Improvements in workplace and household productivity with certolizumab pegol treatment in axial spondyloarthritis: results to week 96 of a phase III study.

OBJECTIVES: To evaluate the effect of certolizumab pegol (CZP) on work and household productivity, and on participation in family, social and leisure activities in patients with axial spondyloarthritis (axSpA), including ankylosing spondylitis (AS) and non-radiographic (nr-) axSpA. METHODS: RAPID-axSpA (NCT01087762) was a phase III, double-blind, placebo-controlled trial to week (Wk) 24, dose-blind to Wk48 and open-label to Wk204. A total of 325 patients were randomised 1:1:1 to placebo, CZP 200 mg Q2W or CZP 400 mg Q4W. The validated arthritis-specific Work Productivity Survey assessed the impact of axSpA on work and household productivity and participation in social activities during the preceding month. Data are shown to Wk96, with responses compared between treatment arms (placebo vs CZP 200 mg and 400 mg dose groups combined) and subpopulations using a non-parametric bootstrap-t method. RESULTS: At baseline, 63.2% of placebo and 72.0% of CZP patients were employed. By Wk24, CZP patients reported on average 1.0 fewer days of absenteeism and 2.6 fewer days of presenteeism per month, compared with 0.4 and 0.9 fewer days for placebo. At home, by Wk24, CZP patients reported on average 3.0 household work days gained per month versus 1.3 for placebo. CZP patients reported fewer days with reduced household productivity or days lost for social participation. Similar improvements were observed in AS and nr-axSpA subpopulations and improvements with CZP were maintained to Wk96. CONCLUSIONS: Compared with placebo, treatment with CZP significantly improved work and household productivity and resulted in greater social participation for patients with axSpA, which could lead to considerable indirect cost gains. TRIAL REGISTRATION NUMBER: NCT01087762.

Treatment efficacy and methotrexate-related toxicity in patients with rheumatoid arthritis receiving methotrexate in combination with adalimumab.

BACKGROUND: Treatment of rheumatoid arthritis (RA) with a combination of methotrexate (MTX)+adalimumab (ADA) is more effective than ADA monotherapy. We assessed the toxicity of different doses of MTX and treatment efficacy of ADA+MTX in two trials. METHODS: Data originated from CONCERTO, in patients with early RA initiating ADA+ 2.5, 5, 10 or 20 mg/week MTX for 26 weeks; and MUSICA, in patients with an inadequate response to MTX initiating ADA+ 7.5 or 20 mg/week MTX for 24 weeks. Efficacy was assessed by the American College of Rheumatology 50 (ACR50). Patient-reported MTX-related toxicity information was collected at each visit on 18 prespecified MTX-related adverse events (AE) in the MTX label. RESULTS: In CONCERTO, ACR50 rates increased over time, ranging from 54% to 68% at week 26, while AE rates remained steady, ranging from 2.4% to 17.8% at week 26. Of 395 patients, 113 (28.6%) reported 345 MTX-related AEs, including one serious AE (SAE, excessive fatigue and/or malaise); 10 AEs (in two patients) led to study discontinuation. In MUSICA, ACR50 rates increased over time, and were 32.3% and 37.5% at week 24, while MTX-related AE rates remained steady and were 6.5% at week 24. Of 309 patients, 71 (23%) reported 185 MTX-related AEs, including 5 SAEs (four infections and one fever/chills); six AEs (in four patients) led to study discontinuation. CONCLUSION: In patients with RA initiating ADA+MTX combination, treatment efficacy was achieved and increased throughout both trials, while rates of MTX-related AEs remained steady. MTX-related AEs were observed in up to 30% of patients and most were mild. MTX was discontinued by 0.5%-1.3% of patients. TRIAL REGISTRATION NUMBER: MUSICA (NCT01185288), CONCERTO (NCT01185301), Post results.

Efficacy of tofacitinib monotherapy in methotrexate-naive patients with early or established rheumatoid arthritis.

