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European League Against Rheumatism recommendations for the management of psoriatic arthritis with pharmacological therapies

Background Psoriatic arthritis (PsA) is a clinically heterogeneous disease. Clear consensual treatment guidance focused on the musculoskeletal manifestations of PsA would be advantageous. The authors present European League Against Rheumatism (EULAR) recommendations for the treatment of PsA with systemic or local (non-topical) symptomatic and disease-modifying antirheumatic drugs (DMARD). Methods The recommendations are based on evidence from systematic literature reviews performed for non-steroidal anti-inflammatory drugs (NSAID), glucocorticoids, synthetic DMARD and biological DMARD. This evidence was discussed, summarised and recommendations were formulated by a task force comprising 35 representatives, and providing levels of evidence, strength of recommendations and levels of agreement. Results Ten recommendations were developed for treatment from NSAID through synthetic DMARD to biological agents, accounting for articular and extra-articular manifestations of PsA. Five overarching principles and a research agenda were defined. Conclusion These recommendations are intended to provide rheumatologists, patients and other stakeholders with a consensus on the pharmacological treatment of PsA and strategies to reach optimal outcomes, based on combining evidence and expert opinion. The research agenda informs directions within EULAR and other communities interested in PsA.

Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis

Background Since initial approval for the treatment of rheumatoid arthritis (RA), rituximab has been evaluated in clinical trials involving various populations with RA. Information has also been gathered from registries. This report therefore updates the 2007 consensus document on the use of rituximab in the treatment of RA. Methods Preparation of this new document involved many international experts experienced in the treatment of RA. Following a meeting to agree upon the core agenda, a systematic literature review was undertaken to identify all relevant data. Data were then interrogated by a drafting committee, with subsequent review and discussion by a wider expert committee leading to the formulation of an updated consensus statement. These committees also included patients with RA. Results The new statement covers wide-ranging issues including the use of rituximab in earlier RA and impact on structural progression, and aspects particularly pertinent to rituximab such as co-medication, optimal dosage regimens, repeat treatment cycles and how to manage non-response. Biological therapy following rituximab usage is also addressed, and safety concerns including appropriate screening for hepatitis, immunoglobulin levels and infection risk. This consensus statement will support clinicians and inform patients when using B-cell depletion in the management of RA, providing up-to-date information and highlighting areas for further research. Conclusion New therapeutic strategies and treatment options for RA, a chronic destructive and disabling disease, have expanded over recent years. These have been summarised in general strategic suggestions and specific management recommendations, emphasising the importance of expedient disease-modifying antirheumatic drug implementation and tight disease control. This consensus statement is in line with these fundamental principles of management.

Rheumatoid Arthritis subtypes identified by genomic profiling of peripheral blood cells: Assignment of a type I interferon signature in a subpopulation of patients

Background: Rheumatoid arthritis (RA) is a heterogeneous disease with unknown cause. Aim: To identify peripheral blood (PB) gene expression profiles that may distinguish RA subtypes. Methods: Large-scale expression profiling by cDNA microarrays was performed on PB from 35 patients and 15 healthy individuals. Differential gene expression was analysed by significance analysis of microarrays (SAM), followed by gene ontology analysis of the significant genes. Gene set enrichment analysis was applied to identify pathways relevant to disease. Results: A substantially raised expression of a spectrum of genes involved in immune defence was found in the PB of patients with RA compared with healthy individuals. SAM analysis revealed a highly significant elevated expression of interferon (IFN) type I regulated genes in patients with RA compared with healthy individuals, which was confirmed by gene ontology and pathway analysis, suggesting that this pathway was activated systemically in RA. A quantitative analysis revealed that increased expression of IFN-response genes was characteristic of approximately half of the patients (IFNhigh patients). Application of pathway analysis revealed that the IFNhigh group was largely different from the controls, with evidence for upregulated pathways involved in coagulation and complement cascades, and fatty acid metabolism, while the IFNlow group was similar to the controls. Conclusion: The IFN type I signature defines a subgroup of patients with RA, with a distinct biomolecular phenotype, characterised by increased activity of the innate defence system, coagulation and complement cascades, and fatty acid metabolism.

