Antineutrophil Cytoplasm Research Articles

Successful outcome of pregnancy in patients with anti-neutrophil cytoplasm antibody–associated small vessel vasculitis

Pregnancy in patients with anti-neutrophil cytoplasm antibody-associated vasculitis is reportedly associated with a high risk of fetal and maternal complications. Here we describe the outcome of pregnancies in patients with granulomatosis with polyangiitis and microscopic polyangiitis at five centers in the United Kingdom using a retrospective case review of all women who became pregnant following diagnosis. We report 15 pregnancies in 13 women resulting in 15 live births including one twin pregnancy and 13 singleton pregnancies. One patient had an unplanned pregnancy and a first trimester miscarriage while taking methotrexate. All other pregnancies were planned following a minimum of 6 months clinical remission. Eleven successful pregnancies were delivered vaginally at full term, whereas three were delivered by cesarean section. All infants were healthy with no neonatal complications on their initial health check within the first 24 h of delivery and no evidence of neonatal vasculitis. One relapse occurred during pregnancy and was successfully treated with an increased dose of azathioprine and corticosteroids, intravenous immunoglobulin, and plasma exchange therapy. One patient developed tracheal crusting and subglottic stenosis of infective etiology in the third trimester requiring tracheal debridement post delivery. No patient had a relapse in the first 12 months postpartum. Thus, successful pregnancy outcomes can occur following planned pregnancy in women in sustained remission on non-teratogenic therapies.

Skewed Fc glycosylation profiles of anti-proteinase 3 immunoglobulin G1 autoantibodies from granulomatosis with polyangiitis patients show low levels of bisection, galactosylation, and sialylation.

Granulomatosis with polyangiitis (GPA) is associated with circulating immunoglobulin (Ig) G anti-proteinase 3 specific (anti-PR3) anti-neutrophil cytoplasm antibodies (ANCA), which activate cytokine primed neutrophils via Fcgamma receptors. ANCA are class switched IgG antibodies implying T cell help in their production. Glycosylation of IgG Fc, under the control of T cell cytokines, determines the interaction between IgG and its receptors. Previous studies have reported aberrant glycosylation of Ig Fc in GPA patients. We investigated whether aberrant Fc glycosylation was present on anti-PR3 ANCA as well as whole IgG subclass preparations compared to healthy controls and whether this correlated with Birmingham vasculitis activity scores (BVAS), serum cytokines, and time to remission. Here, IgG Fc glycosylation of GPA patients and controls and anti-PR3 ANCA Fc glycosylation were determined by mass spectrometry of glycopeptides. IgG1 and IgG2 subclasses from GPA patients showed reduced galactosylation, sialylation, and bisection compared to healthy controls. Anti-PR3 IgG1 ANCA Fc galactosylation, sialylation, and bisection were reduced compared to total IgG1 in GPA. Galactosylation of anti-PR3 ANCA Fc correlated with inflammatory cytokines and time to remission but not BVAS. Bisection of anti-PR3 ANCA Fc correlated with BVAS. Total IgG1 and anti-PR3 IgG1 Fc galactosylation were weakly correlated, while bisection of IgG1 and anti-PR3 showed no correlation. Our data indicate that aberrant ANCA galactosylation may be driven in an antigen-specific manner.

High interpatient variability in response to mycophenolic acid maintenance therapy in patients with ANCA-associated vasculitis.

