Clinical presentation and long-term outcome of 144 patients with microscopic polyangiitis in a monocentric German cohort.

OBJECTIVE: To evaluate the clinical presentation and long-term outcome of a vasculitis centre cohort of patients with microscopic polyangiitis (MPA) with respect to organ manifestations, treatment, chronic damage and mortality. METHODS: We performed a retrospective chart review at our vasculitis referral centre. MPA patients admitted between 1991 and 2013 classified by a modified European Medicines Agency algorithm were diagnosed and treated according to a standardized interdisciplinary approach. RESULTS: Comprehensive data from standardized interdisciplinary workups was available for 144 patients (median follow-up 72 months). The overall standardized mortality ratio was 1.40 (95% CI 0.91, 2.07; P = 0.13). We observed a higher mortality [hazard ratio (HR) 4.04 (95% CI 1.21, 13.45), P = 0.02] in 17 patients with MPA-associated fibrosing interstitial lung disease (ILD) and 56 patients with peripheral nervous system involvement [HR 5.26 (95% CI 1.10, 25.14), P = 0.04] at disease onset. One hundred and fifteen patients (79.9%) responded to the initial treatment. Sixty-one (42.3%) achieved complete remission and 54 (37.5%) achieved partial remission. Twenty (13.9%) showed a refractory disease course. CONCLUSION: MPA patients at our tertiary rheumatology referral centre seemed to have a less severe phenotype resulting in a less severe disease course and better outcome than reported in other cohorts. Fibrosing ILD was significantly associated with mortality in this cohort.

Pathogenesis of anti-neutrophil cytoplasmic antibody-associated vasculitis: challenges and solutions 2014.

Anti-neutrophil cytoplasmic autoantibodies (ANCA) with specificity for proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA) are a defining feature of ANCA-associated vasculitides (AAV). They play a pivotal role in disease pathophysiology and have strongly improved early diagnosis and treatment of these infrequent, but potentially fatal diseases. Neutrophils and their products are major players in initiating the autoimmune response and tissue destruction in vasculitic as well as granulomatous inflammation. This review highlights recent findings on old and novel players (ANCA, neutrophils, neutrophil extracellular traps, fibroblasts, immune cells and complement) and puts them into context with the current understanding of disease mechanisms in AAV.

Plasma cells within granulomatous inflammation display signs pointing to autoreactivity and destruction in granulomatosis with polyangiitis.

INTRODUCTION: Plasma cells residing in inflamed tissues produce antibodies in chronic inflammatory and systemic autoimmune diseases. This study examined if plasma cells, located within inflamed nasal tissue in granulomatosis with polyangiitis (GPA), express features potentially associated with the autoimmune and destructive character of this disease. METHODS: Ig gene mutation patterns of individual tissue-derived plasma cells from GPA (n = 5) were analyzed, by using laser-assisted microdissection followed by semi-nested polymerase chain reaction (PCR). Signs of B-lymphocyte maturation (ectopic lymphoid structures, ELS) and survival (a proliferation-inducing ligand, APRIL; B-cell maturation antigen, BCMA; transmembrane-activator and calcium modulator and cyclophilin interactor, TACI; receptor activator of nuclear factor κB ligand, RANKL) were examined in nasal tissues or serum, respectively, by using immunohistochemistry/fluorescence and enzyme-linked immunosorbent assay, ELISA. RESULTS: Plasma-cell derived Ig genes (light- and heavy-chain pairs, n = 4; heavy chains, n = 33) resembled mutation patterns seen in other autoimmune diseases, predominantly displaying selection against replacement mutations within the framework region of Ig genes (10 of 15), which is responsible for structural integrity. Ectopic lymphoid structures were similar between GPA and a disease control (that is, unspecific chronic rhinosinusitis. However, histomorphologic features distinguishing GPA from rhinosinusitis (that is, neutrophilic microabscess and granuloma) expressed considerable amounts of membrane-associated and secreted APRIL, respectively. The latter was co-localized with CD138 and found in close proximity to cells expressing IgG, TACI, and BCMA. Interestingly, plasma cells strongly expressed receptor activator of nuclear factor κB ligand (RANKL), apart from fibroblast-like cells. CONCLUSIONS: Plasma cells within granulomatous inflammation appear to display features that might be required for autoreactivity and, possibly, RANKL-mediated destruction in GPA.