INTRODUCTION: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Tofacitinib monotherapy was previously shown to inhibit structural damage, reduce clinical signs and symptoms of RA, and improve physical functioning over 24 months in methotrexate (MTX)-naive adult patients with RA. In this post hoc analysis, we compared efficacy and safety of tofacitinib in patients with early (disease duration <1 year) versus established (≥1 year) RA. METHODS: MTX-naive patients ≥18 years with active RA received tofacitinib monotherapy (5 or 10 mg two times a day, or MTX monotherapy, in a 24-month Phase 3 trial. RESULTS: Of 956 patients (tofacitinib 5 mg two times a day, n=373; tofacitinib 10 mg two times a day, n=397; MTX, n=186), 54% had early RA. Baseline disease activity and functional disability were similar in both groups; radiographic damage was greater in patients with established RA. At month 24, clinical response rates were significantly greater in patients with early versus established RA in the tofacitinib 5 mg two times a day group. Both tofacitinib doses had greater effects on clinical, functional and radiographic improvements at 1 and 2 years compared with MTX, independent of disease duration. No new safety signals were observed. CONCLUSIONS: Treatment response was generally similar in early and established RA; significantly greater improvements were observed at month 24 with tofacitinib 5 mg two times a day in early versus established RA. Tofacitinib 5 and 10 mg two times a day demonstrated greater efficacy versus MTX irrespective of disease duration. No difference in safety profiles was observed between patients with early or established RA. TRIAL REGISTRATION NUMBER: NCT01039688; Results.

GRAPPA treatment recommendations: an update from the GRAPPA 2013 Annual Meeting.

Psoriatic arthritis (PsA) is a chronic systemic inflammatory disorder characterized by the association of arthritis and periarticular inflammation in patients with psoriasis. In addition to a heterogeneous and variable clinical course, PsA is complex and multifaceted and may include prominent involvement in the peripheral and axial diarthrodial joints, the skin and nails, and in periarticular structures such as entheses. A central mission of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) is to develop guidelines, based upon the best scientific evidence, for the optimal treatment of patients with PsA. Guidelines were previously published in 2009 based on an evidence-based systematic review. Given important recent developments and robust ongoing research into the treatment of PsA, GRAPPA undertook to update the guidelines. Herein we outline the specific methods and procedures used both in the initial and the current evidence-based, systematic reviews of treatments for PsA. We also review the numerous discussions regarding how best to finalize and publish these new guidelines in 2014.

The problem of choice: current biologic agents and future prospects in RA.

The introduction of biologic agents to clinical practice has had a major bearing on the treatment of patients with chronic inflammatory diseases such as rheumatoid arthritis. These drugs have the potential to improve the outcome of disease and the quality of life for patients. However, clinical criteria alone are inadequate for determining which therapy is most appropriate for an individual patient. Furthermore, why a particular drug is effective in a particular patient, or indeed in any patient, but is ineffective for other individuals, is often unknown. In this Review, we provide an overview of biologic therapies currently available for patients with rheumatoid arthritis, and discuss why certain immunological regulators represent potential targets for intervention. Current agents can be clustered into three major types: cytokine blockers, lymphocyte-targeting agents, and small-molecule inhibitors of signal transduction pathways. We differentiate among the modes of action of each of these types of therapy and consider the challenges associated with their use in clinical practice.

A Delphi Consensus Approach to Challenging Case Scenarios in Moderate-to-Severe Psoriasis: Part 1.

INTRODUCTION: Traditional clinical trials in psoriasis exclude a significant proportion of patients with complex disease and comorbidities. A consensus panel of 14 experts in the field of psoriasis was formed to conduct a Delphi method exercise to identify difficult-to-treat psoriasis clinical scenarios and to rank treatment approaches. METHODS: The exercise consisted of both survey questionnaires and a live meeting to review and discuss current data (as of 2009, when the exercise was conducted) and arrive at a consensus for optimal treatment options. Seventy difficult treatment scenarios were identified, and the top 24 were selected for discussion at the live meeting. RESULTS: Six of the 24 discussed case scenarios are presented in this article (another five are presented in Part 2): (1) psoriasis with human papilloma virus-induced cervical or anogenital dysplasia; (2) concomitant psoriasis and systemic lupus erythematosus; (3) severe psoriatic nail disease causing functional or emotional impairment; (4) psoriasis therapies that potentially reduce cardiovascular morbidity and mortality; (5) older patients (≥65 years of age) with psoriasis; and (6) severe scalp psoriasis that is unresponsive to topical therapy. CONCLUSION: The Delphi exercise resulted in guidelines for practicing physicians to utilize when confronted with challenging patients with psoriasis.

A Delphi Consensus Approach to Challenging Case Scenarios in Moderate-to-Severe Psoriasis: Part 2.

