Evaluation of Improvement in Skin and Nail Psoriasis in Bio-naïve Patients With Active Psoriatic Arthritis Treated With Golimumab: Results Through Week 52 of the GO-VIBRANT Study.

OBJECTIVE: To evaluate whether intravenous (IV) golimumab produces improvements in skin and nail symptoms that are concomitant with improvements in quality of life (QoL) and joint symptoms in patients with psoriatic arthritis. METHODS: Patients were randomized to either IV golimumab 2 mg/kg at weeks 0, 4, then every 8 weeks (q8w) through week 52 or placebo at weeks 0, 4, then q8w, with crossover to IV golimumab 2 mg/kg at weeks 24, 28, and then q8w through week 52. Assessments included Psoriasis Area and Severity Index (PASI), modified Nail Psoriasis Severity Index (mNAPSI), Dermatology Life Quality Index (DLQI), and American College of Rheumatology (ACR) rheumatoid arthritis response criteria. RESULTS: Through week 24, achievement of PASI 75/90/100 responses (P ≤ .0098) and mean improvements in mNAPSI (-11.4 vs -3.7; P < .0001) and DLQI (-9.8 vs -2.9; P < .0001) were significantly greater with golimumab versus placebo. Responses were maintained in patients treated with golimumab through week 52. In placebo-crossover patients, increases in the proportion of patients achieving PASI 75/90/100 responses were observed from weeks 24 to 52, and mean improvements in mNAPSI (from -3.7 to -12.9) and DLQI (from -2.9 to -7.8) increased from weeks 24 to 52. Simultaneous achievement of PASI and DLQI responses, PASI and ACR responses, and mNAPSI and DLQI responses were also observed. Similar responses were observed for all assessments regardless of concomitant methotrexate use. CONCLUSION: Improvements in skin and nail psoriasis symptoms with IV golimumab in patients with psoriatic arthritis were concomitant with improvements in QoL and arthritis disease activity through 1 year.

Disease-specific composite measures for psoriatic arthritis are highly responsive to a Janus kinase inhibitor treatment that targets multiple domains of disease.

BACKGROUND: The multiple disease domains affected in psoriatic arthritis (PsA) may make composite endpoints appropriate for assessing changes in disease activity over time. Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA. Data from two phase 3 studies of patients with PsA were used to evaluate the effect of tofacitinib on composite endpoints. METHODS: Oral Psoriatic Arthritis triaL (OPAL) Broaden was a 12-month study of tumor necrosis factor inhibitor (TNFi)-naïve patients with an inadequate response to at least one conventional synthetic disease-modifying anti-rheumatic drug; OPAL Beyond was a 6-month study of patients with inadequate response to TNFi. Patients with active PsA received tofacitinib 5 or 10 mg doses twice daily (BID), adalimumab 40 mg subcutaneous injection once every 2 weeks (OPAL Broaden only), or placebo advancing at month 3 to tofacitinib 5 or 10 mg BID. The disease-specific composites were Psoriatic Arthritis Disease Activity Score (PASDAS), Disease Activity Index for Reactive Arthritis/Psoriatic Arthritis (DAPSA), and Composite Psoriatic Disease Activity Index (CPDAI). Change from baseline in composite endpoints was also assessed for minimal disease activity (MDA) responders versus non-responders. RESULTS: Overall, 422 patients from OPAL Broaden and 394 patients from OPAL Beyond were treated. The mean changes from baseline to month 3 for tofacitinib 5 mg BID, tofacitinib 10 mg BID (standard error; effect size) were OPAL Broaden: PASDAS, -2.0 (0.14; 1.73), -2.4 (0.14; 2.4); DAPSA, -20.2 (1.72; 0.9), -24.4 (1.73; 1.23); and CPDAI, -2.9 (0.34; 1.03), -4.2 (0.36; 1.53); OPAL Beyond: PASDAS, -1.9 (0.14; 1.53), -2.1 (0.14; 1.84); DAPSA, -22.5 (1.67; 0.81), -21.0 (1.70; 0.84); and CPDAI, -3.3 (0.31; 1.41), -3.4 (0.31; 1.45). Greater changes from baseline to month 3 (P ≤0.05) were seen with both doses of tofacitinib versus placebo for all endpoints except CPDAI for tofacitinib 5 mg BID in OPAL Broaden. Effect sizes generally increased from 3 to 6 months. Mean changes from baseline were greater in MDA responders than MDA non-responders for all composite endpoints across all time points and treatments. CONCLUSIONS: This analysis suggests that disease-specific composite measures are appropriate for evaluating treatment efficacy on multiple disease domains in PsA. TRIAL REGISTRATION: OPAL Broaden: ClinicalTrials.gov Identifier: NCT01877668 , first posted June 12, 2013; OPAL Beyond: ClinicalTrials.gov Identifier: NCT01882439 , first posted June 20, 2013.