Doubled prevalence rates of ANCA-associated vasculitides and giant cell arteritis between 1994 and 2006 in northern Germany.

OBJECTIVES: The aim of this study was to investigate the period prevalences of ANCA-associated vasculitides (AAV), including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic GPA (EGPA)/Churg-Strauss and GCA, in an urban and rural population in northern Germany in 2006 and to compare the data with our previous study performed in 1994. METHODS: We identified of all patients with AAV or GCA via questionnaires to all hospital departments, physicians, health insurance providers, pension funds, reference laboratories for autoimmune diseases and death registries in Luebeck (city) and the rural region of Segeberg (population 468 962) between January and December 2006. The type of vasculitis, gender, year of birth, postal code and death were documented and re-evaluated. RESULTS: One-hundred and fifty patients were identified, indicating a prevalence of 320 per million inhabitants for the complete catchment area (95% CI 285, 355). GCA was more prevalent than AAV: 171 (146, 197) vs 149 (126, 174). GCA and AAV have almost doubled since 1994. GCA increased from 240 (164, 315) to 440 (399, 481) per million in the population ≥ 50 years of age and AAV increased from 74 to 149 cases per million. GCA and AAV were more prevalent in the urban compared with the rural region. CONCLUSION: The prevalence rates of AAV and GCA almost doubled from 1994 to 2006 for this region with a stable population and using an identical study design. Increased awareness has led to an earlier diagnosis of systemic vasculitis and improved activity-adapted treatment mostly based on randomized controlled trials has led to longer survival. Aspects such as environmental factors and exposure to certain substances need further research.

Non-biologic remission maintenance therapy in adult patients with ANCA-associated vasculitis: a systematic review and network meta-analysis.

OBJECTIVE: To determine the comparative efficacy of non-biologic treatments for remission maintenance in ANCA-associated vasculitis. METHODS: We identified all randomized trials comparing leflunomide, azathioprine, methotrexate or mycophenolate mofetil in adult patients with granulomatosis with polyangiitis or microscopic polyangiitis. Relapse-free survival was compared through hazard ratios (HR) using a Bayesian fixed-effects network meta-analysis. Multiple sensitivity analyses were performed to explore biases identified in one trial using original trial data. RESULTS: Three trials were available (leflunomide-methotrexate, methotrexate- azathioprine, azathioprine-mycophenolate). Mycophenolate was inferior to all treatments, although the 95% credible interval (CrI) of the HR relative to methotrexate crossed 1. Leflunomide was superior to azathioprine (HR 0.43 [95% CrI: 0.14-1.3]) and methotrexate (HR 0.47 [95% CrI: 0.18-1.2]), although the 95% CrI also crossed 1. There was a 90% probability that leflunomide was the best treatment. After down weighting the effect of leflunomide vs. methotrexate for early trial termination and slow MTX dose escalation, there remained a 55% probability leflunomide was best. CONCLUSION: Based on indirect evidence, leflunomide is effective in maintaining remission in granulomatosis with polyangiitis or microscopic polyangiitis relative to other non-biologic treatments. Further randomized trials of leflunomide are needed for confirmation.

Treatment of ANCA-associated vasculitis.

