Alina Casian

Long-term follow-up of patients with severe ANCA-associated vasculitis comparing plasma exchange to intravenous methylprednisolone treatment is unclear

Patients with antineutrophil cytoplasm antibody-associated vasculitis (AAV) requiring dialysis at diagnosis are at risk for developing end-stage renal disease (ESRD) or dying. Short-term results of a trial comparing plasma exchange (PLEX) to intravenous methylprednisolone (IV MeP) suggested PLEX improved renal recovery. Here we conducted long-term follow-up to see if this trend persisted. A total of 137 patients with newly diagnosed AAV and a serum creatinine over 500 μmol/l or requiring dialysis were randomized such that 69 received PLEX and 68 received IV MeP in addition to cyclophosphamide and oral glucocorticoids. The patients were followed for a median of 3.95 years. In each group there were 35 deaths, while 23 PLEX and 33 IV MeP patients developed ESRD. The hazard ratio for PLEX compared to IV MeP for the primary composite outcome of death or ESRD was 0.81 (95% confidence interval 0.53-1.23). The hazard ratio for all-cause death was 1.08 with a subhazard ratio for ESRD of 0.64 (95% confidence interval 0.40-1.05). Thus, although short-term results with PLEX are encouraging, the long-term benefits remain unclear. Further research is required to determine the role of PLEX in AAV. Given the poor outcomes of patients with severe AAV, improved treatment is urgently needed.

Plasma exchange in the treatment of Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome and renal limited vasculitis.

Purpose of reviewThe article reviews the use of plasma exchange (PLEX) in the management of the antineutrophil cytoplasm antibody-associated vasculitides (AAV). Recent findingsEarly mortality and end-stage renal disease (ESRD) remain frequent outcomes for AAV patients. Demonstration of the pathogenic potential of anti-neutrophil cytoplasm antibody (ANCA) has provided a rationale for antibody removal by PLEX in vasculitis therapy; however, other mechanisms may contribute to the therapeutic effect. Clinical studies have focused on the use of PLEX to rescue organ function in rapidly progressive glomerulonephritis and lung haemorrhage; other indications, including immunomodulatory actions, have received little attention. Randomized controlled trials of PLEX in renal vasculitis suggest a reduction in the risk of development of ESRD with adjunctive PLEX, although the data are not sufficiently strong to make firm recommendations and there are no controlled trials in alveolar haemorrhage. SummaryIt is unclear at what severity of renal failure PLEX is beneficial, the optimal PLEX dosing and type and dosing of concomitant medications. These subjects are the focus of an ongoing study (PEXIVAS). PLEX remains a nonselective, expensive therapy with common adverse events. Selective apheresis techniques (cytapheresis, immunoadsorption) offer theoretical advantages but their use is limited by incomplete understanding of the mechanism of PLEX in AAV and expense.

Intravenous Cyclophosphamide and Plasmapheresis in Dialysis-Dependent ANCA-Associated Vasculitis

BACKGROUND AND OBJECTIVES Induction therapy with oral cyclophosphamide (CYP) has been a mainstay of treatment in patients with severe renal failure secondary to ANCA-associated vasculitis (AAV). Recent evidence proposes using pulsed intravenous CYP in less severe disease to minimize adverse events. It is unclear if this can be translated to those with dialysis-dependent renal insufficiency. DESIGN, SETTING, PARTICIPANTS, & METHODS All AAV patients presenting between 2005 and 2010 requiring dialysis at presentation were retrospectively analyzed. Patients were treated with plasma exchange, corticosteroids, and intravenous CYP. Rate of dialysis independence at 3 and 12 months and adverse effects were assessed and compared with the outcome of the plasmapheresis, prednisolone, and oral CYP arm of the randomized MEPEX (methylprednisolone versus plasma exchange) trial. RESULTS Forty-one patients were included. At 3 months, 3 (7.3%) patients had died on dialysis, 12 (29.3%) remained dialysis dependent, and 26 (63.4%) were dialysis independent (creatinine, 2.5 mg/dl; GFR, 26 ml/min per 1.73 m(2)). Four patients subsequently reached ESRD at a median time of 83 days. Thirty-seven (90%) patients reached 1 year follow-up, 13 (35%) remained dialysis dependent, and 24 (65%) had independent renal function. Eleven patients (27%) had episodes of leukopenia (white cell count <4×10(9)/L) during CYP therapy and 17 (41%) experienced infectious complications. This compares favorably with the dialysis-dependent cohort treated with plasmapheresis in the MEPEX study in which 51% were alive with independent renal function at 1 year. CONCLUSIONS Intravenous CYP used with corticosteroids and plasmapheresis may be an effective alternative to oral CYP in patients with dialysis-dependent AAV.