INTRODUCTION: Clinicians may be confronted with difficult-to-treat psoriasis cases for which there are scant data to rely upon for guidance. To assist in managing such patients, who are typically excluded from clinical trials, a consensus panel of 14 experts in the field of psoriasis was formed to conduct a Delphi method exercise. METHODS: The exercise consisted of both survey questionnaires and a live meeting to review and discuss current data (as of 2009, when the exercise was conducted) and arrive at a consensus for optimal treatment options. Seventy difficult treatment scenarios were identified, and the top 24 were selected for discussion at the live meeting. RESULTS: Five of the 24 discussed case scenarios are presented in this article: (1) moderate-to-severe psoriasis that has failed to respond to all currently approved therapies for psoriasis; (2) palmoplantar psoriasis that is unresponsive to topical therapy and phototherapy; (3) erythrodermic psoriasis; (4) pustular psoriasis; and (5) the preferred therapeutic choice to combine with low-dose methotrexate. A previous article (part 1) presented six other scenarios. CONCLUSION: The Delphi exercise resulted in guidelines for practicing physicians to utilize when confronted with patients with challenging cases of psoriasis.

Optimizing outcomes in rheumatoid arthritis patients with inadequate responses to disease-modifying anti-rheumatic drugs.

Conventional DMARDs such as MTX are the mainstay of treatment for patients with RA. However, failure to achieve adequate disease control in many patients, even with combination therapy, has spurred the development of agents that target various immune mediators involved in the disease process. In the past decade, biologic agents have proved viable as alternative or add-on therapy to DMARDs in patients whose disease is inadequately controlled. Well-controlled clinical trials have evaluated the effects of these agents not only on disease activity, but also on inhibition of structural change and improvement in physical function. This article reviews phase 3 clinical trial results on biologic agents that inhibit T- and B-cell activation (abatacept and rituximab, respectively), inflammatory cytokines such as TNF-α (adalimumab, etanercept, infliximab, golimumab and certolizumab) and IL-6 (tocilizumab). Although data comparing the efficacy of the various biologic agents are limited, the availability of biologic therapies with differing mechanisms of action expands therapeutic options for patients whose disease is inadequately controlled with DMARDs and allows for greater individualization of treatment.

Minimally important differences of the gout impact scale in a randomized controlled trial.

OBJECTIVE: The Gout Impact Scale (GIS) is a gout-specific quality of life instrument that assesses impact of gout during an attack and impact of overall gout. The GIS has five scales and each is scored from 0 to 100 (worse health). Our objective was to assess minimally important differences (MIDs) for the GIS administered in a randomized controlled trial (RCT) assessing rilonacept vs placebo for prevention of gout flares during initiation of allopurinol therapy. METHODS: Trial subjects (n = 83) included those with two or more gout flares (self-reported) in the past year. Of these, 73 had data for Weeks 8 vs 4 and formed the MID analysis group and were analysed irrespective of the treatment assignment. Subjects completed the GIS and seven patient-reported anchors. Subjects with a one-step change (e.g. from very poor to poor) were considered as the MID group for each anchor. The mean change in GIS scores and effect size (ES) was calculated for each anchor's MID group. The average of these created the overall summary MID statistics for each GIS. An ES of 0.2-0.5 was considered to represent MID estimates. Results. Trial subjects (n = 73) were males (96.0%), White (90.4%), with mean age of 50.5 years and serum uric acid of 9.0 mg/dl. The mean change score for the MID improvement group for scales ranged from -5.24 to -7.61 (0-100 scale). The ES for the MID improvement group for the four scales ranged from 0.22 to 0.38. CONCLUSION: The MID estimates for GIS scales are between 5 and 8 points (0-100 scale). This information can aid in interpreting the GIS results in future gout RCTs. Trial Registration. Clinicaltrials.gov, www.clinicaltrials.gov, NCT00610363.

Predictors of doctor-rated and patient-rated gout severity: gout impact scales improve assessment.

RATIONALE, AIMS AND OBJECTIVES: Our objective was to describe the factors associated with doctor-rated and patient-rated gout severity to explain how doctor assessment involving patient-reported outcomes can improve the clinical management of gout. METHODS: Patients completed a newly validated gout-specific health-related quality of life instrument, the Gout Impact Scale (GIS) and other questions regarding their gout. Both patients and their doctors gave an overall gout severity assessment. We conducted correlation analyses between each predictor of interest and the two different severity ratings (doctor-rated severity and patient-rated severity). Stepwise multiple regressions were performed to determine the best predictors for doctor-rated and patient-rated severity, respectively. RESULTS: Doctor-rated severity more closely correlated with objective clinical and laboratory findings, particularly the presence of tophi, which was not a leading factor in patient-rated severity assessments. Patient-rated severity more closely correlated with the domains of the GIS, which expressed the impact of gout on health-related quality of life. CONCLUSION: Doctors might have a better understanding of their patients' level of disease impact if they incorporate an instrument such as the GIS in their evaluation of gout severity and their decisions regarding aggressiveness of treatment. The increased use of patient-reported outcomes measures has the potential to improve quality of care and patient satisfaction, as well as reduce costs of health care utilization.