Mycophenolic acid (MPA) is used in the maintenance therapy of antineutrophil cytoplasm antibody-associated systemic vasculitis (AASV). MPA exerts its immunosuppression by inhibiting inosine 5'-monophosphate dehydrogenase (IMPDH), depleting activated lymphocytes of guanine nucleotides and retarding their proliferation. The purpose of our study was to examine the correlation between clinical outcome and pharmacokinetic-pharmacodynamic (PD) relationships of MPA in patients with AASV. We studied 358 Caucasian control patients without any MPA therapy to examine basal IMPDH activity. Thirty Caucasian patients with AASV under maintenance therapy with mycophenolate mofetil (MMF) underwent therapeutic drug monitoring. We observed a high interindividual variability with regard to basal IMPDH activity in patients without any MPA treatment (0.8-35 nmol/mg protein/h). Patients were followed for a mean (±SD) period of 22 ± 8 months. During the observation period, seven patients had a relapse with an elevated Birmingham Vasculitis Activity Score of 9.2 ± 6. The basal IMPDH activity (Abasal) in patients who subsequently relapsed was raised at baseline, before receiving their first dose of MMF, and further increased at the time of relapse, when compared with stable patients. Patients with a relapse during the maintenance therapy had significantly higher levels of IMPDH activity [IMPDH enzyme activity curve (AEC) (0-12)] than stable patients (P = 0.001), indicating inadequate IMPDH suppression. MPA-AUC (0-12) was significantly decreased in relapse patients, in contrast to stable patients (P < 0.05). Due to the highly variable response to maintenance therapy with MPA, PD drug monitoring is a new tool for detecting inadequate immunosuppression in AASV patients.

Favourable renal survival in paediatric microscopic polyangiitis: efficacy of a novel treatment algorithm.

Microscopic polyangiitis (MPA) is one of the most common forms of antineutrophil cytoplasm autoantibodies (ANCA)-associated vasculitis in children. Cyclophospamide and glucocorticoid-based treatment protocols are still considered gold standard in managing this multi-system disorder. But treatment-related toxicity is a major cause of chronic morbidity and early mortality in MPA. Hence, the search for an effective and safe alternative immunosuppressant is essential. A retrospective analysis of baseline clinico-pathological presentation and treatment-outcome was performed among 11 paediatric MPA patients. All of whom were treated with a pre-specified cyclophosphamide free, rituximab- and mycophenolate mofetil (MMF)-based management protocol as per centre practice. We describe the clinical course of 11 children with MPA over a median follow-up period of 20.9 months. Both patient survival and renal survival at 1 year follow-up were 100%. In spite of the varying degree of renal involvement at presentation, kidney function was recovered in all patients with a median estimated glomerular filtration rate (eGFR) of 79.5 mL/min/1.73 m(2). At last follow-up, 91% (10/11) of patients were in complete remission and one (9%) child continued partial remission state. There was no treatment failure. In total, 73% (8/11) of patients were off steroids at last follow-up and 82% (9/11) of patients never relapsed during follow-up period. Efficacy and medium-term safety of rituximab- and MMF-based protocol in managing children with MPA was evident in this study.

Long-term Outcomes of Rituximab Therapy in Ocular Granulomatosis with Polyangiitis: Impact on Localized and Nonlocalized Disease

To evaluate the long-term outcomes of rituximab (RTX) treatment in patients with ocular granulomatosis with polyangiitis (GPA) with localized or generalized disease. Retrospective cohort. Thirty-seven patients with ocular GPA receiving RTX in a multidisciplinary vasculitis clinic between 2004 and 2013. A total of 100 patients who received a course of RTX were identified, and notes were reviewed. Baseline demographic details, clinical characteristics (including organ involvement), drugs used, and outcome measures were recorded. The percentage in remission (inactive disease with prednisolone ≤7.5 mg with or without maintenance treatment) at 6 months, time to remission, percentage relapsing, side effects, B-cell count, antineutrophil cytoplasm antibody titers, induction, and maintenance regimens. The median follow-up time after the first RTX course was 36.5 months. Twenty patients had scleritis, and 17 patients had orbital disease; 86% achieved remission at 6 months. The percentage in remission versus partial remission was not statistically significant between patients with scleritis and patients with orbital disease (85% vs. 15% with scleritis and 82% vs. 18% with orbital disease; P = 1.00). The percentage relapsing was not statistically significant (P = 0.33) between scleritis (60%) and orbital disease (41%). Localized disease (ocular ± ear-nose-throat/lung) was observed in 57%, and generalized disease (ocular plus other organs) was observed in 43%, the former having a median duration of disease of 40 months. There was no statistically significant difference (P = 0.37) in the percentage in remission between localized and generalized ocular disease. Relapses occurred in 51%, with localized disease being a significant risk factor for relapse. Fifty percent of patients with generalized disease versus none with localized disease received cyclophosphamide (CYP) as part of the induction regimen. Patients who received CYP during induction had significantly (P = 0.027) lower ratios of baseline 12-month proteinase 3 titers than patients who did not have CYP. Infections were observed in 16% of patients, with 8% requiring hospital admission. Our long-term data suggest that RTX is effective for inducing disease remission in localized and generalized ocular GPA. Localized disease is a significant risk factor for relapse, which may be related to less use of CYP in the induction regimen.

