Progression Of Psoriatic Arthritis Research Articles

Golimumab per il trattamento dell’artrite psoriasica

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of golimumab (Schering-Plough/Centocor) to submit evidence for the clinical and cost effectiveness of this drug for the treatment of active and progressive psoriatic arthritis (PsA) in patients who have responded inadequately to previous disease-modifying anti-rheumatic drugs (DMARDs). The Centre for Reviews and Dissemination and the Centre for Health Economics at the University of York were commissioned to act as the Evidence Review Group (ERG) to critically appraise the evidence presented by the manufacturer. This article provides a description of the company submission, the ERG review and the resulting NICE guidance. The ERG critically reviewed the evidence presented in the manufacturer’s submission and identified areas requiring clarification, for which the manufacturer provided additional evidence.

New developments in our understanding of psoriatic arthritis and their impact on the diagnosis and clinical management of the disease

Psoriatic arthritis (PsA) is a spondyloarthritis with a comorbid association with psoriasis. Without appropriate treatment it can be progressive, severe, deforming and destructive. It has long been recognized that subsets of PsA patients exist, characterized by different patterns of joint involvement. Associations between development of PsA and certain human leukocyte antigens (HLA) have been established. Evidence now suggests that progression of PsA is also genetically determined. The presence of one allele (HLA-B*27) has been associated with a distinct phenotype characterized by early joint involvement, whereas development of musculoskeletal symptoms is much slower in patients with another allele, C*06. Dermatologists need to consider what these differences in genotypes and phenotypes mean for clinical practice. Delay in the diagnosis of PsA is a significant contributor to poor patient outcomes, but there is evidence that PsA is underdiagnosed among psoriasis patients attending dermatology clinics. Dermatologists need to identify PsA symptoms among their psoriasis patients and refer for rheumatological assessment where appropriate. Treatment should address all aspects of the disease, including skin, nail and joint symptoms as well as physical functioning and quality of life. The existence of distinct phenotypic and genetic PsA subsets means dermatologists need to consider which drugs are likely to be most efficacious in which patient populations. Stratification of PsA according to susceptibility genes may in future help identify patients requiring more aggressive treatment to prevent progression. Biologic therapies show efficacy in PsA, but the patient populations of clinical trials are not always representative of patients treated with biologics in clinical practice.

SAT0290 Effect of tnf antagonists on radiographic progression in psoriatic arthritis: Systematic review and meta-analysis of randomized controlled trials

BackgroundPsoriatic arthritis (PsA) can cause important structural damages which can lead to disability. TNF antagonists have shown their clinical efficacy in PsA, but only a few data are available regarding...

Biomarkers of Radiographic Progression in Psoriatic Arthritis: A Report from the GRAPPA 2011 Annual Meeting

Clinical markers of radiographic progression have been studied in patients with psoriatic arthritis (PsA), and results have clearly confirmed the progression of radiographic damage over a 2-year period. Biomarkers of radiographic progression damage (erosion and new bone formation) have also been identified as a critical research issue in these patients. At the 2011 annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), members discussed development of a pivotal observational study (PsA Biodam study) to determine the validity of several soluble biomarkers in predicting structural damage in patients with PsA receiving standard therapies. Specific protocol issues discussed were the inclusion criteria, selection of candidate biomarkers, timing of sample collection, the primary radiographic outcome measure, radiographic scoring methods, possible substudies, and funding strategies.

