Efficacy and safety of low- versus high-dose glucocorticoid regimens for induction of remission of anti-neutrophil cytoplasm antibody-associated vasculitis: a systematic review and meta-analysis.

OBJECTIVE: Glucocorticoids (GCs) remain a cornerstone of the initial management of anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV), but have several dose-dependent side effects, in particular infections. The optimal dosing and tapering of oral GCs for remission induction are unknown. A systematic review and meta-analysis was undertaken to determine the efficacy and safety of low- versus high-dose GC regimens. METHOD: A systematic search of MEDLINE, Embase, and PubMed databases was conducted. Clinical studies using a GC-based induction protocol were selected. A daily dose of 0.5 mg/kg or < 30 mg/day oral prednisolone equivalent by the start of week 4 of the induction tapering schedule marked the threshold between high- and low-dose GCs. Risk ratios (RRs) were calculated by the random effects model for outcomes of remission and infection. Relapse events were summarized using risk differences with 95% confidence intervals (CIs). RESULTS: In total, 1145 participants were included in three randomized controlled trials and two observational studies, of whom 543 were assigned to the low-dose GC group and 602 to the high-dose GC group. A low-dose GC regimen was non-inferior to high-dose GCs with respect to outcomes of remission (RR 0.98, 95% CI 0.95-1.02, p = 0.37; I2 = 0%) and relapse (risk difference 0.03, 95% CI -0.01 to 0.06, p = 0.15; I2 = 12%), while significantly reducing the incidence of infection (RR 0.60, 95% CI 0.39-0.91, p = 0.02; I2 = 65%). CONCLUSION: Studies with low-dose GC regimens in AAV are associated with fewer infections while obtaining equivalent efficacy.

Incidence of malignancy in patients treated for antineutrophil cytoplasm antibody-associated vasculitis: follow-up data from European Vasculitis Study Group clinical trials.

OBJECTIVES: Because standard immunosuppressive treatment for antineutrophil cytoplasm antibody-associated vasculitis (AAV) (granulomatosis with polyangiitis (Wegener's) (GPA) and microscopic polyangiitis (MPA)) has been associated with a significant risk of developing cancer, the cancer incidence of treated AAV patients was assessed. METHODS: This analysis concerned 535 patients with newly diagnosed AAV from 15 countries who had been enrolled between 1995 and 2002 in four European clinical trials. Over the period 2004-7, study participants' follow-up events were updated, including cancers diagnosed. Age, sex and area-standardised incidence ratios (SIR) and their 95% CI were calculated by linkage to five national cancer databases. RESULTS: During the 2650 person-years' observation period, 50 cancers were diagnosed in 46 patients. SIR (95% CI) were 1.58 (1.17 to 2.08) for cancers at all sites, 1.30 (0.90 to 1.80) for cancers at all sites excluding non-melanoma skin cancer (NMSC), 2.41 (0.66 to 6.17) for bladder cancer, 3.23 (0.39 to 11.65) for leukaemia, 1.11 (0.03 to 6.19) for lymphoma and 2.78 (1.56 to 4.59) for NMSC. Subgroup SIR for cancers at all sites were 1.92 (1.31 to 2.71) for GPA and 1.20 (0.71 to 1.89) for MPA. CONCLUSIONS: Cancer rates for AAV patients treated with conventional immunosuppressive therapy exceeded those expected for the general population. This cancer excess was largely driven by an increased incidence of NMSC. The smaller cancer risk magnitude in this cohort, compared with previous studies, might reflect less extensive use of cyclophosphamide in current treatment protocols. Longer follow-up data are warranted to appraise the risk of developing cancers later during the course of AAV.

Deoxyspergualin in relapsing and refractory Wegener's granulomatosis.

OBJECTIVES: Conventional therapy of Wegener's granulomatosis with cyclophosphamide and corticosteroids is limited by incomplete remissions and a high relapse rate. The efficacy and safety of an alternative immunosuppressive drug, deoxyspergualin, was evaluated in patients with relapsing or refractory disease. METHODS: A prospective, international, multicentre, single-limb, open-label study. Entry required active Wegener's granulomatosis with a Birmingham vasculitis activity score (BVAS) > or =4 and previous therapy with cyclophosphamide or methotrexate. Immunosuppressive drugs were withdrawn at entry and prednisolone doses adjusted according to clinical status. Deoxyspergualin, 0.5 mg/kg per day, was self-administered by subcutaneous injection in six cycles of 21 days with a 7-day washout between cycles. Cycles were stopped early for white blood count less than 4000 cells/mm(3). The primary endpoint was complete remission (BVAS 0 for at least 2 months) or partial remission (BVAS <50% of entry score). After the sixth cycle azathioprine was commenced and follow-up continued for 6 months. RESULTS: 42/44 patients (95%) achieved at least partial remission and 20/44 (45%) achieved complete remission. BVAS fell from 12 (4-25), median (range) at baseline to 2 (0-14) at the end of the study (p<0.001). Prednisolone doses were reduced from 20 to 8 mg/day (p<0.001). Relapses occurred in 18 (43%) patients after a median of 170 (44-316) days after achieving remission. Severe or life-threatening (> or = grade 3) treatment-related adverse events occurred in 24 (53%) patients mostly due to leucopaenias. CONCLUSIONS: Deoxyspergualin achieved a high rate of disease remission and permitted prednisolone reduction in refractory or relapsing Wegener's granulomatosis. Adverse events were common but rarely led to treatment discontinuation.