Frequency, risk factors and prophylaxis of infection in ANCA-associated vasculitis.

Antineutrophil cytoplasm antibody (ANCA)-associated vasculitides are potentially life-threatening disorders. Even though immunosuppressive therapy improves the prognosis, adverse events, either attributable to persistent disease activity or side effects of treatment remain a challenge. Infectious complications are the leading cause of death in the first year after diagnosis and a major cause of morbidity and mortality thereafter. Their incidence in clinical trials varies considerably but opportunistic and life-threatening infections, such as Pneumocystis jirovecii pneumonia or systemic cytomegalovirus infections, are frequent and thus predisposing/risk factors need to be defined. Pneumocystis jirovecii pneumonia has been associated with a lymphocyte count below 300/mm(3) . Additionally, besides the aggressiveness of the immunosuppressive regimen administered (especially the cumulative dose of steroids and cyclophosphamide), an elevated serum creatinine or dialysis dependency, older age and pulmonary involvement increase the rate of infectious complications. We suggest to routinely prescribe trimethoprim-sulfamethoxazole or antimicrobial agents such as pentamidine in case of intolerance or contraindication in the early phase of induction therapy irrespective of the immunosuppressive strategy used and to continue therapy, together with other targeted measures (antiviral, antimycotic or antibiotic) in the presence of risk factors for a prolonged period of time. Finally, there is an urgent need to standardize the reporting of infectious complications in clinical trials to enable comparing the adverse event spectrum of distinct treatment approaches more appropriately.

Disease assessment in systemic vasculitis

The anti-neutrophil cytoplasm antibody-associated vasculitides are complex multi-system disorders with many overlapping clinical features. Their outcome has been transformed by effective immunosuppression, preventing death in over 70% of cases. The quality of survival is affected by the disease course, which is characterized by a significant likelihood of relapse in 38%, chronic effects from the disease and its treatment, as well as emerging or worsening comorbidity, all of which contribute to the patient's clinical condition and outcome. Whilst imaging and laboratory testing including histology are important aspects of diagnosis, they are of limited value in assessing response to therapy or subsequent disease course. We have developed standardized validated clinical methods to quantify disease activity and damage; we are developing effective measures of patient experience to complement these procedures. This approach provides a rational basis for clinical management as well as being essential in the conduct of clinical trials and studies in vasculitis, by providing reproducible definitions of relapse, remission and response to therapy for patients with systemic vasculitis. Clinical assessment remains the current gold standard for evaluating disease progress, but requires regular training to ensure standardization. The development of biomarkers in future may produce a more accurate description of disease and identify potential targets for therapy as well as predictors of response to drugs.

