Learnings from previous Roche p38-selective inhibitors were applied to a new fragment hit, which was optimized to a potent, exquisitely selective preclinical lead with a good pharmacokinetic profile.

The development of a new series of p38α inhibitors resulted in the identification of two clinical candidates, one of which was advanced into a phase 2 clinical study for rheumatoid arthritis. The original lead, an lck inhibitor that also potently inhibited p38α, was a screening hit from our kinase inhibitor library. This manuscript describes the optimization of the lead to p38-selective examples with good pharmacokinetic properties.

Methotrexate alone or in combination with other agents is the standard treatment for moderate-to-severe rheumatoid arthritis. As biological agents are expensive, they are not usually used until methotrexate has failed to give a good response. Thus, there is scope for the development of cheaper drugs that can be used instead of methotrexate or in addition to methotrexate. Pamapimod is a p38α inhibitor being developed for use in the treatment of rheumatoid arthritis. The objective of this review was to evaluate the recent clinical trials of pamapimod in subjects with rheumatoid arthritis. There is no clear-cut evidence that pamapimod alone or in the presence of methotrexate is efficacious in subjects with rheumatoid arthritis but it does cause adverse effects. It is unlikely that pamapimod will be useful in the treatment of rheumatoid arthritis.

Decades of signal transduction research have elucidated a complex and dynamic architecture of signaling pathways and networks that are associated with cellular responses, physiological responses as well as various pathologies. Consequently, there is great interest in pharmacological manipulation of these pathways for therapeutic purposes. Pathway complexity brings forth two distinct challenges, one in the systematic generation of pathway-level datasets under multiple conditions and one in the interpretation of such complex data. Mechanistic model-based analysis has been used to aid in drug discovery and development, specifically in understanding and predicting the interaction of small molecule inhibitors with pathways. Examples including the quantitative comparison of multiple compounds and mechanisms of action, target selection and the elucidation of clinical findings are reviewed.

HASH(0x2b60a7061fa0)

The classical role of p38MAPK involves the transmission of death signals from stress stimuli such as ionizing radiation, inflammation and chemotherapy in normal and malignant cells. However emerging evidence point to it having pleiotropic functions, ranging from cellular proliferation and survival, to cell cycle arrest and regulation of the tumor microenviroment. The mechanisms responsible for these diverse and rather contradictory functions of p38MAPK are only now being unraveled. In some hematological malignancies, p38MAPK is constitutively activated. The reasons for this are not fully understood, but can result from underlying genetic lesions such as the bcr/abl translocation. The involvement of p38MAPK in mediating cell cycle arrest in the face of cytotoxic damage suggests that p38MAPK may be a therapeutic target. The role of p38MAPK in cytokine production by the stromal compartment adds another level of complexity to the regulation of hematological malignancies that exhibit a degree of stromal dependence, at least some of which is cytokine driven. p38MAPK dependent cytokine production by malignant hematopoietic cells has also been observed, and promotes tumor cell adhesion, angiogenesis and osteoclastogenesis. This suggests a mutual relationship between tumor and stromal cells. In contrast, p38MAPK is required for the effects of cytotoxic agents in some hematological malignancies. These conflicting qualities point to the importance of careful consideration of the use of p38MAPK inhibitors as a therapeutic strategy.

Rheumatoid arthritis (RA) remains a significant unmet medical need despite significant therapeutic advances. The pathogenesis of RA is complex and includes many cell types, including T cells, B cells, and macrophages. Fibroblast-like synoviocytes (FLS) in the synovial intimal lining also play a key role by producing cytokines that perpetuate inflammation and proteases that contribute to cartilage destruction. Rheumatoid FLS develop a unique aggressive phenotype that increases invasiveness into the extracellular matrix and further exacerbates joint damage. Recent advances in understanding the biology of FLS, including their regulation regulate innate immune responses and activation of intracellular signaling mechanisms that control their behavior, provide novel insights into disease mechanisms. New agents that target FLS could potentially complement the current therapies without major deleterious effect on adaptive immune responses.