Antineutrophil cytoplasmic autoantibody (ANCA)-associated diseases are small-vessel vasculitides, encompassing granulomatosis with polyangiitis (formerly Wegener's granulomatosis), microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis. Once considered life-threatening diseases, the introduction of stage-adapted immunosuppressive therapy and medications with decreased toxicity has improved patients' survival. Treatment is biphasic, consisting of induction of remission (3-6 months) for rapid control of disease activity and maintenance of remission (at least 18 months) to prevent disease relapse using therapeutic alternatives that have reduced toxicity. This Review summarizes current treatment strategies for these diseases, with a special focus on long-term follow-up data from key randomized controlled trials and new developments in remission induction and maintenance therapy. Current treatment strategies have substantial short-term and long-term adverse effects, and relapses are frequent; thus, less-toxic and more-effective approaches are needed. Moreover, the optimal intensity and duration of maintenance therapy remains under debate. Clinical trials have traditionally considered ANCA-associated vasculitides as a single disease entity. However, future studies must stratify participants according to their specific disease, clinical features (different types of organ manifestation, PR3-ANCA or MPO-ANCA positivity) and disease severity.

Granuloma in ANCA-associated vasculitides: another reason to distinguish between syndromes?

The 2012 renewed Chapel Hill Consensus Conference (CHCC) officially named three clinicopathological entities, i.e. granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA), and microscopic polyangiitis (MPA), as major variants of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV). Recent genetic and cohort studies revealed the need for further differentiation between the entities, for example regarding differences in outcome. As well as ANCA reactivity, upper and lower airway disease were found to be differentiating factors for AAV variants, improving prognostic ability regarding relapse prediction and associated clinical features. Extravascular granulomatosis, or "granuloma", which describes both clinically relevant granulomatous manifestations and histopathologically documented granulomatous inflammation, is characteristic of localized and systemic GPA, but not MPA. This review summarizes new knowledge regarding granuloma in the head and neck region of AAV, its histomorphological equivalents in the upper and lower respiratory tract, and evidence for a granulomatous phenotype of a persistent localized GPA variant. This comprises the development of disease activity and damage scores for extravascular lesions in the ear, nose, and throat (ENT) regions, and imaging techniques. In addition, findings linking extravascular manifestations to granulomatous inflammation are described. We hypothesize that, as for ANCA, necrotizing granulomatous inflammation and its clinical manifestations are discriminators, assisting subclassification of AAV and/or GPA subphenotypes which will be useful both for designing clinical trials and for treating patients successfully.

Current understanding of the pathogenesis of granulomatosis with polyangiitis (Wegener's).

Granulomatosis with polyangiitis (Wegener's) (GPA) is a multisystem disease of unknown etiology, characterized by granulomata of the respiratory tract and systemic necrotizing vasculitis. Antineutrophil cytoplasmic antibodies (ANCA) with specificity for proteinase 3 (PR3) are a defining feature of this disease. GPA usually starts as a granulomatous disease of the respiratory tract and, in the majority of patients, progresses to systemic disease with PR3-ANCA-associated vasculitis. Today, epidemiological evidence indicates that GPA develops as a result of complex gene-environment interactions. The nature of these risk factors and pathogenic mechanisms involved, however, are only just beginning to be understood. Clinical data and in vitro experimental results point to the pathogenic pathways involved in tissue lesion development, in which ANCA, cellular immunity, neutrophils extracellular traps, fibroblasts, vascular endothelial cells and inflammatory mediators play a major role. Today, the pathophysiological significance of PR3-ANCA is still unclear and the pathogenic pathways leading to granuloma formation are not explained. New data unexpectedly suggest that the destruction of nasal cartilage in GPA is mainly mediated by fibroblasts that can be blocked by corticosteroids.

Toll-like receptor TLR2 and TLR9 ligation triggers neutrophil activation in granulomatosis with polyangiitis.