CD4+CD28– T-cell expansions in ANCA-associated vasculitis and association with arterial stiffness: baseline data from a randomised controlled trial

BackgroundCardiovascular risk is increased in the anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV). CD4+CD28– T cells are expanded in patients with AAV who are seropositive for cytomegalovirus (CMV), and are associated with increased mortality. CMV seropositivity in other conditions is associated with arterial stiffness, a marker of cardiovascular risk. We assessed whether CD4+CD28– T cells in CMV seropositive patients with AAV are associated with arterial stiffness and whether treatment with valaciclovir reduces this cell population. MethodsIn this open-label phase 2 trial, patients were randomised (1:1) by computer to valaciclovir (8 g daily) or no additional treatment for 6 months. Primary outcome was proportion of patients with CMV reactivation. Arterial stiffness (carotid to femoral pulse wave velocity [PWV]) was measured and peripheral blood CD4+CD28– T cells analysed by flow cytometry at baseline and 6 months. CD4+CD28– T-cell interferon γ (IFNγ) secretion was stimulated with CMV lysate. Data are presented as median (IQR). Between-group differences were tested by Mann-Whitney U test and correlations by Spearman's rank. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01633476. FindingsBaseline data are presented from the first 28 patients enrolled, with 6 months' follow-up completed in five treatment and six control patients. More CD4+CD28– than CD4+CD28+ T cells expressed T-bet (83·5% [47·5–89·9] vs 12·9 [4·7–22·2], p<0·0001) and secreted IFNγ after stimulation (14·3% [8·4–26·0] vs 0·8 [0·2–1·3], p<0·0001). CX3CR1, a cell surface marker whose expression is associated with endothelial dysfunction, was only expressed on CD4+CD28– T cells. The proportion of CD4+CD28– T cells correlated with PWV (r=0·408, p=0·035). At 6 months, reduction in proportion of CD4+CD28– T cells was greater in the treatment than in the control group (−1·8% [–5·2 to −0·6] vs 0·5 [–0·8 to 2·5], p=0·044). InterpretationThese preliminary results suggest that CD4+CD28– T cells in AAV are proinflammatory cells with high expression of the fractalkine receptor CX3CR1 that has been implicated in endothelial dysfunction. This cell population is associated with arterial stiffness, and its expansion is attenuated with valaciclovir treatment. This research has important implications, because cardiovascular disease is a major cause of mortality in AAV. FundingWellcome Trust, Vasculitis UK.

Getting the balance right: adverse events of therapy in anti-neutrophil cytoplasm antibody vasculitis.

Antineutrophil cytoplasm antibody associated systemic vasculitides (AASV) have traditionally been managed with a combination of cyclophosphamide and glucocorticoids during the induction phase, followed by azathioprine in the maintenance phase. Whilst these therapies have markedly improved the prognosis in AASV, treatment related adverse events remain a major challenge and include complications such as infection, glucocorticoid related side effects, malignancy, cardiovascular disease, infertility and death. Newer biologic therapies have been shown to demonstrate equivalent efficacy as cyclophosphamide for remission but the hoped for reduction in adverse events has yet to be realised. More recent efforts have been focused on refining existing therapeutic regimens and strategies, tailoring individual treatment to disease severity, patient age and kidney function to derive maximum treatment efficacy while minimising treatment toxicity. In particular, current interventional trials are targeting a reduction in corticosteroid exposure in an effort to make induction and maintenance regimens safer.

Ear, nose, and throat involvement in eosinophilic granulomatosis with polyangiitis

Eosinophilic granulomatosis with polyangiitis (EGPA) is the rarest of the anti-neutrophil cytoplasm antibody (ANCA)-associated small-vessel vasculitides. In Europe, its prevalence ranges from 10 to 15/million and annual incidence from 0.9 to 1.2/million. EGPA affects men and woman equally, with a mean age of 50 years at diagnosis. The most characteristic features include late-onset asthma, pulmonary infiltrates, mono- or polyneuropathy, and peripheral and extravascular eosinophils. Ear, nose, and throat (ENT) manifestations are particularly frequent, occurring in 30–80% of patients and most often early in the disease process. ENT features include allergic rhinitis, chronic sinusitis and polyposis, lacrimal and salivary gland involvement, otitis media and, rarely, cranial nerve involvement. The diagnosis of EGPA may be relatively straightforward in the 30–40% of ANCA-positive patients and in those with biopsies demonstrating vasculitis, but it can be more challenging, or even debatable, in ANCA-negative patients who do not present clear evidence of vasculitis. Because EGPA is a multisystem disease, it requires a multidisciplinary approach for diagnosis and management, including by an otolaryngologist. Keywords: vasculitis; eosinophilic granulomatosis with polyangiitis; Churg-Strauss syndrome; hypereosinophilia; ANCA (Published: 1 April 2015) Citation: Advances in Cellular and Molecular Otolaryngology 2015, 3: 27181 - http://dx.doi.org/10.3402/acmo.v3.27181