Modification and validation of the Birmingham Vasculitis Activity Score (version 3).

BACKGROUND: Comprehensive multisystem clinical assessment using the Birmingham Vasculitis Activity score (BVAS) is widely used in therapeutic studies of systemic vasculitis. Extensive use suggested a need to revise the instrument. The previous version of BVAS has been revised, according to usage and reviewed by an expert committee. OBJECTIVE: To modify and validate version 3 of the BVAS in patients with systemic vasculitis. METHODS: The new version of BVAS was tested in a prospective cross-sectional study of patients with vasculitis. RESULTS: The number of items was reduced from 66 to 56. The subscores for new/worse disease and persistent disease were unified. In 313 patients with systemic vasculitis, BVAS(v.3) correlated with treatment decision (Spearman's r(s) = 0.66, 95% CI 0.59 to 0.72), BVAS1 of version 2 (r(s) = 0.94, 95% CI 0.92 to 0.96), BVAS2 of version 2 in patients with persistent disease (r(s) = 0.60, 95% CI 0.21 to 0.83), C-reactive protein levels (r(s) = 0.43, 95% CI 0.31 to 0.54), physician's global assessment (r(s) = 0.91, 95% CI 0.89 to 0.93) and vasculitis activity index (r(s) = 0.88, 95% CI 0.86 to 0.91). The intraclass correlation coefficients for reproducibility and repeatability were 0.96 (95% CI 0.95 to 0.97) and 0.96 (95% CI 0.92 to 0.97), respectively. In 39 patients assessed at diagnosis and again at 3 months, the BVAS(v.3) fell by 17 (95% CI 15 to 19) units (p<0.001, paired t test). CONCLUSION: BVAS(v.3) demonstrates convergence with BVAS(v.2), treatment decision, physician global assessment of disease activity, vasculitis activity index and C-reactive protein. It is repeatable, reproducible and sensitive to change. The new version of BVAS is validated for assessment of systemic vasculitis.

Development of comprehensive disease assessment in systemic vasculitis.

The systemic vasculitides are multisystem disorders with considerable mortality and morbidity and frequent relapses. In the absence of reliable serological markers, accurate clinical tools are required to assess disease activity and damage for treatment decisions, and for the performance of clinical trials. This article reviews and summarises the development and use of disease assessment tools for determining activity and damage in systemic vasculitis and reports ongoing initiatives for further development of disease assessment tools. A literature search was conducted using PubMed and reference lists for vasculitis, assessment, clinical trials, outcome and prognosis. The findings indicate that comprehensive disease assessment in vasculitis requires documentation of disease activity, chronic irreversible damage and impairment of function.

Outcomes from studies of antineutrophil cytoplasm antibody associated vasculitis: a systematic review by the European League Against Rheumatism systemic vasculitis task force.

OBJECTIVES: We undertook a systematic literature review as a background to the European League Against Rheumatism (EULAR) recommendations for conducting clinical trials in anti-neutrophil cytoplasm antibody associated vasculitis (AAV), and to assess the quality of evidence for outcome measures in AAV. METHODS: Using a systematic Medline search, we categorised the identified studies according to diagnoses. Factors affecting remission, relapse, renal function and overall survival were identified. RESULTS: A total of 44 papers were reviewed from 502 identified by our search criteria. There was considerable inconsistency in definitions of end points. Remission rates varied from 30% to 93% in Wegener granulomatosis (WG), 75% to 89% in microscopic polyangiitis (MPA) and 81% to 91% in Churg-Strauss syndrome (CSS). The 5-year survival for WG, MPA and CSS was 74-91%, 45-76% and 60-97%. Relapse (variably defined) was common in the first 2 years but the frequency varied: 18% to 60% in WG, 8% in MPA, and 35% in CSS. The rate of renal survival in WG varied from 23% at 15 months to 23% at 120 months. METHOD: used to assess morbidity varied between studies. Ignoring the variations in definitions of the stage of disease, factors influencing remission, relapse, renal and overall survival included immunosuppressive therapy used, type of organ involvement, presence of ANCA, older age and male gender. CONCLUSIONS: Factors influencing remission, relapse, renal and overall survival include the type of immunosuppressive therapy used, pattern of organ involvement, presence of ANCA, older age and male gender. Methodological variations between studies highlight the need for a consensus on terminology and definitions for future conduct of clinical studies in AAV.