Imaging in psoriasis and psoriatic arthritis: GRAPPA 2008.

At the 2008 meeting of GRAPPA (Group for Research and Assessment of Psoriasis and Psoriatic Arthritis), the primary focus of the imaging session was the enthesis. Presentations from Dennis McGonagle (Leeds, UK), Richard Hodgson (Leeds, UK), and Paolo Gisondi (Verona, Italy) elaborated on this theme and prepared the meeting attendees for group discussions of further work in this area. Imaging, notably magnetic resonance imaging (MRI) and ultrasonography, provides evidence of pathological change at the enthesis in psoriatic arthritis (PsA). Further, imaging abnormalities are found at sites that are asymptomatic in both PsA and psoriasis. The role of newer imaging modalities, such as ultra-short echo time (UTE) MRI, is promising but remains to be fully elucidated. The implication of these findings in relation to subclinical and predisease status is intriguing and requires further study in longitudinal studies. Further work is also required to examine the proposed common biomechanical basis between joint and skin, the mechanism of the resulting inflammation, and how these mechanisms differ from those seen in rheumatoid arthritis.

Composite measures in psoriatic arthritis: GRAPPA 2008.

At the 2008 annual meeting of GRAPPA (Group for Research and Assessment of Psoriasis and Psoriatic Arthritis) in Leeds, UK, members discussed the value and current status of composite measures for the assessment of psoriatic arthritis (PsA). In plenary presentations, examples of composite measures developed for rheumatoid arthritis (RA) and ankylosing spondylitis (AS) were reviewed, followed by a presentation of the assessment of disease activity in systemic lupus erythematosus. Three recently devised composite methods of assessing activity or response in PsA also were presented. Considerable discussion followed in breakout groups, and members agreed that a new composite measure specifically for PsA is necessary. The composite measure should include components that encompass the spectrum of psoriatic disease, i.e., in addition to assessment of peripheral joints, it should include assessment of sacroiliitis, spondylitis, enthesitis, and dactylitis, as well as skin and nail disease.

Biomarkers in psoriasis and psoriatic arthritis: GRAPPA 2008.

Biomarkers can provide valuable insights into disease susceptibility and natural history and may serve as surrogate endpoints for a variety of different outcomes. At the 2008 annual meeting of GRAPPA (Group for Research and Assessment of Psoriasis and Psoriatic Arthritis), members were updated on the development of biomarkers in psoriatic arthritis (PsA). Plenary presentations included a translational approach to biomarker development (Christopher Ritchlin, University of Rochester, NY, USA), biomarkers for psoriasis (Abrar Qureshi, Harvard Medical School, MA, USA), new data on biomarkers for damage in PsA (Kurt de Vlam, University Hospitals Leuven, Belgium), and design considerations for a longitudinal study of joint damage being undertaken under the OMERACT umbrella with colleagues working on rheumatoid arthritis and ankylosing spondylitis (Costantino Pitzalis, Barts and the London School of Medicine, London, UK; Oliver FitzGerald, St. Vincent's Hospital, Dublin, Ireland). At the conclusion of this session, the meeting attendees discussed specific design issues of the proposed longitudinal study, including study duration, disease process core domains, and the instruments to be used in recording enthesitis, dactylitis, nail involvement, quality of life and structural damage. The appearance of new therapeutic options in PsA raises the need for sensitive biomarkers for both disease activity and outcome.

A series of critically challenging case scenarios in moderate to severe psoriasis: a Delphi consensus approach.

Clinical trials for systemic psoriasis therapy typically enroll healthy patients and exclude patients with cardiovascular disease, latent tuberculosis, liver disease, histories of malignancies, viral infections, children, and pregnant or breast-feeding women. Physicians often require guidance for optimum management of severe psoriasis in patients that have a combination of underlying disease states. To provide treatment recommendations for complex psoriasis scenarios, a consensus panel comprising 15 experts in psoriatic disease convened to review and discuss available evidence-based data and to arrive at a consensus for treatment options of difficult cases. An application of the Delphi Method was used to select case scenarios, provide medical treatment options, present the case study with existing medical evidence, and anonymously vote on treatment options. The top 10 treatment options were ranked and statistically analyzed to compare the differences between treatments. The final rankings and analysis provide guidance for practical, safe, and efficacious treatment options in a number of complex psoriasis scenarios.