Heart transplantation in a patient with eosinophilic granulomatosis with polyangiitis known as Churg-Strauss syndrome

Eosinophilic granulomatosis with polyangiitis (EGPA), also known as Churg-Strauss syndrome, is a rare systemic necrotizing vasculitis affecting smallto medium-sized vessels. EGPA is associated with severe asthma and eosinophilia. The most frequently involved organs are skin and peripheral nerves; however, EGPA may involve other organs, such as the gastrointestinal tract, kidney, and heart. Antineutrophil cytoplasm antibodies (ANCAs)-related abnormal immune reactions are known to be associated with EGPA, but only 30%–40% of patients have a positive marker of ANCA. ANCA-negative patients are at higher risk of cardiac involvement than ANCApositive patients. Cardiac involvement is one of the leading causes of mortality and could be resistant to conventional treatment. Early treatment with steroid plus cyclophosphamide is important because it could give chances of restoration of cardiac function. For patients undergoing heart transplantation, we should consider the severity of cardiac disease and the presence of systemic diseases, including vasculitis. Here, we report a case of a 25-year-old EGPA patient with cardiac involvement who eventually received heart transplantation for progressive heart failure, although treated with systemic corticosteroid with cyclophosphamide. EGPA patients undergoing heart transplantion are rarely reported worldwide, and this is the first case report in Korea. (Allergy Asthma Respir Dis 2015;3:159-163)

Retiform purpura caused by the use of cocaine, that was probably adulterated with levamisole.

Dear Editor: Retiform purpura is a dermatological condition characterized by reticulated, stellate, or serpentine shaped purple lesions on the skin and mucous membranes. New, multiple cases of retiform purpura after the use of levamisole adulterated cocaine have been reported. Levamisole is an anthelmintic drug with immunomodulatory and immunostimulating properties. It has been used in humans to treat rheumatoid arthritis, cancer of the colon and nephritic syndrome in children. It was withdrawn from use in the United States in 2000 because of the risk of agranulocytosis1. We report the case of a 52-year-old woman receiving treatment with levothyroxine for hypothyroidism. Two days after consuming cocaine, she developed painful skin lesions with arthralgia on both wrists. Physical examination revealed plaques and papules infiltrated to touch, purpuric on the edges and necrotic in the center, with reticular and stellate lesions on both cheeks, the tip of the nose, outer left ear, and lower limbs (Fig. 1). Biopsy revealed thrombotic vasculopathy of the small and medium blood vessels in the dermis and subcutaneous cell tissue (Fig. 2). Blood tests revealed leukopenia, neutropenia, and lymphopenia. Antinuclear antibodies (ANA, titer 1 : 1.280) in anti-neutrophil cytoplasm antibodies (ANCAs) against myeloperoxidase with a p-ANCA pattern (titer, >100 [0~5]), and ANCAs against proteinase 3 with a c-ANCA pattern (titer, 6.8 [0~5]) were also found. Hypocomplementemia of C3 was detected. The tests for thrombosis and coagulation, serology, cryoglobulins and antiphospholipid antibodies were normal or negative. Cocaine was detected in the urine sample. The results of chest radiography and urine sediment test were normal. A diagnosis of retiform purpura resulting from the use of cocaine, that was probably adulterated with levamisole was made. She was prescribed with low dose oral prednisone. The hematological symptoms cleared 5 days later, after one month, the skin lesions had healed without sequelae. Fig. 1 (A) A reticular plaque with purpuric edges and necrotic center on the left cheek. (B) Reticular and stellate plaques with purpuric edges and necrotic center on low limbs. Fig. 2 Hematoxylin-eosin staining image (×10) showing thrombotic vasculopathy of the small and medium blood vessels in the dermis and subcutaneous cell tissue. Levamisole is currently only used in veterinary medicine as an anthelmintic; however, it has recently begun to be used as an adulterant in cocaine in many countries, including Spain2. Levamisole poisoning should be suspected in the case of a young patient presenting bilateral cutaneous necrosis on the earlobes, cheeks, or nose, that may be accompanied with retiform purpura lesions, primarily on the legs3. There may also be signs of arthralgia, fatigue, and general malaise. In the literature, some cases showing convulsions, kidney failure, or pulmonary haemorrhage have also been reported. The most common alterations in laboratory tests are neutropenia, a p-ANCA pattern, and the presence of antiphospholipid antibodies. More specific immune markers include antielastase antibodies. However, to confirm the diagnosis, levamisole detection in urine by using gas chromatography-mass spectrometry is required. However, most of the reported cases, including ours, are unconfirmed. This is because of the unavailability of testing techniques4 and the short half-life of levamisole (5.5~6 h)5. Two histological patterns have been documented: leukocytoclastic vasculitis and thrombotic vasculopathy. In most patients, skin lesions resolve spontaneously 2~3 weeks after stopping levamisole. However, the serological alterations may persist for up to 14 months3.