PURPOSE OF REVIEW: Due to the cost and parenteral mode of administration of biologics, efforts to develop oral small molecule inhibitors to protein kinases involved in cellular signaling that impact inflammatory cytokine production have been ongoing. This article will review the recent publications on these efforts. RECENT FINDINGS: On preclinical work, p38 mitogen-activated kinases were considered attractive targets to suppress cytokine production. Three different molecules (SCIO_469, Pamapimod, VX-702) that target the p38alpha isoform have been evaluated in phase 2 trials. Unfortunately, clinical efficacy was not observed, and dose-related toxicity was seen. The future of this approach is unclear. Targeting more upstream protein tyrosine kinases such as spleen tyrosine kinase (SyK) and the JAK family of kinases has been associated with greater success in clinical trials, with efficacy demonstrated. Adverse events occurred in a dose-dependent fashion with the SyK inhibitor, such as diarrhea and hypertension. Neutropenia, elevated liver-function tests, serum creatinine elevations and lipid elevations have occurred with JAK-kinase inhibition. Dose modifications have been made based on the phase 2 trial results; phase 3 clinical trials are ongoing. SUMMARY: Inhibiting downstream proteins involved in cellular signaling, such as p38, has not been successful to date. Inhibitors of more upstream protein-tyrosine kinases involved in cellular signaling appear to be viable molecular candidates for rheumatoid arthritis. If the results seen in phase 2 studies are confirmed in larger phase 3 studies, we may soon have new, oral DMARD therapies available.

This study evaluated the potential pharmacokinetic interaction of pamapimod, a p38 mitogen-activated protein kinase inhibitor, and methotrexate (MTX) when administered concomitantly in patients with rheumatoid arthritis (RA); the study also evaluated the pharmacodynamic effects of pamapimod. Twenty-two RA patients on a stable regimen of MTX (10-25 mg/wk; administered on days 1 and 8) were randomized to receive 300 mg of pamapimod (n = 17) or placebo (n = 5) once daily (qd) for 10 days (days 5-14). Blood and urine samples were collected pre-and postdose on days 1 (MTX alone), 7 (pamapimod alone), and 8 (MTX and pamapimod coadministered). No clinically significant changes were observed in plasma exposures and renal clearance of pamapimod, MTX, or their metabolites, whether administered separately or concomitantly. The combination of pamapimod (300 mg qd) for 10 days and weekly MTX was generally well tolerated. Parameters of RA disease-namely, tender joint count, swollen joint count, erythrocyte sedimentation rate, and C-reactive protein-generally decreased between days 5 and 14. The results of this study suggest that dose adjustments for either drug are not necessary when concomitantly administered and that pamapimod can decrease pharmacodynamic markers of disease activity.

Objective. To compare cardiovascular (CV) and other safety and efficacy parameters of etoricoxib 60 and 90 mg, and diclofenac 150 mg. Methods. This double-blind study randomized OA patients to etoricoxib 90 mg, then to 60 mg once daily vs diclofenac 75 mg twice daily; RA patients were randomized to etoricoxib 90 mg once daily or diclofenac 75 mg twice daily. The primary endpoint was non-inferiority of etoricoxib vs diclofenac for thrombotic CV events (95% CI upper bound of hazard ratio <1.30). Other safety and efficacy parameters were evaluated in cohorts of patients based on etoricoxib dose and disease. Results. A total of 23 504 patients were randomized with mean treatment duration from 19.4 to 20.8 months. The thrombotic CV risk hazard ratio (HR)(etoricoxib to diclofenac) was 0.96 (95% CI 0.81, 1.15), consistent with non-inferiority of etoricoxib to diclofenac. The cumulative gastrointestinal (GI)/liver adverse events (AEs) discontinuation rate was significantly lower for etoricoxib than diclofenac in each patient cohort; HR (95% CI) of 0.46 (0.39, 0.54), 0.52 (0.42, 0.63) and 0.49 (0.39, 0.62) for the 60 mg OA, 90 mg OA and RA cohorts. The maximum average change in systolic blood pressure (BP) with etoricoxib was 3.4-3.6 mmHg (diastolic BP: 1.0-1.5 mmHg), while diclofenac produced a maximum average change of 0.9-1.9 mmHg (diastolic BP: 0.0-0.5 mmHg). Both agents resulted in similar efficacy regardless of etoricoxib dose. Conclusion. Long-term etoricoxib use is associated with a risk of thrombotic CV events comparable with that of diclofenac. Compared with diclofenac, etoricoxib demonstrated a greater risk of renovascular AEs, but a more favourable GI/liver tolerability profile.