Recombinant human relaxin in the treatment of systemic sclerosis with diffuse cutaneous involvement: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: A phase II randomized controlled trial of recombinant human relaxin suggested that a dosage of 25 microg/kg/day was safe and clinically effective in improving skin disease and reducing functional disability in scleroderma (systemic sclerosis; SSc). We undertook a large randomized, double-blind, placebo-controlled clinical trial to compare placebo with 10 microg/kg/day and 25 microg/kg/day recombinant human relaxin, given for 24 weeks in patients with stable, diffuse, moderate-to-severe SSc. METHODS: Men and women ages 18-70 years with diffuse cutaneous SSc (dcSSc) were administered recombinant human relaxin (10 microg/kg/day or 25 microg/kg/day) or placebo for 24 weeks as a continuous subcutaneous infusion. There was a followup safety visit at week 28. RESULTS: The primary outcome measure, the modified Rodnan skin thickness score, was similar among the 3 groups at baseline and at weeks 4, 12, and 24. Secondary outcomes such as functional disability were similar in all 3 groups, while the forced vital capacity decreased significantly in the relaxin groups. The discontinuation of both doses of relaxin at week 24 led to statistically significant declines in creatinine clearance and serious renal adverse events (defined as doubling of serum creatinine, renal crisis, or grade 3 or 4 essential hypertension) in 7 patients who had received relaxin therapy but in none who had received placebo. CONCLUSION: Recombinant relaxin was not significantly better than placebo in improving the total skin score or pulmonary function or in reducing functional disability in patients with dcSSc. In addition, relaxin was associated with serious renal adverse events, the majority of which occurred after stopping the infusion. If relaxin is used therapeutically for any conditions other than scleroderma, close monitoring of blood pressure and renal function must be performed.

Initiative for quality in psoriasis and psoriatic arthritis.

Psoriasis is a common and severe skin disease. Up to 30% of psoriasis patients develop psoriatic arthritis (PsA), another severe disease that contributes significantly to the burden of psoriatic disease in patients. The treatment of patients with both psoriasis and PsA is particularly challenging, because different strategies are often followed, and considerable resources are needed for these chronic inflammatory diseases. Of note, psoriasis patients tend to be undertreated. Efforts to improve the management of psoriasis and PsA are urgently needed, to incorporate improvement of patient outcomes by promotion of best practice from both the medical and the pharmacoeconomic perspective. These are the goals of the Quality Movement in the USA and of quality management in general. The need for evidence-based guidance on safety, efficacy, overall outcome, and cost-effectiveness is being addressed by numerous initiatives striving to generate practice guidelines, control costs, and optimize cost-effectiveness of treatments. The 2007 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis's (GRAPPA) Initiative for Quality aims to secure and improve management of psoriasis and PsA, elaborating on these evidence-based guidelines by defining major domains of quality and creating a checklist that identifies physicians who can administer state-of-the-art medical services to patients who need their services.

B cell targeted therapies: safety considerations.

Reported data from recent clinical trials have contributed substantially to our growing understanding of the potential effectiveness and safety of B cell targeted therapy in the treatment of rheumatic diseases. Trials with rituximab, an anti-CD20 monoclonal antibody that depletes mature B cells, have amassed the most data of any B cell targeted therapy to date. A number of other B cell directed therapies are under investigation. Interestingly, although they may share a common target, the different agents have quite distinct mechanisms of action, and therefore their efficacy and safety profiles may differ. A common concern with all B cell directed therapies is the potential effect these agents may have on humoral immunity. The safety profile of rituximab in the oncology setting is well known, based on a database of well over 370,000 patients. Phase II trials of rituximab in rheumatoid arthritis (RA) have begun to examine safety issues specifically in the RA population, including issues surrounding longterm and repeated treatment safety profiles. Questions about the longterm safety of B cell therapy remain to be clarified: What will be the safety profile for repeated treatment courses? What will be the safety profile when B cell targeted therapies are used in sequence or in conjunction with other agents? Answers to these important questions are likely to come from careful observations by treating clinicians, data from registries, and longterm followup of patients enrolled in clinical trials.