Golimumab for the Treatment of Psoriatic Arthritis

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of golimumab (Schering-Plough/Centocor) to submit evidence for the clinical and cost effectiveness of this drug for the treatment of active and progressive psoriatic arthritis (PsA) in patients who have responded inadequately to previous disease-modifying anti-rheumatic drugs (DMARDs). The Centre for Reviews and Dissemination and the Centre for Health Economics at the University of York were commissioned to act as the Evidence Review Group (ERG) to critically appraise the evidence presented by the manufacturer. This article provides a description of the company submission, the ERG review and the resulting NICE guidance. The ERG critically reviewed the evidence presented in the manufacturer's submission and identified areas requiring clarification, for which the manufacturer provided additional evidence. The main clinical effectiveness data were derived from a single phase III randomized controlled trial (GO-REVEAL) that compared golimumab with placebo for the treatment of active and progressive patients who were symptomatic despite the use of previous DMARDs or NSAIDs. The 14-week data showed that, compared with placebo, golimumab 50 mg significantly improved joint disease response as measured by American College of Rheumatology (ACR) 20 (relative risk [RR] 5.73, 95% CI 3.24, 10.56) and Psoriatic Arthritis Response Criteria (PsARC) [RR 3.45, 95% CI 2.49, 4.87], and significantly improved skin disease response as measured by Psoriasis Area and Severity Index (PASI) 75 (RR 15.95, 95% CI 4.62, 59.11). The 24-week absolute data showed that these treatment benefits were maintained. There was a significant improvement in patients' functional status as measured by Health Assessment Questionnaire change from baseline at 24 weeks (-0.33; p < 0.001). The open-label extension data showed that these beneficial effects were also maintained at 52 and 104 weeks. The ERG identified several issues relating to the clinical effectiveness results. Analyses of the 24-week data were less robust, failing to adjust for treatment contamination due to patient crossover at week 16. It was also unclear if these results were generalizable to clinical practice. No randomized controlled trial compared the effectiveness of different biologic therapies head-to-head. To compare the effectiveness of the biologics etanercept, infliximab, adalimumab and golimumab, the manufacturer conducted a network meta-analysis, including the comparator palliative care (usual care including use of NSAIDs or DMARDs). The ERG considered the assumption of exchangeability between the trials for the purpose of the network meta-analysis to be acceptable and the statistical approach to be reliable. The results indicated somewhat lower efficacy with golimumab than with comparator biologics. The ERG identified a number of issues relating to the cost-effectiveness results. The manufacturer calculated incremental cost-effectiveness ratios (ICERs) incorrectly by comparing golimumab with palliative care instead of the most cost-effective alternative (etanercept). Despite the manufacturer's claim that golimumab was a cost-effective treatment option, the manufacturer's own model showed that golimumab was unlikely to be cost effective, relative to currently accepted thresholds, when the ICERs were correctly calculated using an incremental analysis (i.e. comparing each treatment to the next best alternative). None of the sensitivity analyses carried out by the manufacturer or the ERG regarding uncertainty in the estimates of clinical effectiveness, the acquisition and administration cost of drugs, the cost of treating psoriasis and the utility functions estimated to generate health outcomes changed this conclusion. However, a key area in determining the cost effectiveness of biologics was whether they should be treated as a class. The ERG concluded that if all biologics were considered equally effective, then etanercept, adalimumab and golimumab had almost equal costs and equal QALYs, and all had an ICER of about £15 000 per QALY versus palliative care, whilst infliximab, with a higher acquisition cost, was dominated by the other biologics. The Appraisal Committee altered its position between the Appraisal Consultation Document and the Final Appraisal Determination. It ultimately recommended that golimumab be provided as an option for the treatment of active and progressive PsA in adults only if (i) it is used as described for other tumour necrosis factor inhibitor treatments in 'Etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis' (NICE clinical guideline 199); and (ii) the manufacturer provides the 100 mg dose of golimumab at the same cost as the 50 mg dose.

The Path Forward to Biomarker Discovery in Psoriatic Disease: A Report from the GRAPPA 2010 Annual Meeting

At the 2010 annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), wide-ranging discussions were held regarding biomarker research in psoriatic disease. Consensus was reached on 2 areas of priority: (1) the study of soluble biomarkers of radiographic progression in psoriatic arthritis (PsA); and (2) the analysis of comorbidity biomarkers, specifically cardiovascular and articular, in a psoriasis inception cohort. For each of these areas, rigorous definition of the clinical phenotype of PsA will be essential. To date, 2 instruments have been identified to define the phenotype: the ClASsification of Psoriatic ARthritis criteria and various screening questionnaires. In this overview, we discuss the challenges of the clinical phenotype of PsA and review GRAPPA plans for developing a research program for biomarker discovery.