Background: The safety and efficacy of weight-based ribavirin (RBV) dosing regimens in patients with HIV-HCV coinfection has not been demonstrated in randomized clinical trials. Objective: This randomized, double-blind, international, parallel-group study in specialist outpatient clinics in the United States, Spain, and Portugal compares the efficacy and safety of 2 RBV dose regimens (800 mg/day and 1000/1200 mg/day) combined with peginterferon alfa-2a (40KD) in patients with HIV-HCV (genotype 1) coinfection. Methods: Patients with HIV-HCV coinfec-tion, quantifiable HCV RNA in serum, HCV genotype-1 infection, compensated liver disease, and stable HIV disease (CD4+ count ≥100 cells/µL) with or without ongoing antiretroviral therapy were randomized to 48 weeks' treatment with RBV at standard dose (800 mg/day) or weight-based dose (1000 mg/day for patients weighing <75 kg; 1200 mg/day for patients weighing ≥75 kg) in combination with peginterferon alfa-2a (40KD) 180 µg once a week. Planned enrollment was 400 patients with ≥100 non-Latino African Americans. The primary endpoint was sustained virological response (SVR)(undetectable HCV RNA [<20 IU/mL] at the end of a 24-week untreated follow-up period [week 72]). Results: SVR rates were 19%(26/135) and 22%(60/275) in patients randomized to RBV 800 mg/day and 1000/1200 mg/day, respectively (odds ratio, 1.15; 95% CI, 0.68-1.93; P =.6119). In the 1000/1200 mg/day RBV dose group, the incidence of hemoglobin reductions <100 g/L and anaemia reported as an adverse event were higher versus the standard 800 mg/day RBV dose group. Conclusions: Compared with the standard RBV dose (800 mg/day), weight-based RBV dosing (1000/1200 mg/day) did not significantly increase SVR rates, but did increase the incidence of anemia in HIV-HCV (genotype 1) coinfected patients.

OBJECTIVES: Gouty arthritis patients for whom non-steroidal anti-inflammatory drugs and colchicine are inappropriate have limited treatment options. Canakinumab, an anti-interleukin-1β monoclonal antibody, may be an option for such patients. The authors assessed the efficacy/safety of one dose of canakinumab 150 mg (n=230) or triamcinolone acetonide (TA) 40 mg (n=226) at baseline and upon a new flare in frequently flaring patients contraindicated for, intolerant of, or unresponsive to non-steroidal anti-inflammatory drugs and/or colchicine. Core study co-primary endpoints were pain intensity 72 h postdose (0-100 mm visual analogue scale and time to first new flare.METHODS: Two 12-week randomised, multicentre, active-controlled, double-blind, parallel-group core studies with double-blind 12-week extensions (response in acute flare and in prevention of episodes of re-flare in gout (β-RELIEVED and β-RELIEVED-II)).RESULTS: 82.6% patients had comorbidities. Mean 72-h visual analogue scale pain score was lower with canakinumab (25.0 mm vs 35.7 mm; difference,-10.7 mm; 95% CI -15.4 to -6.0; p<0.0001), with significantly less physician-assessed tenderness and swelling (ORs=2.16 and 2.74; both p≤0.01) versus TA. Canakinumab significantly delayed time to first new flare, reduced the risk of new flares by 62% versus TA (HR: 0.38; 95% CI 0.26 to 0.57) in the core studies and by 56%(HR: 0.44; 95% CI 0.32 to 0.60; both p≤0.0001) over the entire 24-week period, and decreased median C-reactive protein levels (p≤0.0001 at 72 h and 7 days). Over the 24-week period, adverse events were reported in 66.2%(canakinumab) and 52.8%(TA) and serious adverse events were reported in 8.0%(canakinumab) and 3.5%(TA) of patients. Adverse events reported more frequently with canakinumab included infections, low neutrophil count and low platelet count.CONCLUSION: Canakinumab provided significant pain and inflammation relief and reduced the risk of new flares in these patients with acute gouty arthritis.

