCA-associated vasculitis. The patient was referred to the Department of Rheumatology and Clinical Immunology for steroid pulse and cyclophosphamide treatment. CONCLUSIONS: Delayed screening may lead to progression of the autoimmune disease, so prompt diagnosis is necessary. In this case, we could make an immediate diagnosis and refer the patient to the Department of Rheumatology and Clinical Immunology.

Case report: A pediatric case of MPO-ANCA-associated granulomatosis with polyangiitis superimposed on post-streptococcal acute glomerulonephritis.

An eight-year-old girl was admitted with vomiting, gross hematuria, and progressive renal dysfunction. A renal biopsy revealed endocapillary proliferative glomerulopathy and crescent formation. Immunofluorescence staining revealed diffuse granular deposits of IgG and C3. Post-streptococcal acute glomerulonephritis (PSAGN) was suspected, based on the elevated anti-streptolysin O levels, decreased serum C3 concentrations, and histologic findings. The myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) test was positive, and the young patient gradually developed palisaded neutrophilic and granulomatous dermatitis (PNGD), orbital and paranasal sinus granulomatous neoplasms, along with intermittent nose, head, and orbital pain. Finally, she was diagnosed with the rare MPO-ANCA-associated granulomatosis with polyangiitis (GPA) superimposed on PSAGN. The patient was treated with aggressive renal replacement therapy, methylprednisolone pulse therapy, and intravenous pulse cyclophosphamide; her renal function normalized, and her pain symptoms improved.

Clinical and Prognostic Significance of p-ANCA Positivity in Idiopathic Pulmonary Fibrosis: A Retrospective Observational Study.

Perinuclear Anti Neutrophil Cytoplasmic Antibody (p-ANCA) is a serological marker of Microscopic Polyangiitis (MPA), a vasculitis associated with lung involvement potentially mimicking Idiopathic Pulmonary Fibrosis (IPF). In this study, we evaluated the role of p-ANCA in predicting clinical evolution and prognosis in a cohort of IPF patients. In this observational, retrospective, case-control study, we compared 18 patients with an IPF diagnosis and p-ANCA positivity with 36 patients with seronegative IPF, matched for age and sex. IPF patients with and without p-ANCA showed similar lung function decline during the follow-up, but IPF p-ANCA+ showed better survival. Half of IPF p-ANCA+ patients were classified as MPA for the development of renal involvement (55%) or skin signs (45%). The progression towards MPA was associated with high levels of Rheumatoid Factor (RF) at baseline. In conclusion, p-ANCA, mainly when associated with RF, could predict the evolution of Usual Interstitial Pneumonia (UIP) towards a definite vasculitis in patients, with a better prognosis compared with IPF. In this view, ANCA testing should be included in the diagnostic workup of UIP patients.

Clarithromycin-induced eosinophilic granulomatosis with polyangiitis: A case report.

A 75-year-old man presented to our hospital with chronic sinusitis, bronchiectasis, and chronic lower respiratory tract infections. He began taking erythromycin in August, X-2. The chronic lower respiratory tract infection gradually worsened, and clarithromycin was started on May 11, X. He became aware of fever and numbness in his lower legs on June 4, X. The sign occurred soon after oral clarithromycin and blood tests showed an elevated eosinophil count and C-reactive protein (CRP) levels, positive MPO-ANCA antibodies, and positive for drug-induced lymphocyte stimulation test (DLST); we diagnosed eosinophilic granulomatosis with polyangiitis (EGPA) associated with clarithromycin administration.

Clinical characteristics and primary outcomes of patients with ANCA-associated vasculitis and central diabetes insipidus.

Introduction: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is characterized by systemic small-vessel vasculitis and may rarely present as central diabetes insipidus (CDI). In this study, we aimed to determine the clinical characteristics and prognosis of patients with AAV-associated CDI. Methods: This was a nested case-control study where AAV patients with CDI at the Peking Union Medical College Hospital were followed from January 2012 to April 2022. Case-control matching with AAV patients without CDI was performed (1:5), and participants were matched by age, sex, and AAV classification. We collected clinical data every 3-6 months and conducted a literature review using PubMed to identify relevant articles published from 1983-2022. Results: Among 1203 hospitalized AAV patients, 16 patients with CDI were included (1.3%). The average age was 49 years, and men accounted for 56.3%. Granulomatosis with polyangiitis (GPA) accounted for 87.5% of patients. AAV patients with CDI had more ear, nose, and throat (ENT) (81.3%) involvement and less renal impairment than those in the control group (P<0.05). After a mean follow-up of four years, 50% of patients were in remission from AAV, 37.5% relapsed, and 12.5% died. Our literature review suggested that patients in Asian countries tend to be older men and have higher myeloperoxidase (MPO-ANCA) positivity than those in Western countries. Furthermore, proteinase 3 (PR3-ANCA) positivity may predict disease recurrence. Discussion: AAV patients with CDI had more ENT involvement and a higher eGFR. MPO-ANCA positivity is more commonly observed in Asian countries than Western countries, and PR3-ANCA positivity may predict recurrence.