Zoledronic acid does not reduce MRI erosive progression in PsA but may suppress bone oedema: the Zoledronic Acid in Psoriatic Arthritis (ZAPA) Study

BackgroundThe effect of zoledronic acid (ZA) on articular bone in patients with psoriatic arthritis (PsA) was investigated using MRI.MethodsPatients with erosive PsA were randomised to receive 3-monthly infusions of ZA...

Etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis: a systematic review and economic evaluation

Background Etanercept, infliximab and adalimumab are licensed in the UK for the treatment of active and progressive psoriatic arthritis (PsA) in adults who have an inadequate response to standard treatment. Objective To determine the clinical effectiveness, safety and cost-effectiveness of these biologic agents in the treatment of active and progressive PsA. Data sources Systematic reviews were performed, with data sought from 10 electronic databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Science Citation Index, Conference Proceedings Citation Index – Science, ClinicalTrials.gov, metaRegister of Current Controlled Trials, NHS Economic Evaluation Database, Health Economic Evaluations Database and EconLit) up to June 2009. Review methods Full paper manuscripts of titles/abstracts considered relevant were obtained and assessed for inclusion by two reviewers according to criteria on study design, interventions, participants and outcomes. Data on study and participant characteristics, efficacy outcomes, adverse effects, costs to the health service and cost-effectiveness were extracted, along with baseline data where reported. The primary efficacy outcomes were measures of anti-inflammatory response, skin lesion response and functional status, and the safety outcome was the incidence of serious adverse events. The primary measure of cost-effectiveness was incremental cost per additional quality-adjusted life-year (QALY). Standard meta-analytic techniques were applied to efficacy data. Published cost-effectiveness studies and the economic analyses submitted to the National Institute for Health and Clinical Excellence (NICE) by the biologic manufacturers were reviewed. An economic model was developed by updating the model produced by the York Assessment Group for the previous NICE appraisal of biologics in PsA. Results Pooled estimates of effect demonstrated a significant improvement in patients with PsA for all joint disease and functional status outcomes at 12–14 weeks’ follow-up. The biologic treatment significantly reduced joint symptoms for etanercept [relative risk (RR) 2.60, 95% confidence interval (CI) 1.96 to 3.45], infliximab (RR 3.44, 95% CI 2.53 to 4.69) and adalimumab (RR 2.24, 95% CI 1.74 to 2.88), with 24-week data demonstrating maintained treatment effects. Trial data demonstrated a significant effect of all three biologics on skin disease at 12 or 24 weeks. Evidence synthesis found that infliximab appeared to be most effective across all outcomes of joint and skin disease. The response in joint disease was greater with etanercept than with adalimumab, whereas the response in skin disease was greater with adalimumab than with etanercept, although these differences are not statistically significant. Under base-case assumptions, etanercept was the most likely cost-effective strategy for patients with PsA and mild-to-moderate psoriasis if the threshold for cost-effectiveness was £20,000 or £30,000 per QALY. All biologics had a similar probability of being cost-effective for patients with PsA and moderate-to-severe psoriasis at a threshold of £20,000 per QALY. Limitations Limited available efficacy data and difficulty in assessing PsA activity and its response to biologic therapy. Conclusions The data indicated that etanercept, infliximab and adalimumab were efficacious in the treatment of PsA compared with placebo, with beneficial effects on joint symptoms, functional status and skin. Short-term data suggested that these biologic agents can delay joint disease progression and evidence to support their use in the treatment of PsA is convincing. Future research would benefit from long-term observational studies with large sample sizes of patients with PsA to demonstrate that beneficial effects are maintained, along with further monitoring of the safety profiles of the biologic agents. Funding The National Institute for Health Research Health Technology Assessment programme.