OBJECTIVE -: The aim of this study was to assess the sensitivity and specificity of the CASPAR criteria in early psoriatic arthritis (PsA) and to compare with the Moll & Wright criteria. Methods - The CASPAR criteria were applied to cases of early PsA (<24 months symptom duration) and controls with other inflammatory arthritides who were all disease-modifying anti-rheumatic drug naive. Gold standard diagnosis was confirmed by a consultant rheumatologist. Proportions of cases and controls meeting the criteria were compared using McNemars test. RESULTS -: 111 early PsA cases and 111 early arthritis controls (RA n=82, undifferentiated arthritis n=13, spondyloarthritis n=9, inflamm OA n=4, crystal arthritis n=3) were recruited. The sensitivity of the CASPAR criteria in classifying early PsA was 87.4% compared to 80.2% for the Moll and Wright criteria. The specificity for both criteria was 99.1%. When considering different cut-points for the CASPAR criteria, the best cut-point for classification remained a score of ≥3 as in the original CASPAR analysis. Considering a score of ≥2 gave a higher sensitivity of 99.1% but resulted in a drop in specificity to 94.6%. Regression analysis identified that psoriasis and a negative RF were the most important features to differentiate PsA, followed by nail psoriasis and the presence of dactylitis. CONCLUSION -: The CASPAR criteria are more sensitive than Moll & Wright in classifying early PsA. Although the sensitivity is lower than established disease, the CASPAR criteria are valid for use as inclusion criteria for early psoriatic arthritis trials.

OBJECTIVES: To determine the prevalence of autonomic dysfunction (dysautonomia) among patients with primary Sjögren's syndrome (PSS) and the relationships between dysautonomia and other clinical features of PSS.METHODS: Multicentre, prospective, cross-sectional study of a UK cohort of 317 patients with clinically well-characterised PSS. Symptoms of autonomic dysfunction were assessed using a validated instrument, the Composite Autonomic Symptom Scale (COMPASS). The data were compared with an age- and sex-matched cohort of 317 community controls. The relationships between symptoms of dysautonomia and various clinical features of PSS were analysed using regression analysis.RESULTS: COMPASS scores were significantly higher in patients with PSS than in age- and sex-matched community controls (median (IQR) 35.5 (20.9-46.0) vs 14.8 (4.4-30.2), p<0.0001). Nearly 55% of patients (vs 20% of community controls, p<0.0001) had a COMPASS score >32.5, a cut-off value indicative of autonomic dysfunction. Furthermore, the COMPASS total score correlated independently with EULAR Sjögren's Syndrome Patient Reported Index (a composite measure of the overall burden of symptoms experienced by patients with PSS)(β=0.38, p<0.001) and disease activity measured using the EULAR Sjögren's Syndrome Disease Activity Index (β=0.13, p<0.009).CONCLUSIONS: Autonomic symptoms are common among patients with PSS and may contribute to the overall burden of symptoms and link with systemic disease activity.

For patients with rheumatoid arthritis (RA), remission can be achieved with tight control of inflammation and early use of disease modifying agents. The importance of remission as an outcome has been recently highlighted by European League Against Rheumatism recommendations. However, remission when defined by clinical remission criteria (disease activity score, simplified disease activity index, etc) does not always equate to the complete absence of inflammation as measured by new sensitive imaging techniques such as ultrasound (US). There is evidence that imaging synovitis is frequently found in these patients and associated with adverse clinical and functional outcomes. This article reviews the data regarding remission, ultrasound imaging and outcomes in patients with RA to provide the background to a consensus statement from an international collaboration of ultrasonographers and rheumatologists who have recently formed a research network - the Targeted Ultrasound Initiative (TUI) group. The statement proposes that targeting therapy to PD activity provides superior outcomes compared with treating to clinical targets alone and introduces the rationale for a new randomised trial using targeted ultrasound in RA.