CanVasc recommendations for the management of antineutrophil cytoplasm antibody (ANCA)-associated vasculitides - Executive summary.

The Canadian Vasculitis research network (CanVasc) is composed of physicians from different medical specialties, including rheumatology and nephrology and researchers with expertise in vasculitis. One of its aims was to develop recommendations for the diagnosis and management of antineutrophil cytoplasm antibody (ANCA)-associated vasculitides in Canada. This executive summary features the 19 recommendations and 17 statements addressing general AAV diagnosis and management, developed by CanVasc group based on a synthesis of existing international guidelines, other published supporting evidence and expert consensus considering the Canadian healthcare context.

Macrolide Therapy and Alveolar Hemorrhage Secondary to Granulomatosis With Polyangiitis

We report the case of a 64-year-old woman with severe alveolar haemorrhage secondary to granulomatosis with polyangiitis (GPA), who was unknowingly treated with only penicillin and macrolide antibiotics, resulting in successful initial disease remission. The immunomodulatory effects of the macrolide antibiotic used could underlie this novel observation, which may shed new light on the pathogenesis and potential treatment of anti-neutrophil cytoplasm antibody (ANCA) associated vasculitis. The role of macrolides as an adjunct to conventional therapy in cases of AAV with respiratory involvement may be worthy of further investigation.