OBJECTIVE: The aim of the study was to characterize the expression of TLR2, TLR4 and TLR9 in PMNs of patients with granulomatosis with polyangiitis (GPA) and to elucidate the role of these receptors in GPA with respect to neutrophil activation. METHODS: The expression of TLR2, TLR4 and TLR9 was determined on ex vivo PMNs in whole blood samples of GPA patients (n = 35) and healthy controls (HCs) (n = 24). Isolated PMNs were stimulated in vitro with TLR agonists and assessed for degranulation, membrane proteinase 3 (mPR3) expression, soluble l-selectin shedding and cytokine production (IL-8) in five GPA patients and five HCs. The priming effects of TLR2 and TLR9 ligation were assessed by measurement of serine protease activity after stimulation with PR3-ANCA. RESULTS: There were no significant differences in the ex vivo expression of TLRs on PMNs in HCs and GPA patients. Stimulation of TLR4 and TLR9 induced MPO release, stimulation with TLR2, TLR4 and TLR9 ligands elicited IL-8 production and stimulation of TLR2 and TLR9 led to an upregulation in mPR3 expression on PMNs with no significant differences between GPA and HC after 1 or 24 h stimulation. Priming of PMNs with TLR2 and TLR9 ligands induced degranulation after subsequent stimulation with PR3-ANCA, which was comparable to priming with TNF-α. CONCLUSION: Expression of TLR2, TLR4 and TLR9 in PMNs and the TLR-induced activation of PMNs was comparable in GPA and HC. mPR3 upregulation by TLR2 and TLR9 stimulation and the priming effect of TLR ligands on PMNs may have a potential implication for triggering disease activity during infection in GPA.

Orbital masses in granulomatosis with polyangiitis are associated with a refractory course and a high burden of local damage.

OBJECTIVES: To identify and characterize patients with orbital masses in a monocentric cohort of 1142 GPA patients followed up from 1990 until the end of 2010 with regard to disease stage, local orbital inflammation, course of disease and outcome and to assess the efficacy of immunosuppressive treatment. METHODS: All GPA patients fulfilling ACR criteria or Chapel Hill Consensus Conference definitions or who had localized GPA and who developed orbital masses were evaluated regarding the course and outcome of the orbital masses (assessed by MRI, ophthalmologist and ENT specialist), all other clinical manifestations, disease stages, ANCA status, immunosuppression and its side effects and surgical procedures. RESULTS: Of 1142 GPA patients 58 developed orbital masses during a median follow-up of 101.5 months (range 23-255 months). Forty patients fulfilled the inclusion criteria and had complete clinical assessments [44% females, median age 43 (20-74) years, 85% ANCA positive]. Seventy-five per cent (29/40) had systemic disease when orbital masses occurred; both orbits were affected in 30%. Seventy-two per cent had evidence of infiltration from paranasal sinuses. Under highly potent immunosuppression (mostly CYC and glucocorticoids), 41% were refractory, 24% had unchanged activity, 24% showed a response and 8.1% had complete remission. Forty-four per cent had relapses of orbital masses. Seventy-two per cent developed visual impairment, 19% suffered blindness. Blindness was associated with a longer time to remission and a relapsing and refractory course. CONCLUSION: Orbital masses are a rare manifestation of GPA and are characterized by a refractory course and by a high rate of local damage. Patients with a refractory or relapsing course are at higher risk of developing blindness.

Treatment of ANCA-associated vasculitides (AAV).

Treatment of AAV follows the principle of a combined remission induction and maintenance strategy and is adapted in a stage and activity-adapted fashion. So far the combination therapy of glucocorticoids and conventional immunosuppressive drugs has mainly been used to control disease. This approach has led to a significant improvement in outcome in spite of persistently high early mortality rates of nearly 11% within the first year. Besides conventional treatment, biologics have emerged as a new treatment option. The paper summarizes the current evidence for the use of conventional therapy and biologics in AAV.

Progranulin antibodies in autoimmune diseases.