Plasma exchange induces vitamin D deficiency

BACKGROUND Plasma exchange is used in the treatment of diseases mediated by pathogenic circulating proteins, or for transplant desensitization. Its non-targeted nature results in the depletion of physiologically important molecules, and it is often complicated by hypocalcaemia. AIM To determine the effects of plasma exchange on vitamin D binding protein (DBP) and associated vitamin D metabolites. DESIGN Single-centre prospective cohort study of 11 patients. METHODS DBP and vitamin D metabolites were measured before and immediately after five plasma exchanges, and 7 and 28 days after discontinuation of plasma exchange. RESULTS Plasma exchange reduced plasma DBP concentration from 196.9 ± 53.2 to 98.5 ± 34 μg/ml (P = 0.0001), 1,25-dihydroxyvitamin D from 103 ± 52 to 42 ± 4 pmol/l (P = 0.003) and 25-hydroxyvitamin D from 49.7 ± 29 to 22 ± 9.4 nmol/l (P = 0.0017), through their removal in effluent. After 7 days, DBP and 1,25-dihydroxyvitamin D were not significantly different from baseline, but 25-hydroxyvitamin D remained significantly lower after 7 days (26.4 ± 9.8 nmol/l, P = 0.02) and 28 days (30.8 ± 15.5 nmol/l, P = 0.048). Corrected calcium decreased from 2.23 ± 0.11 to 1.98 ± 0.08 mmol/l (P = 0.0007) immediately after five treatments. Plasma calcium was significantly associated with 1,25-dihydroxyvitamin D (r(2) = 0.79, P < 0.0001). CONCLUSION Plasma exchange induced an acute reversible decrease in plasma 1,25-dihydroxyvitamin D, DBP, calcium and a sustained decrease in plasma 25-hydroxyvitamin D.

Neurological Manifestations of IgG4-Related Disease

Opinion statementIgG4-related disease (IgG4-RD) is a multisystem inflammatory disorder. Early recognition of IgG4-RD is important to avoid permanent organ dysfunction and disability. Neurological involvement by IgG4-RD is relatively uncommon, but well recognised—hypertrophic pachymeningitis and hypophysitis are the most frequent manifestations. Although the nervous system may be involved in isolation, this more frequently occurs in conjunction with involvement of other systems. Elevated circulating levels of IgG4 are suggestive of the condition, but these are not pathognomonic and exclusion of other inflammatory disorders including vasculitis is required. Wherever possible, a tissue diagnosis should be established. The characteristic histopathological changes include a lymphoplasmacytoid infiltrate, storiform fibrosis and obliterative phlebitis. IgG4-RD typically responds well to treatment with glucocorticoids, although relapse is relatively common and treatment with a steroid-sparing agent or rituximab may be required. Improved understanding of the pathogenesis of IgG4-RD is likely to lead to the development of more specific disease treatments in the future.

Current modalities in the diagnosis of pulmonary vasculitis.

INTRODUCTION This review addresses the pulmonary manifestations of the vasculitides, with a focus on diagnostic modalities. Haemorrhagic presentations (usually associated with nephritis: the pulmonary-renal syndrome) are the most common vasculitic cause of early death. AREAS COVERED The diagnostic modalities in the pulmonary vasculitides are reviewed, with a focus on primary systemic vasculitis. A literature search of original research and review articles on pulmonary vasculitides was undertaken using the PubMed database. EXPERT OPINION Small-vessel anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, especially granulomatosis with polyangiitis (Wegeners granulomatosis) are the most frequent causes of pulmonary vasculitis and typically present as nodules, alveolar infiltrates (haemorrhagic or not), cavities or tracheobronchial stenosis. Lung involvement is less common in large-vessel vasculitis when pulmonary vascular abnormalities can be seen. No single test is pathogonomonic and diagnosis requires integration of clinical, laboratory, imaging and histological findings. Treatment follows similar regimens to other vasculitic presentations, with glucocorticoids in conjunction with immunosuppressive agents, and management of intercurrent sepsis and the increased risk of cardiovascular and thromboembolic events. Prompt diagnosis and intensive treatment of pulmonary vasculitis is essential to improve early mortality and long-term outcomes.