Inhibition of joint damage and improved clinical outcomes with rituximab plus methotrexate in early active rheumatoid arthritis: the IMAGE trial

Objectives Rituximab is an effective treatment in patients with established rheumatoid arthritis (RA). The objective of the IMAGE study was to determine the efficacy of rituximab in the prevention of joint damage and its safety in combination with methotrexate (MTX) in patients initiating treatment with MTX. Methods In this double-blind randomised controlled phase III study, 755 MTX-naïve patients with active RA were randomly assigned to MTX alone, rituximab 2×500 mg + MTX or rituximab 2×1000 mg + MTX. The primary end point at week 52 was the change in joint damage measured using a Genant-modified Sharp score. Results 249, 249 and 250 patients were randomly assigned to MTX alone, rituximab 2×500 mg + MTX or rituximab 2×1000 mg + MTX, respectively. At week 52, treatment with rituximab 2×1000 mg + MTX compared with MTX alone was associated with a reduction in progression of joint damage (mean change in total modified Sharp score 0.359 vs 1.079; p=0.0004) and an improvement in clinical outcomes (ACR50 65% vs 42%; p<0.0001); rituximab 2×500 mg + MTX improved clinical outcomes (ACR50 59% vs 42%; p<0.0001) compared with MTX alone but did not significantly reduce the progression of joint damage. Safety outcomes were similar between treatment groups. Conclusions Treatment with rituximab 2×1000 mg in combination with MTX is an effective therapy for the treatment of patients with MTX-naïve RA. CLinicalTrials.gov identifier NCT00299104.

Chemokine blockade and chronic inflammatory disease: proof of concept in patients with rheumatoid arthritis

Background: Chemokines and their receptors are considered important contributors in cell migration and inflammation in chronic inflammatory disorders. Chemokines affecting monocytes/macrophages are considered potential therapeutic targets, but no studies of the effects of blocking the chemokine repertoire in humans with a chronic inflammatory disease have been reported. Objective: To carry out a double blind, placebo controlled, phase Ib clinical trial with a specific, oral CCR1 antagonist. Methods: 16 patients with active rheumatoid arthritis (RA) were randomised 3:1 to active:placebo treatment for 14 days. Synovial biopsy specimens were obtained on days 1 and 15. Immunohistochemistry was used to detect the presence of various cell types before and after treatment and the results measured by digital image analysis. Results before and after treatment were compared by paired t test, and a two sample t test was used to compare the changes from baseline in the two groups. Results: All patients completed the study. A significant reduction in the number of macrophages (p=0.016), intimal macrophages (p=0.026), and CCR1+cells (p=0.049) in patients treated with the chemokine antagonist compared with the placebo group occurred in the synovium. Significant decreases in overall cellularity, intimal lining layer cellularity, CD4+ T cells, and CD8+ T cells also occurred in treated patients. Cells lacking CCR1 were not affected. Trends towards clinical improvement were seen in the treated patients but not in the placebo group. Severe side effects were not reported. Conclusion: Specific chemokine receptor blockade can result in relevant biological effects in patients with active RA.

Atacicept in patients with rheumatoid arthritis: results of a multicenter, phase Ib, double-blind, placebo-controlled, dose-escalating, single- and repeated-dose study.

