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.

The role of dynamic contrast-enhanced MRI in the differential diagnosis of psoriatic and rheumatoid arthritis.

OBJECTIVE: The purpose of this study was to investigate the role of dynamic contrast-enhanced MRI in the differential diagnosis of psoriatic and rheumatoid arthritis in the hand and wrist. SUBJECTS AND METHODS: Forty-five consecutive patients (31 patients with rheumatoid arthritis and 14 patients with psoriatic arthritis) were examined in a 3-T whole-body MR unit. After contrast injection, a 3D encoded spoiled gradient-echo sequence was used for measurement of the time course of contrast-medium uptake in the synovial tissue. On the basis of the gained uptake curves, the rate of early enhancement was calculated after 35 and 52 seconds, and the relative enhancement rate was calculated after 35 seconds, 52 seconds, 3 minutes, and 15 minutes (late enhancement). Dynamic contrast-enhanced MRI rates of patients with rheumatoid arthritis and psoriatic arthritis were compared and correlated with laboratory and clinical data. RESULTS: A statistically significant difference between the two groups was found regarding the relative enhancement rate after 15 minutes (p < 0.01). In contrast, no difference in relative enhancement rate was found 35 seconds, 52 seconds, or 3 minutes after contrast injection (p = 0.695, p = 0.573, and p = 0.278, respectively). Regarding the rate of early enhancement at 35 and 52 seconds, no significant difference between patients with rheumatoid arthritis and those with psoriatic arthritis was found. Significant correlations were found between inflammatory parameters and dynamic contrast-enhanced parameters in patients with rheumatoid arthritis but not in those with psoriatic arthritis. CONCLUSION: Fifteen minutes after contrast injection, a statistically significant difference between rheumatoid arthritis and psoriatic arthritis was found in synovial enhancement that might play an important role in differentiating the two diseases.

Magnetic resonance spin-labeling perfusion imaging of synovitis in inflammatory arthritis at 3.0 T.

OBJECTIVE: The aim of this study was to test the feasibility of arterial spin labeling (ASL) perfusion imaging of synovitis in inflammatory joint diseases on a clinical 3.0 T whole-body scanner. MATERIALS AND METHODS: Fifteen patients (geometric mean 47 years, range 8-69 years) with different types of inflammatory arthritis of the finger or wrist joints participated in the study. In addition to conventional spin-echo and dynamic contrast-enhanced FLASH3D sequences, a novel spin-labeling technique (FAIR-TrueFISP) for quantitative assessment of tissue perfusion was applied. Perfusion maps were calculated pixel-wise by means of the extended Bloch equations. RESULTS: Perfusion maps showed good image quality with clear visualization of hyperaemia in synovitis. The computed perfusion maps corresponded best to subtraction images of the dynamic series from 30 to 60 s after contrast-medium injection. The quantitative perfusion values of synovitis showed a good correlation with the disease activity. Perfusion values for inflamed synovium in phase of high activity were up to 230 ml/100 g tissue/min. CONCLUSION: The proposed modality allows for the assessment of disease activity in arthritis without the application of contrast-medium offering a new tool for therapy monitoring. As the technique provides quantitative information on hyperaemia, it potentially offers new insights in the pathophysiology of arthritic diseases.

Diagnostic and interventional MRI of the sacroiliac joints using a 1.5-T open-bore magnet: a one-stop-shopping approach.