Clinical associations with venous thromboembolism in anti-neutrophil cytoplasm antibody-associated vasculitides

Objective To assess potential associations for the development of venous thromboembolic events in patients with ANCA-associated vasculitides (AAV). Methods Four hundred and seventeen patients enrolled to participate in randomized controlled trials conducted by the European Vasculitis Society were identified. Univariate and multivariate analyses were performed to validate previously proposed and identify novel risks associated with venous thromboembolism (VTE) in AAV. Results VTE occurred in 41 of 417 (9.8%) patients. Uncorrected univariate analysis identified BVAS (odds ratio, OR = 1.05, 95% CI: 1.01, 1.10; P = 0.013), subsequent development of malignancy (OR = 2.6, 95% CI: 1.19, 5.71; P = 0.017), mucous membrane or eye involvement (OR = 2.13, 95% CI: 1.10, 4.11; P = 0.024) and baseline creatinine (OR = 1.08, 95% CI: 0.99, 1.18; P = 0.037) as being associated with the development of VTE. Multivariate analysis highlighted CRP (per 10 mg/l increase, OR = 1.05, 95% CI: 1.01, 1.09; P = 0.025), cutaneous involvement (OR = 4.83, 95% CI: 1.63, 14.38; P = 0.005) and gastrointestinal involvement (OR = 6.27, 95% CI: 1.34, 29.37; P = 0.02) among the BVAS items as well as baseline creatinine (per 100 µmol/l increase, OR = 1.17, 95% CI: 1.02, 1.35; P = 0.029) as being associated with VTEs. Conclusion Our results highlight a role of CRP, baseline creatinine, and cutaneous and gastrointestinal involvement in the risk stratification as being associated with thromboembolic events. Moreover, there might be an association between VTEs and subsequent development of malignancy and disease activity in general.

The European Vasculitis Society 2016 Meeting Report

The 2016 European Vasculitis Society (EUVAS) meeting, held in Leiden, the Netherlands, was centered around phenotypic subtyping in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV). There were parallel meetings of the EUVAS petals, which here report on disease assessment; database; and long-term follow-up, registries, genetics, histology, biomarker studies, and clinical trials. Studies currently conducted will improve our ability to discriminate between different forms of vasculitis. In a project that involves the 10-year follow-up of AAV patients, we are working on retrieving data on patient and renal survival, relapse rate, the cumulative incidence of malignancies, and comorbidities. Across Europe, several vasculitis registries were developed covering over 10,000 registered patients. In the near future, these registries will facilitate clinical research in AAV on a scale hitherto unknown. Current studies on the genetic background of AAV will explore the potential prognostic significance of genetic markers and further refine genetic associations with distinct disease subsets. The histopathological classification of ANCA-associated glomerulonephritis is currently evaluated in light of data coming out of a large international validation study. In our continuous search for biomarkers to predict clinical outcome, promising new markers are important subjects of current research. Over the last 2 decades, a host of clinical trials have provided evidence for refinement of therapeutic regimens. We give an overview of clinical trials currently under development, and consider refractory vasculitis in detail. The goal of EUVAS is to stimulate ongoing research in clinical, serological, and histological management and techniques for patients with systemic vasculitis, with an outlook on the applicability for clinical trials.

SAT0342 Features of Orbital Inflammatory Disease and Response To Immunosuppressive Therapy

Objectives To characterize a single centre retrospective case series of patients with infra-orbital inflammatory masses with autoimmune disease including granulomatosis with polyangiitis (GPA) (formerly Wegeners granulomatosis), eGPA (eosinophillic granulomatosis with polyangiitis) or Immunoglobulin G4 (IgG4) related disease (IgG4-RD). Methods We identified 30 patients with infra-orbital inflammation on MRI imaging. Clinical and laboratory data was collected from electronic clinical records. Comprehensive Diagnostic Criteria were used for IgG4-RD and Chapel Hill criteria for GPA and eGPA. Statistical analysis was performed by GraphPad software; continuous variables were compared between IgG4-RD and GPA groups using non-parametric Mann-Whitney test and categorical variables were compared by Fishers exact test. Results The study included 21 Caucasian, 6 Asian and 3 patients of African descent. There were 19 female and 11 male patients. The median age of the patients was 44 years (range 29–76). 13 patients were diagnosed with GPA, 1 with eosinophillic granulomatosis with polyangitis 9eGPA), 11 patients had IgG-RD, 1 patient with lymphoma, 2 other vasculitis, 1 IgA dacryoadenitis, 1 non-specific granuloma. 7/12 patients with IgG4-RD had isolated infra-orbital masses whereas all 14 GPA patients suffered extra-ocular manifestations (p=0.01), usually sino-nasal or pulmonary. 11/14 GPA patients had positive ANCA vs 2/12 patients with Ig4-RD (p=0.04). IgG4 level was elevated pre-treatment in IgG4 RD patients (median 2.46 g/l (range 1.2–23.7)) and dropped to 1.25 g/l (range 0.37–10.4) after therapy; immunoglobulin subclasses were not checked routinely in GPA. All 12 patients with IgG4-RD underwent diagnostic orbital biopsy vs 3/14 GPA (p=0.0001). All 30 patients were treated with corticosteroids (used alone in 3/12 IgG4-RD patients). The median number of DMARDs ever used to treat GPA was 3 vs 1 DMARD for IgG4-RD (p=0.001). Rituximab was effectively administered to 10/14 GPA patients vs 3/12 IgG4-RD (p=0.04), is planned for 2 further IgG4-RD patients and approval was refused for 1 case. Surgical debulking was undertaken in 6/12 IgG4-RD vs 1/14 GPA (p=0.03). All 40 patients had subsequent MRI to assess response to therapy. Conclusions IgG4-RD is an important differential diagnosis of infra-orbital inflammation, especially if ANCA is negative. Unlike GPA that was associated with extra-ocular manifestations in all patients, IgG4-RD was more likely to present with isolated orbital inflammation and to require biopsy or surgical debulking as the diagnosis was initially uncertain. Treatment with corticosteroids +/− DMARDs was effective. Rituximab can specifically deplete the pool of autoreactive B lymphocytes producing IgG4 and future systematic studies are required to establish the optimum therapeutic strategy. Disclosure of Interest None declared