Cost-effectiveness of infliximab for the treatment of active and progressive psoriatic arthritis

Background Despite its proven efficacy, infliximab is often considered to be an expensive treatment for patients with psoriatic arthritis. Objectives To estimate the cost-effectiveness of infliximab among patients with active and progressive psoriatic arthritis. Methods A decision analytic model was constructed to simulate disease progression in hypothetical cohorts of patients with psoriatic arthritis receiving infliximab maintenance treatment. The primary response measure was change in Health Assessment Questionnaire score from a baseline estimated from mixed treatment models drawn from published clinical trials. Palliative care, comprising nonbiologic disease-modifying antirheumatic drugs, was used as a comparator. The primary outcome was quality-adjusted life years. The dose of infliximab was estimated for a range of 60 to 80 kg per patient body weight. The costs and outcomes were discounted at 3.5% for a period of 40 years. Uncertainty around the results was explored with probabilistic sensitivity analysis. Results The mixed treatment comparison showed a significant reduction in Health Assessment Questionnaire score across all patients. The tumor necrosis factor α inhibitors were significantly superior to palliative care but comparable with one another. The incremental cost-effectiveness ratios for etanercept, adalimumab, and infliximab relative to palliative care were £17,327; £19,246; and £16,942 to £23,022, respectively, across all patients with psoriatic arthritis and £16,613; £18,170; and £15,788 to £21,736, respectively, in the subgroup with significant psoriasis. Conclusion Infliximab represents a cost-effective treatment option well within the National Institute for Health and Clinical Excellence threshold relative to palliative care. In light of equivalent outcomes with other tumor necrosis factor α inhibitors, its position in the treatment pathway is likely to be governed by treatment costs.

Role of Th17 cells in human autoimmune arthritis

To delineate the role of Th17 cells in the pathogenesis of autoimmune arthritides. Th17 cells were analyzed in well-defined homogeneous cohorts of patients with the prototypical autoimmune arthritides rheumatoid arthritis (RA) and psoriatic arthritis (PsA), grouped according to patients who had very early active RA (n = 36; mean disease duration 2.8 months, Disease Activity Score in 28 joints 5.0) and those who had very early active PsA (n = 20; mean disease duration 2.3 months), none of whom had received treatment with glucocorticoids or disease-modifying antirheumatic drugs, as well as patients with established RA (n = 21; mean disease duration 68 months) who were considered either responders or nonresponders to therapy. Groups of healthy individuals and patients with osteoarthritis (a noninflammatory arthritis) were used as control cohorts. Expression of T lineage-specific transcription factors (RORC, T-bet, GATA-3, and FoxP3) and the response of CD4 T cells to Th17 cell-inducing conditions were analyzed in vitro. The frequencies of Th17 cells and levels of interleukin-17 strongly correlated with systemic disease activity at both the onset and the progression of RA or PsA. The values were reduced to control levels in patients with treatment-controlled disease activity. Th17 cells were enriched in the joints, and increased frequencies of synovial Th17 cells expressed CCR4 and CCR6, indicative of selective migration of Th17 cells to the joints. The intrinsically elevated expression of RORC, accompanied by biased Th17 cell development, and the resistance of Th17 cells to a natural cytokine antagonist in patients with RA and patients with PsA were suggestive of the underlying molecular mechanisms of uncontrolled Th17 activity in these patients. Th17 cells play an important role in inflammation in human autoimmune arthritides, both at the onset and in established disease.

Emerging drugs for psoriatic arthritis

Importance of the field: The socioeconomic burden of psoriatic arthritis (PsA) is considerable and not different from that of rheumatoid arthritis. Current treatment options do not always allow reaching the therapeutic objectives consisting of the remission of symptoms and prevention of the appearance of damage in the early stage of PsA or the blocking of PsA progression in the established cases.Areas covered in this review: After reviewing the current treatment choices, we examine the new drugs in clinical Phase II and III trials for PsA up to January 2010. Information was mainly obtained from the network of international clinical trial registries.What the reader will gain: The current management of PsA includes NSAIDs, corticosteroids, disease-modifying antirheumatic drugs (DMARDs) and anti-TNF-α blocking agents. These last drugs are more effective than traditional DMARDs on symptoms/signs of inflammation, quality of life and function and can inhibit the progression of the structural joint damage. Recent advancement in the knowledge of the immunopathogenesis of PsA has permitted the development of novel drugs including new TNF-α blockers, IL-1, -6, -12, -23 and -17 inhibitors, co-stimulator modulation inhibitors, B-cell depleting agents, small molecules and receptor activator of NF-κB/receptor activator of NF-κB ligand inhibitors.Take home message: The currently available anti-TNF-α blocking agents have revolutionized the management of PsA. However, there is a need for more effective and safer drugs.