OBJECTIVE Atacicept is a recombinant fusion protein that binds and neutralizes B lymphocyte stimulator and a proliferation-inducing ligand. The purpose of this study was to investigate the tolerability, pharmacokinetics, and pharmacodynamics of atacicept treatment in patients with rheumatoid arthritis (RA) and to collect exploratory data on clinical outcomes. METHODS In this multicenter, phase Ib, randomized, placebo-controlled, dose-escalating trial, 73 patients were enrolled into 6 escalating-dose cohorts. Patients received atacicept or placebo as single doses (70, 210, or 630 mg) or as repeated doses given at 2-week intervals (3 doses of 70 mg, 3 doses of 210 mg, or 7 doses of 420 mg), followed by 10 weeks of trial assessments, with a followup assessment at 3 months after the final dose. RESULTS Atacicept was well tolerated, with few differences between treatment groups and no obvious safety concerns. The pharmacokinetics profile was nonlinear, but was consistent and predictable across all doses and regimens. Treatment-related decreases in immunoglobulin (particularly IgM) and rheumatoid factor levels were evident, and a clear decrease in anti-citrullinated protein antibodies was observed in the cohort that received 7 doses of 420 mg. The B cell response was biphasic, with an initial transient increase (dominated by memory B cells) followed by a dose-related decrease (dominated by mature B cells). Clinical assessments showed trends toward improvement with the 3-month treatment. Little effect on the erythrocyte sedimentation rate or C-reactive protein levels was seen. CONCLUSION Atacicept was well tolerated both systemically and locally. The results demonstrated that the biologic activity of atacicept was consistent with its mechanism of action.

Receptor activator NF-kappaB ligand (RANKL) expression in synovial tissue from patients with rheumatoid arthritis, spondyloarthropathy, osteoarthritis, and from normal patients: semiquantitative and quantitative analysis

Objectives: To compare receptor activator of NF-κB ligand (RANKL) production in the synovial tissue from patients with active rheumatoid arthritis (RA), inactive RA, spondyloarthropathies (SpA), osteoarthritis, and from normal subjects. In addition, to establish the cell lineages expressing RANKL in these tissues. Methods: Immunohistological analysis of frozen synovial tissue biopsy specimens was performed using a monoclonal antibody (mAb) to detect RANKL. Sections were evaluated by computer assisted image analysis and semiquantitative analysis to compare RANKL expression between groups. Dual and sequential labelling with mAb RANKL and cell lineage specific monoclonal antibodies were used to determine the types of cells expressing RANKL. Results: Higher levels of RANKL were expressed in tissues from patients with active RA and SpA than in tissues from patients with inactive RA, osteoarthritis, and from normal subjects. RANKL protein was associated with CD3 antigen-positive lymphocytes and some macrophages. RANKL was predominantly associated with activated, memory T cells (CD45Ro positive cells) in patients with active RA and spondyloarthropathy (SpA). Conclusions: The highest levels of RANKL were detected in patients with RA with active synovitis and in some patients with SpA. An increase in RANKL in the inflamed joint of patients with RA, produced by infiltrating activated T cells and macrophages, is likely to be an important cause of joint erosions in RA.

Detailed analysis of the cell infiltrate and the expression of mediators of synovial inflammation and joint destruction in the synovium of patients with psoriatic arthritis: implications for treatment

Background: The synovial tissue is a primary target of many inflammatory arthropathies, including psoriatic arthritis (PsA). Identification of proinflammatory molecules in the synovium may help to identify potentially therapeutic targets. Objective: To investigate extensively the features of cell infiltration and expression of mediators of inflammation and joint destruction in the synovium of patients with PsA compared with patients with rheumatoid arthritis matched for disease duration and use of drugs. Methods: Multiple synovial tissue biopsy specimens were obtained by arthroscopy from an inflamed joint in 19 patients with PsA (eight oligoarthritis, 11 polyarthritis) and 24 patients with rheumatoid arthritis. Biopsy specimens were analysed by immunohistochemistry to detect T cells, plasma cells, fibroblast-like synoviocytes, macrophages, proinflammatory cytokines, matrix metalloproteinases and tissue inhibitor metalloproteinase-1, adhesion molecules and vascular markers. Stained sections were evaluated by digital image analysis. Results: The synovial infiltrate of patients with PsA and rheumatoid arthritis was comparable with regard to numbers of fibroblast-like synoviocytes and macrophages. T cell numbers were considerably lower in the synovium of patients with PsA. The number of plasma cells also tended to be lower in PsA. The expression of tumour necrosis factor alpha (TNFα), interleukin (IL) 1β, IL6 and IL18 was as high in PsA as in rheumatoid arthritis. The expression of matrix metalloproteinases, adhesion molecules and vascular markers was comparable for PsA and rheumatoid arthritis. Conclusion: These data show increased proinflammatory cytokine expression in PsA synovium, comparable to results obtained for rheumatoid arthritis, and support the notion that, in addition to TNFα blockade, there may be a rationale for treatments directed at IL1β, IL6 and IL18.