Systemic vasculitides constitute a heterogeneous group of diseases. Autoimmunity mediated by B lymphocytes and their humoral effector mechanisms play a major role in ANCA-associated vasculitis (AAV) as well as in non-ANCA associated primary systemic vasculitides and in the different types of autoimmune connective tissue disorders and rheumatoid arthritis. In order to detect autoantibodies in systemic vasculitides, we screened protein macroarrays of human cDNA expression libraries with sera from patients with ANCA-associated and ANCA-negative primary systemic vasculitides. This approach led to the identification of antibodies against progranulin, a 88 kDA secreted glycoprotein with strong anti-inflammatory activity in the course of disease of giant-cell arteritis/polymyalgia rheumatica (14/65), Takayasu's arteritis (4/13), classical panarteritis nodosa (4/10), Behcet's disease (2/6) and in the course of disease in granulomatosis with polyangiitis (31/75), Churg-Strauss syndrome (7/23) and in microscopic polyangiitis (7/19). In extended screenings the progranulin antibodies were also detected in other autoimmune diseases such as systemic lupus erythematosus (39/91) and rheumatoid arthritis (16/44). Progranulin antibodies were detected only in 1 of 97 healthy controls. Anti-progranulin positive patients with systemic vasculitides, systemic lupus erythematosus or rheumatoid arthritis had significant lower progranulin plasma levels, indicating a neutralizing effect. In light of the anti-inflammatory effects of progranulin, progranulin antibodies might exert pro-inflammatory effects thus contributing to the pathogenesis of the respective autoimmune diseases and might serve as a marker for disease activity. This hypothesis is supported by the fact that a positive progranulin antibody status was associated with active disease in granulomatosis with polyangiitis.

A vasculitis centre based management strategy leads to improved outcome in eosinophilic granulomatosis and polyangiitis (Churg-Strauss, EGPA): monocentric experiences in 150 patients.

OBJECTIVE: To evaluate a vasculitis centre based management strategy for eosinophilic granulomatosis and polyangiitis (Churg-Strauss, EGPA). METHODS: A retrospective cohort study at a vasculitis referral centre was performed. All EGPA patients admitted from 1990 to 2009 were included. A structured interdisciplinary work-up for proof of diagnosis, Disease Extent Index and Birmingham Vasculitis Activity Score was performed. Immunosuppressive therapy was initiated and regularly adapted. Treatment targets were induction and maintenance of remission according to definitions given by the European League Against Rheumatism and the European Vasculitis Study Group. Outcomes were mortality, rate of remission, relapses, adverse events and prednisolone-dose. RESULTS: Out of 269 patients with suspected EGPA 150 fulfilled the inclusion criteria. Of those, 104 had more than one follow-up visit resulting in a mean follow up of 53±4.9 months. By using additional data sources the follow-up concerning survival was extended to 92±5 month. Severe organ manifestations occurred at heart (46%), kidney (18%) and lungs (10%). Cyclophosphamide was used in 107 patients (71%). The prednisolone-doses of all patients were within the targeted range (i.e. ≤7.5 mg) in 69% of the total follow-up time; the median dose at end of follow-up was 5mg/d. The 10-year survival rate was 89% resulting in mortality comparable to the general population (SMR 1.29). Only patients with cardiac failure associated with EGPA had an increased mortality (SMR 3.06). CONCLUSIONS: Regular re-evaluation and target-orientated adaption of therapy may lead to normalization of life expectancy and attenuation of disease progression. Continued centre based interdisciplinary treatment should be standard of care.

Genetically distinct subsets within ANCA-associated vasculitis.

BACKGROUND: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a severe condition encompassing two major syndromes: granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis) and microscopic polyangiitis. Its cause is unknown, and there is debate about whether it is a single disease entity and what role ANCA plays in its pathogenesis. We investigated its genetic basis. METHODS: A genomewide association study was performed in a discovery cohort of 1233 U.K. patients with ANCA-associated vasculitis and 5884 controls and was replicated in 1454 Northern European case patients and 1666 controls. Quality control, population stratification, and statistical analyses were performed according to standard criteria. RESULTS: We found both major-histocompatibility-complex (MHC) and non-MHC associations with ANCA-associated vasculitis and also that granulomatosis with polyangiitis and microscopic polyangiitis were genetically distinct. The strongest genetic associations were with the antigenic specificity of ANCA, not with the clinical syndrome. Anti-proteinase 3 ANCA was associated with HLA-DP and the genes encoding α(1)-antitrypsin (SERPINA1) and proteinase 3 (PRTN3) (P=6.2×10(-89), P=5.6×10(-12,) and P=2.6×10(-7), respectively). Anti-myeloperoxidase ANCA was associated with HLA-DQ (P=2.1×10(-8)). CONCLUSIONS: This study confirms that the pathogenesis of ANCA-associated vasculitis has a genetic component, shows genetic distinctions between granulomatosis with polyangiitis and microscopic polyangiitis that are associated with ANCA specificity, and suggests that the response against the autoantigen proteinase 3 is a central pathogenic feature of proteinase 3 ANCA-associated vasculitis. These data provide preliminary support for the concept that proteinase 3 ANCA-associated vasculitis and myeloperoxidase ANCA-associated vasculitis are distinct autoimmune syndromes. (Funded by the British Heart Foundation and others.).