Clinical efficacy of TNF-α inhibitors: an update

Over the last decade, TNF-α antagonists became the most powerful tools for controlling patient suffering from a number of rheumatic diseases. Infliximab, etanercept and adalimumab can induce remission and prevent both clinical and radiological disease progression in rheumatoid arthritis with significant improvement in patients’ symptoms, function and quality of life. They improve joint symptoms and significantly retard radiographic progression in psoriatic arthritis. TNF-α antagonists have been demonstrated to reduce disease activity, retard radiologic progression and increase quality of life in ankylosing spondylitis patients. Long-term follow-up studies demonstrated sustained efficacy and acceptable safety profiles that were comparable in rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis. Etanercept is the only US FDA-approved TNF antagonist for juvenile rheumatoid arthritis. TNF-α antagonists may improve some clinical manifastations of Behcet’s disases, including uveitis. Tuberculosi...

Risk factors for radiographic progression in psoriatic arthritis: subanalysis of the randomized controlled trial ADEPT

IntroductionTo identify independent predictors of radiographic progression in psoriatic arthritis (PsA) for patients treated with adalimumab or placebo in the Adalimumab Effectiveness in PsA Trial (ADEPT).MethodsUnivariate analyses and multivariate linear regression analyses assessed risk for radiographic progression (change in modified total Sharp score, ΔmTSS > 0.5) from baseline to week 24 for C-reactive protein (CRP) and other baseline variables, and for 24-week time-averaged CRP (univariate analysis only). Subanalyses determined mean ΔmTSS for CRP subgroups. Analyses were post hoc, with observed data.ResultsOne hundred and forty-four adalimumab-treated patients and 152 placebo-treated patients were assessed. Mean CRP was 64% lower by week 2 with adalimumab and essentially unchanged with placebo. Univariate analyses indicated that elevated CRP at baseline and time-averaged CRP were strongly associated with radiographic progression for placebo-treated patients but not for adalimumab-treated patients. Multivariate analysis confirmed that elevated baseline CRP was the only strong independent risk factor for radiographic progression (for CRP ≥1.0 mg/dl: odds ratio = 3.28, 95% confidence interval = 1.66 to 6.51, P < 0.001). Adalimumab treatment reduced risk of progression approximately fivefold. The difference between mean ΔmTSS for adalimumab versus placebo was greatest for patients with baseline CRP ≥2.0 mg/dl (-0.5 vs. 2.6).ConclusionsSystemic inflammation in PsA, as indicated by elevated baseline CRP, was the only strong independent predictor of radiographic progression. This association was observed predominantly for placebo-treated patients. Adalimumab treatment substantially reduced the overall risk of radiographic progression, and provided greatest radiographic benefit for patients with the greatest CRP concentrations at baseline.Trial RegistrationTrial registration: NCT00195689.

Golimumab: A novel anti-TNF-alpha human monoclonal antibody for rheumatoid arthritis, psoriatic arthritis and ankylosing spondilytis

Tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine, has been implicated in the pathology of a variety of chronic autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. The introduction of TNF-alpha inhibitors represented a significant advance in the management of these diseases but the responses of individual patients to TNF-alpha inhibitors are not homogeneous and more therapeutic tools are needed. Golimumab (CNTO-148) is a novel anti-TNF-alpha human monoclonal antibody that blocks both soluble and transmembrane TNF-alpha. It is indicated in the treatment of adults with moderately to severely active rheumatoid arthritis in combination with methotrexate, in adults with active and progressive psoriatic arthritis either alone or in combination with methotrexate, and in adult patients with active ankylosing spondylitis who have had an inadequate response to conventional therapies. Golimumab has generally been well tolerated in clinical trials with a safety profile comparable to other currently available TNF-alpha inhibitors. Its advantages are that it can be administered s.c. once monthly, it is labeled for patient self-administration and is suitable for both s.c. and i.v. administration. Golimumab is currently being investigated in other chronic inflammatory diseases.