Rituximab versus Azathioprine for Maintenance in ANCA-Associated Vasculitis

BackgroundThe combination of cyclophosphamide and glucocorticoids leads to remission in most patients with antineutrophil cytoplasm antibody (ANCA)–associated vasculitides. However, even when patients receive maintenance treatment with azathioprine or methotrexate, the relapse rate remains high. Rituximab may help to maintain remission.MethodsPatients with newly diagnosed or relapsing granulomatosis with polyangiitis, microscopic polyangiitis, or renal-limited ANCA-associated vasculitis in complete remission after a cyclophosphamide–glucocorticoid regimen were randomly assigned to receive either 500 mg of rituximab on days 0 and 14 and at months 6, 12, and 18 after study entry or daily azathioprine until month 22. The primary end point at month 28 was the rate of major relapse (the reappearance of disease activity or worsening, with a Birmingham Vasculitis Activity Score >0, and involvement of one or more major organs, disease-related life-threatening events, or both).ResultsThe 115 enrolled patients (87 with granulomatosis with polyangiitis, 23 with microscopic polyangiitis, and 5 with renal-limited ANCA-associated vasculitis) received azathioprine (58 patients) or rituximab (57 patients). At month 28, major relapse had occurred in 17 patients in the azathioprine group (29%) and in 3 patients in the rituximab group (5%) (hazard ratio for relapse, 6.61; 95% confidence interval, 1.56 to 27.96; P=0.002). The frequencies of severe adverse events were similar in the two groups. Twenty-five patients in each group (P=0.92) had severe adverse events; there were 44 events in the azathioprine group and 45 in the rituximab group. Eight patients in the azathioprine group and 11 in the rituximab group had severe infections, and cancer developed in 2 patients in the azathioprine group and 1 in the rituximab group. Two patients in the azathioprine group died (1 from sepsis and 1 from pancreatic cancer).ConclusionsMore patients with ANCA-associated vasculitides had sustained remission at month 28 with rituximab than with azathioprine. (Funded by the French Ministry of Health; MAINRITSAN ClinicalTrials.gov number, NCT00748644; EudraCT number, 2008-002846-51.)

Plasma exchange in antineutrophil cytoplasm antibody-associated vasculitis.

This article reviews the use of plasma exchange for the treatment of antineutrophil cytoplasm antibody-associated vasculitis (AAV) with a focus on current controversies and knowledge gaps. Experimental evidence suggesting that antineutrophil cytoplasm antibodies are pathogenic continues to evolve and support the theory that rapid removal of antineutrophil cytoplasm antibody with plasma exchange may be beneficial. Although early, small trials of plasma exchange in rapidly progressive glomerulonephritis and vasculitis suggested that plasma exchange may improve a patient's potential for renal recovery, more recent analyses have called the net benefit of plasma exchange into question. Furthermore, there is uncertainty as to whether plasma exchange is beneficial to patients with particular organ manifestations of their AAV (e.g., lung hemorrhage). Whether plasma exchange should be used routinely in antineutrophil cytoplasm antibody-associated vasculitis, in patients with certain manifestations or severity of disease only, or not at all, remains unclear. Given that plasma exchange is expensive and invasive, further research to resolve these uncertainties is required.

State of the art in the treatment of systemic vasculitides.

Anti-neutrophil cytoplasm antibodies (ANCA) are associated with small vessel vasculitides (AASV) affecting the lungs and kidneys. Structured clinical assessment using the Birmingham Vasculitis Activity Score and Vasculitis Damage Index should form the basis of a treatment plan and be used to document progress, including relapse. Severe disease with organ or life threatening manifestations needs cyclophosphamide or rituximab, plus high dose glucocorticoids, followed by lower dose steroid plus azathioprine, or methotrexate. Additional plasmapheresis is effective for very severe disease, reducing dialysis dependence from 60 to 40% in the first year, but with no effect on mortality or long-term renal function, probably due to established renal damage. In milder forms of ANCA-associated vasculitis, methotrexate, leflunomide, or mycophenolate mofetil are effective. Mortality depends on initial severity: 25% in patients with renal failure or severe lung hemorrhage; 6% for generalized non-life threatening AASV but rising to 30–40% at 5 years. Mortality from GPA is four times higher than the background population. Early deaths are due to active vasculitis and infection. Subsequent deaths are more often due to cardiovascular events, infection, and cancer. We need to improve the long-term outcome, by controlling disease activity but also preventing damage and drug toxicity. By contrast, in large vessel vasculitis where mortality is much less but morbidity potentially greater, such as giant cell arteritis (GCA) and Takayasu arteritis, therapeutic options are limited. High dose glucocorticoid results in significant toxicity in over 80%. Advances in understanding the biology of the vasculitides are improving therapies. Novel, mechanism based therapies such as rituximab in AASV, mepolizumab in eosinophilic granulomatosis with polyangiitis, and tocilizumab in GCA, but the lack of reliable biomarkers remains a challenge to progress in these chronic relapsing diseases.