Remission in antineutrophil cytoplasmic antibody-associated systemic vasculitis.

The definition of remission in patients with systemic vasculitis must be distinguished from the term "cure," which implies that patients are well and not requiring ongoing therapy. Remission should be defined using a standardised approach to measuring clinical disease activity, and the definition should be qualified by the duration of the remission and the type of maintenance therapy required to sustain remission. Remission is an important goal of management in the systemic vasculitides and is achievable in most patients. Maintenance of remission is a more difficult target, and evidence from studies of patients with antineutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis indicates that durable, lasting remission is unlikely to occur. Despite good disease control, damage or scarring from disease or its treatment is a common finding and is a separate outcome from remission. Future studies of vasculitis therapies should address the concept of rapid and sustained disease control, so that patients spend most of their time in a state of good health, with minimal damage.

Clinical and biological assessment in systemic necrotizing vasculitides.

The systemic vasculitides are multi-system disorders with significant mortality and morbidity and frequent relapses. Treatment is usually effective but fraught with potentially serious effects. Disease Assessment is important to ensure that patients receive the appropriate treatment. Disease Assessment should comprise measurement of disease activity, chronic irreversible damage and impairment of function. Serological markers can be helpful in assessing disease activity but lack sufficient sensitivity and specificity to be used on their own. Radiological techniques such as Magnetic Resonance Imaging, Ultrasound and Positron Emission Tomography show promise in the large vessel vasculitides but require validation in large studies. Clinical Assessment tools are the current gold standard for the assessment of disease activity, damage and function.

The role of biologic therapies in the management of systemic vasculitis.

The recent development of biologic therapies capable of selectively targeting components of the immune system has revolutionised the treatment of inflammatory arthritides. The steady increase in use of biologic agents coupled with the expansion in the knowledge of the pathogenesis of vascular inflammation has led to their application in the treatment of primary systemic vasculitis. These agents may have a role in addition to or in place of conventional immunosuppression and also be effective when the latter fails to induce remission. The use of biologics as targeted therapies has also, in reverse, improved our understanding of the pathophysiology of vascular inflammation. While the advent of biologics heralds a new era in the management of the systemic vasculitis, evidence for their efficacy is still in its infancy and has yet to match that of conventional immunosuppressants. In this review, we examine the up-to-date evidence for the use of biologics in systemic vasculitis, including TNF-alpha inhibitors, and highlight the challenges facing their use. We examine the rationale for using biologics based on the pathophysiology of vasculitis. Issues of toxicity and pharmacovigilance with the use of biologics are also discussed. Finally, future directions and predictions are presented.

Jeg-3 human choriocarcinoma-induced immunosuppression: downregulation of interleukin-2, interleukin-2 receptor alpha-chain, and its Jak/Stat signaling pathway.

PROBLEM: The mechanisms of the immunosuppressive and immunosuppression-inducing capacities of Jeg-3 human choriocarcinoma cell line supernatants (HCSs) are not yet completely understood. The influence on interleukin (IL)-2, IL-4 and interferon (IFN)-gamma production; IL-2 receptor (IL-2R) alpha-, beta-, and gamma-chain; and the signaling pathway molecules Janus kinase (Jak)1, Jak3, signal transducers and activators of transcription (Stat)1, Stat3, and Stat5 should be investigated. METHOD OF STUDY: For assessment of IL production, whole peripheral venous blood from healthy donors was stimulated with phorbol-myristate-acetate and ionomycine. Secretion of ILs was blocked with monensine. Intracellular ILs were analyzed by flow cytometry. For IL-2R and signaling pathway molecule analysis, peripheral blood lymphocytes were stimulated with phytohemagglutinin (PHA). IL-2R chains were measured by flow cytometry, and Jaks/Stats by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot. RESULTS: Phorbol-myristate-acetate and ionomycine strongly increase the percent-age of IL-2+ cells; an additional 50% HCSs significantly suppresses the percentage to, or below the level of unstimulated cells. IFN-gamma production is strongly decreased by HCSs in some cases, but not in others. PHA stimulates IL-2R alpha-, beta-, and gamma-chain expression and their signaling pathway molecules Jak1, Jak3, Stat1, Stat3, and Stat5. 50% HCS downregulates the alpha-chain and slightly upregulates the beta-chain. Jak1, Jak3, Stat1, Stat3, and Stat5 expression is suppressed approximately to, or below the level of unstimulated cells. CONCLUSIONS: HCS forcefully blocks the production of IL-2; the IL-2R alpha-chain; and Jak1, Jak3, Stat1, Stat3, and Stat5 expression. The observed phenomena might be caused by downregulation of an IL-2R regulation gene, and might play a key role in the expansion of choriocarcinoma, and possibly in the survival of the fetal allograft.