Long-term experience with etanercept in psoriatic arthritis patients: A 3-year observational study

Objective: To evaluate the clinical efficacy and tolerability of etanercept in the treatment of active and progressive psoriatic arthritis (PsA) in patients who have previously demonstrated an inadequate response to standard treatments, such as disease-modifying anti-rheumatic drugs (DMARDs) and non-steroidal anti-inflammatory drugs (NSAIDs). Methods: An open-label, non-controlled, prospective study was conducted including 32 patients affected by PsA with variable skin involvement who had responded inadequately to at least two DMARDs. Patients received etanercept subcutaneously administered as monotherapy at the dosage of 50 mg twice weekly for 12 weeks followed by 25 mg twice weekly. Clinical response was evaluated using the EULAR (European League Against Rheumatism) disease activity score (DAS) in 28 joints (DAS-28) and the Psoriasis Area and Severity Index (PASI). The percentage improvement in DAS-28 and the proportion of patients achieving a PASI improvement from baseline of between 50% and 75% (PASI 50), > 75% (PASI 75) and > 90% (PASI 90) were analysed as primary endpoints. Results: Twenty-seven (27/32) patients (84.3%) completed 3 years (144 weeks) of continuous treatment, while 5/32 (15.6%) patients were withdrawn from the study. At week 144, a significant improvement in DAS-28 was registered with a reduction in mean DAS-28 from 5.3 at baseline to 1.8, while 25/27 patients (92.5%) achieved PASI 75 with a mean PASI score of 0.7; the mean pain visual analogue scale (pain-VAS) score decreased from 64.2 at baseline to 2 at week 144, corresponding to an improvement of 94.7%. Conclusions: Etanercept is a safe and effective agent in the long-term management of PsA patients. After 3 years of continuous treatment, symptoms were under control in the majority of patients and there was a low level of disease activity.

Adalimumab for the treatment of psoriatic arthritis

Psoriatic arthritis (PsA) is a chronic inflammatory joint disease occurring in 6–39% of patients with psoriasis. Standard therapy of PsA includes nonsteroidal anti-inflammatory drugs, intra-articular steroids and disease-modifying antirheumatic drugs. Failure of standard therapy is an indication for anti-TNF-α therapy. Adalimumab – a fully human monoclonal antibody against TNF-α – is an effective and generally reasonably well-tolerated drug for treating signs and symptoms of PsA. In placebo-controlled clinical trials, adalimumab showed American College of Rheumatology (ACR)20 response rates of 39–58% and ACR50 response rates of 25–39% in patients with active PsA who had failed previous standard therapy. Significant improvement of psoriatic skin changes and disease-related quality of life were also noted. The response of joints and skin and quality of life improvement was sustained over 2 years of therapy. In addition, adalimumab suppressed structural joint damage and retards radiographic progression of PsA.

Latest news and product developments

Latest news and product developments

Infliximab (Remicade) in the treatment of psoriatic arthritis

Elucidation of the cellular immunopathology and cytokine profile of psoriatic arthritis (PsA), a chronic inflammatory disease associated with psoriasis, has resulted in the development of a number of novel biologic therapies. Among these biologics, tumor necrosis factor-alpha (TNF-alpha) inhibitors have been used successfully to treat patients suffering from rheumatoid arthritis or psoriasis. The pivotal role of TNF-alpha in the pathogenesis and progression of PsA suggested that anti-TNF-alpha agents could be effective in controlling PsA. The results from two large, randomized, double-blind, placebo-controlled trials in patients with moderate to severe PsA indicated that the anti-TNF-inhibitor, infliximab, can control both the joint and skin manifestations of the disease. This review focuses on the clinical development of infliximab as a treatment for PsA. The development of other anti-TNF-alpha biologics is also discussed.

Etanercept and infliximab for the treatment of psoriatic arthritis: a systematic review and economic evaluation

Etanercept and infliximab for the treatment of psoriatic arthritis: a systematic review and economic evaluation

Recent advances in rheumatology: biological agents for the treatment of rheumatoid arthritis, the progression of psoriatic arthritis, autoantibodies in systemic lupus erythematosus

Recent advances in rheumatology: biological agents for the treatment of rheumatoid arthritis, the progression of psoriatic arthritis, autoantibodies in systemic lupus erythematosus