Association of HLA-class II alleles with risk of relapse in myeloperoxidase-antineutrophil cytoplasmic antibody positive vasculitis in the Japanese population.

Background: Disease relapse remains a major problem in the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). In European populations, HLA-DPB1*04:01 is associated with both susceptibility and relapse risk in proteinase 3-ANCA positive AAV. In a Japanese population, we previously reported an association between HLA-DRB1*09:01 and DQB1*03:03 with susceptibility to, and DRB1*13:02 with protection from, myeloperoxidase-ANCA positive AAV (MPO-AAV). Subsequently, the association of DQA1*03:02, which is in strong linkage disequilibrium with DRB1*09:01 and DQB1*03:03, with MPO-AAV susceptibility was reported in a Chinese population. However, an association between these alleles and risk of relapse has not yet been reported. Here, we examined whether HLA-class II is associated with the risk of relapse in MPO-AAV. Methods: First, the association of HLA-DQA1*03:02 with susceptibility to MPO-AAV and microscopic polyangiitis (MPA) and its relationship with previously reported DRB1*09:01 and DQB1*03:03 were examined in 440 Japanese patients and 779 healthy controls. Next, the association with risk of relapse was analyzed in 199 MPO-ANCA positive, PR3-ANCA negative patients enrolled in previously reported cohort studies on remission induction therapy. Uncorrected P values (Puncorr) were corrected for multiple comparisons in each analysis using the false discovery rate method. Results: The association of DQA1*03:02 with susceptibility to MPO-AAV and MPA was confirmed in a Japanese population (MPO-AAV: Puncorr=5.8x10-7, odds ratio [OR] 1.74, 95% confidence interval [CI] 1.40-2.16, MPA: Puncorr=1.1x10-5, OR 1.71, 95%CI 1.34-2.17). DQA1*03:02 was in strong linkage disequilibrium with DRB1*09:01 and DQB1*03:03, and the causal allele could not be determined using conditional logistic regression analysis. Relapse-free survival was shorter with nominal significance in carriers of DRB1*09:01 (Puncorr=0.049, Q=0.42, hazard ratio [HR]:1.87), DQA1*03:02 (Puncorr=0.020, Q=0.22, HR:2.11) and DQB1*03:03 (Puncorr=0.043, Q=0.48, HR:1.91) than in non-carriers in the log-rank test. Conversely, serine carriers at position 13 of HLA-DRß1 (HLA-DRß1_13S), including DRB1*13:02 carriers, showed longer relapse-free survival with nominal significance (Puncorr=0.010, Q=0.42, HR:0.31). By combining DQA1*03:02 and HLA-DRß1_13S, a significant difference was detected between groups with the highest and lowest risk for relapse (Puncorr=0.0055, Q=0.033, HR:4.02). Conclusion: HLA-class II is associated not only with susceptibility to MPO-AAV but also with risk of relapse in the Japanese population.

C-Reactive Protein Levels Are Associated with Complement C4 Deposits and Interstitial Arteritis in ANCA-Associated Renal Vasculitis.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a potentially life-threatening systemic small-vessel vasculitis that is characterized by pauci-immune glomerulonephritis in case of kidney involvement, representing a major denominator of AAV mortality. Innate immunity with complement system activation is increasingly recognized in the pathogenesis of AAV and as an attractive therapeutic target. Although C-reactive protein (CRP) was thought to be a passive, nonspecific marker of inflammation, recent studies indicate that CRP plays a key role in the innate immune system by recognizing pathogens and altered self-determinants. Elevated baseline CRP at disease onset of AAV has already been described as a determinant of poor long-term outcomes. However, its clinical implications at disease onset of AAV, with respect to vasculitis manifestations and complement system activation that might also affect long-term outcomes, remain elusive. CRP levels were retrospectively analyzed in 53 kidney-biopsy-confirmed cases of ANCA-associated renal vasculitis; a total of 138 disease controls were also evaluated. Univariate and multivariate regression analysis was performed on clinicopathological parameters associated with CRP levels in ANCA-associated renal vasculitis. Results: Compared to disease controls, CRP elevation was common in ANCA-associated renal vasculitis and associated with de novo disease (p = 0.0169), critical illness (p = 0.0346), and severe deterioration of kidney function (p = 0.0167), independent of extrarenal disease manifestations. As confirmed by multiple regression analysis, CRP levels were correlated with active lesions predominated by interstitial arteritis in renal vasculitis, specifically with MPO-ANCA seropositivity (p = 0.0017). Based on analysis of systemic complement system activation and intrarenal complement deposits, CRP elevation was correlated specifically with complement C4 deposits in interstitial arteries in the subgroup with myeloperoxidase (MPO)-ANCA seropositivity (p = 0.039). Finally, this association was independent of systemic complement system activation, as reflected by the consumption of respective complement components. Here, we expand our current understanding of CRP in ANCA-associated renal vasculitis not only as an inflammatory marker, but potentially also as being involved in the pathogenesis of kidney injury by interaction with the complement system.