OBJECTIVE: The objective of our study was to prospectively test the hypothesis that combined diagnostic and interventional MRI of the sacroiliac joints can be performed efficiently and effectively. SUBJECTS AND METHODS: Over a 12-month period, 60 patients (32 women and 28 men; median age, 28 years; age range, 18-49 years) with chronic lower back pain suspected to originate from the sacroiliac joints were enrolled in the study. Based on diagnostic MRI findings, MR fluoroscopy-guided sacroiliac joint injections were performed in 57 (95%) patients. Diagnostic injections (35, 58.3%) were performed if nonspecific or degenerative MRI findings were present. Therapeutic injections (22, 36.7%) were performed in patients with inflammatory arthropathy. In three (5%) patients, no injections were performed. Technical effectiveness was assessed by analyzing, first, the rate of intraarticular injection; second, the time required for the procedure; third, image quality; and, fourth, occurrence of complications and clinical outcome by analyzing pain intensity changes and volume and signal intensity of sacroiliac inflammatory changes. RESULTS: The rate of intraarticular injection was 90.4% (103/114). The mean length of time for the procedure was 50 minutes (range, 34-103 minutes), with exponential shortening over time (p < or = 0.001). The contrast-to-noise ratios of the needle and tissues were sufficiently different for excellent delineation of the needle. No complications occurred. Diagnostic injections identified the sacroiliac joints as generating significant pain in 46.9% (15/32) of the patients. Three months after therapeutic injections, pain intensity had decreased by 62.5% (p < or = 0.001) and the volume and relative signal intensity of inflammatory changes had decreased by 37.5% (p = 0.003) and 47.6% (p < or = 0.001), respectively. CONCLUSION: We accept the hypothesis that combined diagnostic and interventional MRI of the sacroiliac joints can be performed efficiently and effectively for comprehensive diagnosis and therapy of lower back pain originating from the sacroiliac joints.

Whole Exome Sequencing Identifies Rare Protein-Coding Variants in Behçet's Disease.

OBJECTIVE: Behçet's disease (BD) is a systemic inflammatory disease with an incompletely understood etiology. Despite the identification of multiple common genetic variants associated with BD, rare genetic variants have been less explored. We undertook this study to investigate the role of rare variants in BD by performing whole exome sequencing in BD patients of European descent. METHODS: Whole exome sequencing was performed in a discovery set comprising 14 German BD patients of European descent. For replication and validation, Sanger sequencing and Sequenom genotyping were performed in the discovery set and in 2 additional independent sets of 49 German BD patients and 129 Italian BD patients of European descent. Genetic association analysis was then performed in BD patients and 503 controls of European descent. Functional effects of associated genetic variants were assessed using bioinformatic approaches. RESULTS: Using whole exome sequencing, we identified 77 rare variants (in 74 genes) with predicted protein-damaging effects in BD. These variants were genotyped in 2 additional patient sets and then analyzed to reveal significant associations with BD at 2 genetic variants detected in all 3 patient sets that remained significant after Bonferroni correction. We detected genetic association between BD and LIMK2 (rs149034313), involved in regulating cytoskeletal reorganization, and between BD and NEIL1 (rs5745908), involved in base excision DNA repair (P = 3.22 × 10(-4) and P = 5.16 × 10(-4) , respectively). The LIMK2 association is a missense variant with predicted protein damage that may influence functional interactions with proteins involved in cytoskeletal regulation by Rho GTPase, inflammation mediated by chemokine and cytokine signaling pathways, T cell activation, and angiogenesis (Bonferroni-corrected P = 5.63 × 10(-14) , P = 7.29 × 10(-6) , P = 1.15 × 10(-5) , and P = 6.40 × 10(-3) , respectively). The genetic association in NEIL1 is a predicted splice donor variant that may introduce a deleterious intron retention and result in a noncoding transcript variant. CONCLUSION: We used whole exome sequencing in BD for the first time and identified 2 rare putative protein-damaging genetic variants associated with this disease. These genetic variants might influence cytoskeletal regulation and DNA repair mechanisms in BD and might provide further insight into increased leukocyte tissue infiltration and the role of oxidative stress in BD.

Efficacy and safety of rituximab treatment in patients with antineutrophil cytoplasmic antibody-associated vasculitides: results from a German registry (GRAID).

OBJECTIVE: Rituximab (RTX) therapy is a treatment option in patients with refractory antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We investigated the tolerability and clinical efficacy of RTX in a cohort of patients with refractory AAV. METHODS: Clinical and safety data of patients with AAV treated with RTX were retrospectively assessed from the data of a German national registry. RESULTS: In total, 58 patients were included in this analysis (50/58 with granulomatosis with polyangiitis; 8/58 with microscopic polyangiitis who received at least 1 cycle, 17 patients who received 2 cycles, and 3 patients who received 3 cycles of RTX). Response was classified as complete and partial in 22 (40%) and in 29 cases (52.7%), respectively. Four patients (7.3%) were classified as nonresponders. CONCLUSION: RTX was well tolerated with good clinical efficacy in patients with refractory AAV.