AB0531 The Role of Hydroxychloroquine in ANCA Positive and Negative Vasculitis

Background There is an unmet need for a less toxic, corticosteroid sparing therapy in ANCA vasculitis (AAV), as up to 50% of patients relapse by 5 years and 20% have sub-optimal disease control. Hydroxychloroquine (HCQ) has been effective and safe in autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. There is mechanistic rationale for the effectiveness of hydroxychloroquine in vasculitis, considering its effect on immune mediators involved in pathogenesis, including B cell activating factors, Toll-like receptors, autoreactive T cells and cytokines. Objectives To assess retrospectively the efficacy and safety of hydroxychloroquine (HCQ) in patients with systemic vasculitis Methods Patients were identified by searching our departmental vasculitis database including 248 patients in total and electronic clinical records. Twenty-six patients received hydroxychloroquine along with corticosteroids and immunosuppressants. We assessed the effect of hydroxychloroquine on clinical symptoms and the median dose of corticosteroids required. Results Twenty six patients with various vasculitides were treated with hydroxychloroquine (median dose 200 mg OD): 6 patients with Henoch Schonlein purpura (HSP), 6 urticarial vasculitis, 6 with ANCA+ vasculitis (AAV) (4 PR3-ANCA, 2 MPO-ANCA), 1 Eosinophilic Granulomatosis with Polyangiitis (EGPA), 2 Takayasu arteritis, 2 Behcets disease, 1 adult Stills disease (AOSD), 1 relapsing polychondritis, 1 polyarteritis nodosa (PAN). The female: male ratio was 21:5. Median age was 53 years. The median duration of HCQ treatment was 3 years. Sixteen patients experienced a reduction in arthralgia, skin rashes improved in 8 patients and completely resolved in a further 4. Eight patients could reduce corticosteroid doses (from 9 mg to 6 mg) and 3 discontinued corticosteroids. Four patients developed fewer vasculitic relapses, 6 felt less fatigued, 2 patients no longer experienced abdominal pain and diarrhoea, 2 improved their mood and ability to think clearly. The 6 patients with AAV experienced improvement in arthralgia, reduced their prednisolone doses by a third, had fewer relapses and felt less tired. One patient developed asymptomatic QT prolongation and stopped the hydroxychloroquine, with no other adverse events reported. Additional immunosuppressive therapy Patient No. Diagnosis Nil 8 3 Behcet 2, HSP, 1 AAV, 1 PAN,1 urticarial vasculitis Methotrexate + prednisolone 5 2 HSP, 1 AAV, 1 AOSD, 1 polychondritis Azathioprine + prednisolone 3 1 HSP, 1 AAV, 1 urticarial vasculitis Mycophenolate mofetil + prednisolone 2 1 urticarial vasculitis, 1 EGPA Mycophenolate mofetil 2 1 AAV, 1 Takayasu Methotrexate 2 Urticarial vasculitis Azathioprine 1 Takayasu Prednisolone 1 AAV Mepacrine 1 HSP Rituximab 1 AAV Conclusions All 26 patients reported symptomatic benefits associated with hydroxychloroquine treatment, especially improvement in joint pains, fatigue, rash. Vasculitic relapses were less frequent, with a reduction in corticosteroid doses. Hydroxychloroquine was generally well tolerated. Disclosure of Interest None declared