Elevated levels of plasma symmetric dimethylarginine and increased arginase activity as potential indicators of cardiovascular comorbidity in rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) patients are at high risk of developing cardiovascular disease (CVD). In RA, chronic inflammation may lead to endothelial dysfunction, an early indicator of CVD, owing to diminished nitric oxide (NO) production. Because L-arginine is the sole precursor of NO, we hypothesized that levels of L-arginine metabolic products reflecting NO metabolism are altered in patients with RA. METHODS: Plasma samples from patients with RA (n = 119) and age- and sex-matched control subjects (n = 238) were used for this study. Using LC-MS/MS, we measured plasma levels of free L-arginine, L-ornithine, L-citrulline, L-NG-monomethyl arginine (MMA), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA). We compared global arginine bioavailability ratio (GABR) (i.e., ratio of L-arginine to L-ornithine + L-citrulline) and arginine methylation index (ArgMI) (i.e., ADMA + SDMA/MMA) in patients with RA vs. control subjects. Plasma arginase activity was measured using a sensitive arginase assay kit. The relationship of L-arginine metabolites and arginase activity to CVD risk factors was evaluated using Pearson's chi-square test. RESULTS: Compared with healthy control subjects, the RA cohort showed significantly lower levels of plasma L-arginine (46.11 ± 17.29 vs. 74.2 ± 22.53 µmol/L, p < 0.001) and GABR (0.36 ± 0.16 vs. 0.73 ± 0.24, p < 0.001), elevated levels of ADMA (0.76 ± 0.12 vs. 0.62 ± 0.12 µmol/L, p < 0.001), SDMA (0.54 ± 0.14 vs. 0.47 ± 0.13 µmol/L, p < 0.001), and ArgMI (6.51 ± 1.86 vs. 5.54 ± 1.51, p < 0.001). We found an approximately fourfold increase in arginase activity (33.8 ± 1.1 vs. 8.4 ± 0.8 U/L, p < 0.001), as well as elevated levels of arginase-mediated L-arginine catalytic product L-ornithine (108.64 ± 30.26 vs. 69.3 ± 20.71 µmol/L, p < 0.001), whereas a nitric oxide synthase (NOS) catalytic product, the L-citrulline level, was diminished in RA (30.32 ± 9.93 vs. 36.17 ± 11.64 µmol/L, p < 0.001). Patients with RA with existing CVD had higher arginase activity than patients with RA without CVD (p = 0.048). CONCLUSIONS: Global L-arginine bioavailability was diminished, whereas plasma arginase activity, ADMA, and SDMA levels were elevated, in patients with RA compared with healthy control subjects. Plasma SDMA was associated with hypertension and hyperlipidemia in patients with RA. This dysregulated L-arginine metabolism may function as a potential indicator of CVD risk in patients with RA.

Network meta-analysis and cost per responder of targeted Immunomodulators in the treatment of active psoriatic arthritis.

BACKGROUND: Multiple targeted immunomodulators (TIMs) for psoriatic arthritis (PsA) treatment are available, but limited studies have directly compared these agents. This study indirectly compared the efficacy of TNF-α, interleukins, and phosphodiesterase-4 inhibitors for treatment of active PsA. METHODS: A systematic literature review was conducted to identify phase III randomized controlled trials (RCTs) for adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, ustekinumab, secukinumab, and apremilast in active PsA. Joint (ACR20/50/70) and skin outcomes (PASI75/90) at Week 24 with each TIM were estimated via a Bayesian network meta-analysis, and the incremental cost per responder over the first 24 weeks of treatment was calculated. Similar analyses were conducted in a subgroup of biologic-naïve patients. RESULTS: Seventeen RCTs were identified; 13 included ACR and/or PASI responses at Week 24. Among the overall population, patients receiving adalimumab, golimumab, and infliximab showed higher ACR20/50/70 (adalimumab: 61.2/42.8/40.8%, golimumab: 61.6/39.8/27.4%, infliximab: 56.2/57.1/34.2%) and PASI75/90 (72.7/55.5%, 74.1/57.2%, and 77.1/61.0%, respectively) responses at Week 24 compared with other TIMs. In terms of cost-effectiveness, these treatments were also associated with the lowest incremental cost per responder for both skin and joint outcomes. Similar rankings of efficacy and incremental cost per responder were observed in the analysis among biologic-naive patients. CONCLUSIONS: Adalimumab, golimumab, and infliximab were associated with higher efficacy and lower incremental costs per responder for both joint and skin responses in active PsA.