Intra- and inter-rater reliability of endonasal activity estimation in granulomatosis with polyangiitis (Wegener´s).

OBJECTIVES: Granulomatosis with polyangiitis (GPA) frequently starts with an affection of the nasal and paranasal mucosa. Localised GPA of the nasal mucosa or persistent disease activity ('grumbling disease') is often encountered even under immunosuppressive therapy. Necessity for reconstructive surgery is common and careful scheduling to prevent failure and minimise revision rates is crucial. Therefore, reliable estimation of GPA activity in the upper airways using a score is mandatory for diagnosis, follow-up and scheduling reconstructive surgery. METHODS: Fifty endoscopic, endonasal images of 45 patients with GPA were used. Twelve (4 German, 8 Mexican) experienced (n=7) and inexperienced (n=5) physicians assessed GPA-activity at two times (T1/T2) in dichotomy and in a grading approach (none, mild, moderate and high activity) using the novel ENT Activity Score (ENTAS). All documents were written in English. RESULTS: Estimation of activity in dichotomy (none vs. mild/moderate/high): Cohen's Kappa (κ) for intra-rater reliability T1/T2 in inexperienced and experienced physicians was κ=0.58 (agreement 85%) and κ=0.72 (agreement 91%). The inter-rater reliability (Fleiss's κ) T1/T2 for inexperienced and experienced physicians was κ=0.62/κ=0.59 and κ=0.50/κ=0.58 respectively. Estimation of activity in grading approach (none, mild, moderate, high): for inexperienced physicians the intra-rater reliability T1/T2 was κ=0.67 (agreement 56%) and the inter-rater reliability at T1/T2 was κ=0.29 (intraclass correlation coefficient, ICC=0.69) and κ=0.27 (ICC=0.59). For experienced physicians the intra-rater reliability T1/T2 was κ=0.80 (agreement 67%) and the inter-rater reliability at T1 and T2 was κ=0.41 (ICC=0.77) and κ=0.39 (ICC=0.75) respectively. CONCLUSIONS: Intra-rater reliability is high in decision in dichotomy and even in grading activity. There is no difference for experienced or inexperienced physicians. Inter-rater reliability is high in dichotomy, but low for activity grading. Thus, the ENTAS provides a reliable instrument for assessing, documenting and following GPA-related disease activity in the upper respiratory tract. The relationship of activity and following damage needs to be investigated in further studies.

Treatment of refractory giant cell arteritis with cyclophosphamide:a retrospective analysis of 35 patients from three centres.

UNLABELLED: Patients with giant cell arteritis (GCA) refractory to standard immunosuppressive therapy may constitute a significant clinical problem with a high risk of glucocorticoid-related adverse effects. OBJECTIVES: To evaluate efficacy and safety of cyclophosphamide for remission induction in GCA patients with persistent disease activity despite standard immunosuppressive treatment. METHODS: Thirty-five individuals from 3 tertiary rheumatological centres treated for persistently active GCA unresponsive to treatment with glucocorticoids plus at least either methotrexate or azathioprine for a minimum of 3 months and unable to reduce daily glucocorticoid dose to <10 mg prednisolone equivalent. We recorded signs of disease activity (clinical, laboratory, imaging); course of glucocorticoid doses during cyclophosphamide treatment and follow-up; relapse rate; treatment-related adverse events; and survival. Since all patients had been refractory to standard therapy, a matched control group could not be defined. RESULTS: Data from 31 patients completing cyclophosphamide treatment were available for analysis. Twenty-eight patients (90.3%) responded with improved disease activity and sustained reduction of daily prednisolone intake to <10 mg (mean reduction -13.1 mg or -51.6%, p<0.001). Twelve months later, doses <7.5 or <5 mg were achieved in 89.3% and 67.7% of these patients on maintenance immunosuppressive treatment, respectively. Relapses occurred in 12 patients after a median of 20.5 months. Survival over 5 years was similar to expected rates of the general population. Adverse events comprised transient leucopenia, infections and 1 case of haemorrhagic cystitis. CONCLUSIONS: Cyclophosphamide can be considered a therapeutic option with an acceptable safety profile for remission induction in GCA refractory to standard immunosuppressive treatment.