Evidence-based therapy for the ANCA-associated vasculitides: what do the trials show so far?

Anti-neutrophil cytoplasm antibody-associated vasculitides are rare multisystem inflammatory diseases including granulomatosis with polyangiitis, microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis. Previously these diseases were almost universally fatal, however, with current therapy 5-year survival for microscopic polyangiitis and granulomatosis with polyangiitis is approximately 80%. This review discusses the recent randomized controlled trials and other studies that have driven the improvement in survival and also highlights treatment-related morbidity and areas of unmet need in the management of anti-neutrophil cytoplasm antibody-associated vasculitides.

Glucocorticoid treatment and damage in the anti-neutrophil cytoplasm antibody-associated vasculitides: long-term data from the European Vasculitis Study Group trials.

Granulomatosis with polyangiitis and microscopic polyangiitis are ANCA-associated vasculitides (AAVs). The Vasculitis Damage Index (VDI) quantifies damage. This study aims to determine the factors associated with long-term damage in the AAVs. Data from 535 patients from four European Vasculitis Study Group trials were studied. A long-term follow-up (LTFU) questionnaire at 7 years post-diagnosis was completed. The associations between baseline (age, creatinine and BVAS score) and cumulative (number of relapses and duration of glucocorticoid use) factors and damage accrued (total VDI scores and individual treatment-related damage items) during follow-up were explored. Multiple regressions identified independent associations between baseline measures, cumulative factors and VDI scores at LTFU. Two hundred and ninety-six patients had glucocorticoid use and VDI data available at LTFU, with the mean length of glucocorticoid use being 40.4 months (S.D. 16.7). High levels of damage were independently associated with older age at baseline (P = 0.051), lower glomerular filtration rate (P = 0.041), higher BVAS scores (P = 0.046), increased cumulative glucocorticoid use (P = 0.016) and increasing number of relapses. Patients with longer duration of glucocorticoid treatment were more likely to have a total VDI score ≥5 [odds ratio 1.26 per 12 months of glucocorticoid use (95% CI 1.03, 1.53), P = 0.022]. The main limitation is that approximately half of the patients enrolled had no LTFU data available; these patients were older with more severe initial disease. Long-term damage in the AAVs may be associated with severity of initial disease, age, number of relapses and duration of glucocorticoid use.

Antineutrophil Cytoplasm Antibody: Positivity and Clinical Correlation

ObjectiveTo determine positivity and clinical correlation of anti-neutrophil cytoplasmic antibodies (ANCA), taking into account the interference of antinuclear antibodies (ANA). Material and methodsA prospective study was conducted in the Laboratory of Immunology of the National Cuban Center of Medical Genetic during one year. Two hounded sixty-seven patients with indication for ANCA determination were included. ANCA and ANA determinations with different cut off points and assays were determined by indirect immunofluorescense. Anti proteinase 3 and antimyeloperoxidase antibodies were determined by ELISA. ResultsMost positivity for ANCA was seen in patients with ANCA associated, primary small-vessel vasculitides, rheumatoid arthritis and systemic lupus erythematosus. Presence of ANCA without positivity for proteinase 3 and myeloperoxidase was higher in patients with ANA and little relation was observed between the perinuclear pattern confirmed in formalin and specificity by myeloperoxidase. Highest sensibility and specificity values for vasculitides diagnostic were achieved by ANCA determination using indirect immunofluorescense with a cut off 1/80 and confirming antigenic specificities with ELISA. ConclusionANCA can be present in a great number of chronic inflammatory or autoimmune disorders in the population studied. This determination using indirect immunofluorescence and following by ELISA had a great value for vasculitis diagnosis. Anti mieloperoxidasa assay has a higher utility than the formalin assay when ANA is present.