OBJECTIVE: To assess the efficacy and safety of low-dose prednisone chronotherapy using a new modified-release (MR) formulation for the treatment of rheumatoid arthritis (RA).METHODS: In this 12-week, double-blind, placebo-controlled study, patients with active RA (n=350) were randomised 2:1 to receive MR prednisone 5 mg or placebo once daily in the evening in addition to their existing RA disease-modifying antirheumatic drug (DMARD) treatment. The primary end point was the percentage of patients achieving a 20% improvement in RA signs and symptoms according to American College of Rheumatology criteria (ie, an ACR20 response) at week 12. Changes in morning pain, duration of morning stiffness, 28-joint Disease Activity Score and health-related quality of life were also assessed.RESULTS: MR prednisone plus DMARD treatment produced higher response rates for ACR20 (48% vs 29%, p<0.001) and ACR50 (22% vs 10%, p<0.006) and a greater median relative reduction from baseline in morning stiffness (55% vs 35%, p<0.002) at week 12 than placebo plus DMARD treatment. Significantly greater reductions in severity of RA (Disease Activity Score 28)(p<0.001) and fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue score)(p=0.003) as well as a greater improvement in physical function (36-item Short-Form Health Survey score)(p<0.001) were seen at week 12 for MR prednisone versus placebo. The incidence of adverse events was similar for MR prednisone (43%) and placebo (49%).CONCLUSION: Low-dose MR prednisone added to existing DMARD treatment produced rapid and relevant improvements in RA signs and symptoms.ClinicalTrials.gov, numberNCT00650078.

OBJECTIVE: To assess the efficacy and safety of adalimumab plus methotrexate (ADA+MTX) compared with methotrexate monotherapy in achieving stable low disease activity (LDA; disease activity score (DAS28(CRP))<3.2 at weeks 22 and 26) and clinical, radiographic and functional outcomes in methotrexate-naive patients with early rheumatoid arthritis (RA).METHODS: 1032 patients with active RA were randomly assigned 1:1 to ADA+MTX or placebo plus methotrexate (PBO+MTX) for 26 weeks. Treatment modifications were to be made in a subsequent study period based on the achievement of DAS28(CRP)<3.2 at weeks 22 and 26. Post-hoc analyses compared patients achieving stable remission using DAS28 and 2010 ACR/EULAR criteria with those achieving LDA but not remission.RESULTS: Among patients completing 6 months, 44%(207/466) ADA+MTX versus 24%(112/460) PBO+MTX patients achieved stable LDA at weeks 22 and 26 (p<0.001). Combination therapy was statistically superior to methotrexate in obtaining higher ACR20/50/70 responses, more clinical remissions, greater mean reductions in DAS28(CRP), no radiographic progression, and normal functional status at week 26 (p<0.001 for all). The only factor predicting stable LDA was disease activity at week 12. Patients achieving ACR/EULAR remission, particularly in the PBO+MTX group, had some advantage in radiographic outcomes compared with patients who only achieved LDA (but not remission). The overall frequency of adverse events was comparable between groups. There were more serious infections and deaths in the ADA+MTX group, with a possible age effect.CONCLUSIONS: Treatment with ADA+MTX was significantly superior to methotrexate alone with respect to clinical, radiographic and functional outcomes in patients with early active RA. Before initiating treatment with adalimumab, individual patient evaluation of the benefit/risk ratio should be carefully considered.

BACKGROUND: Despite the importance of timely management of patients with inflammatory arthritis (IA), delays exist in its diagnosis and treatment.OBJECTIVE: To perform a systematic literature review to identify strategies addressing these delays to inform an American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) taskforce.METHODS: The authors searched literature published between January 1985 and November 2010, and ACR and EULAR abstracts between 2007-2010. Additional information was obtained through a grey literature search, a survey conducted through ACR and EULAR, and a hand search of the literature.RESULTS:(1) From symptom onset to primary care, community case-finding strategies, including the use of a questionnaire and autoantibody testing, have been designed to identify patients with early IA. Several websites provided information on IA but were of varying quality and insufficient to aid early referral.(2) At a primary care level, education programmes and patient self-administered questionnaires identified patients with potential IA for referral to rheumatology. Many guidelines emphasised the need for early referral with one providing specific referral criteria.(3) Once referred, early arthritis clinics provided a point of early access for rheumatology assessment. Triage systems, including triage clinics, helped prioritise clinic appointments for patients with IA. Use of referral forms standardised information required, further optimising the triage process. Wait times for patients with acute IA were also reduced with development of rapid access systems.CONCLUSIONS: This review identified three main areas of delay to care for patients with IA and potential solutions for each. A co-ordinated effort will be required by the rheumatology and primary care community to address these effectively.