Does glucocorticosteroid-resistant large-vessel vasculitis (giant cell arteritis and Takayasu arteritis) exist and how can remission be achieved? A critical review of the literature.

OBJECTIVES: The mainstay in the treatment of the large-vessel vasculitides giant cell arteritis (GCA) and Takayasu arteritis (TA) are glucocorticosteroids (GC) for induction of remission as well as for its maintenance in low doses for 1 to 2 years. However, clinical practice includes GC-resistant cases without sufficient response to standard GC for induction of remission and GC-dependent cases where a dose reduction of GC without relapse is impossible after successful induction of remission. The aim of this study was to evaluate the data on treatment options in these situations. METHODS: A literature search in PubMed matching the terms TA and GCA as well as temporal arteritis with all possible immunosuppressive and biological agents as well as with the terms 'treatment, therapy and management' was performed. RESULTS: Sixty-four publications were found. Five case series described large cohorts of patients with GCA (n=2) or TA (n=3) showing that 40.8% to 48% of GCA patients and 46% to 84% of TA patients require additional immunosuppressive agents to achieve remission and taper GC. Most were on biologic agents (mainly infliximab, 24 publications/123 patients), followed by methotrexate (MTX) (14/113), cyclophosphamide (CYC) (9/27), azathioprine (AZA) (8/51), cyclosporine A (CSA) (6/47), mycophenolate mofetil (MMF) (3/32), leflunomide (LEF) (2/2), chlorambucil (1/1) and antimalarials (1/36). There were also 2 case reports on autologous stem cell transplantation. The distribution of the two entities TA and GCA was as follows: MTX: 98% GCA, 2% TA; IFX: 26.8% GCA, 73.2% TA; CYC: 70.4% GCA, 29.6% TA; AZA: 100% GCA; LEF: 100% TA; MMF: 100% TA; antimalarials: 100% GCA, autologous stem cell transplantation: 100% TA. A distinction between GC-resistant and GC-dependent cases could not be made from the data available. However, 50 (79%) of the publications described GC-resistant cases. Whereas almost all case reports and retrospective case series (with the exception of CSA) revealed steroid-sparing effects, the 3 prospective randomised trials and 2 open prospective controlled trials on MTX gave conflicting results. However, a recent meta-analysis which recalculated the original data resulted in superiority of MTX after 24 months, there were less relapses and lower GC doses in the MTX group. The prospective controlled IFX trial where IFX was randomised against placebo after GC-induced remission of GCA did not show advantages for IFX over GC alone for maintenance of remission. The prospective controlled ETA trial, which comprised 17 GCA patients, showed small, non-significant advantages but was too small to draw definite conclusions. CONCLUSIONS: Although GCA is the commonest systemic vasculitis, prospective randomised trials on steroid sparing agents are rare and mostly included only small patient numbers. Inclusion and response criteria were heterogeneous, and observation periods and follow-up were often short. Criteria for GC-resistance or GC-dependence and for disease remission have not been uniformly defined. There is still an urgent need for prospective randomised trials with larger patient groups, longer follow-up and well defined inclusion criteria and criteria for response and relapse, using standardised disease activity scoring systems, in order to be able to give evidence-based recommendations for patients not responding to GC alone in the future.