Analysis of the cell infiltrate and expression of proinflammatory cytokines and matrix metalloproteinases in arthroscopic synovial biopsies: comparison with synovial samples from patients with end stage, destructive rheumatoid arthritis

Background: Synovial tissue (ST) from end stage destructive rheumatoid arthritis (RA) and arthroscopic biopsies obtained during active inflammation might exhibit different characteristics. Objective: To define the cell infiltrate and the expression of proinflammatory cytokines, angiogenic factors, and matrix metalloproteinases (MMPs) in ST selected at arthroscopy compared with that from end stage RA. Methods: Synovial biopsy specimens were obtained from the actively inflamed knee joints of 13 patients with chronic RA by arthroscopy and compared with ST from 10 patients with end stage, destructive RA. Immunohistological analysis was performed to detect T cells, plasma cells, macrophages, fibroblast-like synoviocytes (FLS), and the expression of interleukin (IL)1β, IL6, tumour necrosis factor α (TNFα), MMP-1, MMP-3, MMP-13, TIMP-1, and VEGF. Results: The expression of CD68+ macrophages was significantly higher in ST selected at arthroscopy than in samples obtained at surgery, both in the intimal lining layer and in the synovial sublining. The expression of CD3+ T cells also tended to be higher in arthroscopic samples. The expression of TNFα, IL6, MMP-1, MMP-3, MMP-13, TIMP-1, and VEGF was on average higher in ST obtained at arthroscopy. In contrast, the expression of IL1β was on average higher in surgical samples. Conclusion: Active arthritis activity is associated with increased cell infiltration, expression of proinflammatory cytokines, MMPs, and angiogenic growth factors in synovial biopsy samples selected at arthroscopy. Increased expression of IL1β in the synovium of patients with destructive RA requiring joint replacement may well reflect the important role of IL1β in cartilage and bone destruction.

The clinical response to infliximab in rheumatoid arthritis is in part dependent on pretreatment tumour necrosis factor α expression in the synovium

Objective: To determine whether the heterogeneous clinical response to tumour necrosis factor (TNF)α blocking therapy in rheumatoid arthritis (RA) can be predicted by TNFα expression in the synovium before initiation of treatment. Methods: Prior to initiation of infliximab treatment, arthroscopic synovial tissue biopsies were obtained from 143 patients with active RA. At week 16, clinical response was evaluated using the 28-joint Disease Activity Score (DAS28). Immunohistochemistry was used to analyse the cell infiltrate as well as the expression of various cytokines, adhesion molecules and growth factors. Stained sections were evaluated by digital image analysis. Student t tests were used to compare responders (decrease in DAS28 ⩾1.2) with non-responders (decrease in DAS28 <1.2) and multivariable regression was used to identify the independent predictors of clinical response. Results: Synovial tissue analysis confirmed our hypothesis that the baseline level of TNFα expression is a significant predictor of response to TNFα blocking therapy. TNFα expression in the intimal lining layer and synovial sublining were significantly higher in responders than in non-responders (p = 0.047 and p = 0.008, respectively). The numbers of macrophages, macrophage subsets and T cells (all able to produce TNFα) were also significantly higher in responders than in non-responders. The expression of interleukin (IL)1β, IL6, IL18, IL10, E-selectin, intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) was not associated with response to anti-TNFα treatment. Conclusion: The effects of TNFα blockade are in part dependent on synovial TNFα expression and infiltration by TNFα producing inflammatory cells. Clinical response cannot be predicted completely, indicating involvement of other as yet unknown mechanisms.