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Introduction Peficitinib is a novel orally bioavailable, once-daily Janus kinase (JAK) inhibitor approved in Japan for the treatment of rheumatoid arthritis (RA). This 2-year extension study of two global phase IIb trials investigated the long-term safety and effectiveness of peficitinib. Methods All eligible patients with moderate-to-severe RA including patients in the placebo group who participated in one of two global phase IIb trials (‘with methotrexate’ or ‘without methotrexate’) were included in this 2-year open-label extension study and were converted to peficitinib 100 mg once daily. The primary objective was to evaluate an additional 2 years of safety by assessing treatment-emergent adverse events (AEs) and clinical laboratory evaluations for 105 weeks. Evaluation of an additional 2 years of effectiveness using American College of Rheumatology (ACR) 20/50/70 responses was the exploratory objective. Results Overall, 611 patients were enrolled in the extension study: 319 (52.2%) patients completed the study and 292 (48%) discontinued treatment, including for withdrawal of patient consent (n = 96), failure to achieve low disease activity (n = 62), and AE not including death (n = 41). AEs were reported in 463 (76%) patients. The most common AEs (per 100 patient-years) were upper respiratory tract infections (9.9) and urinary tract infections (7.2). Serious AEs were reported in 80 (13%) patients, with incidences per 100 patient-years of serious infections 2.7, herpes zoster 1.5 (including one herpes zoster ophthalmic), and malignancies 0.6 (most frequently basal cell carcinoma). At week 105, 269 (44%) patients demonstrated an ACR20 response relative to their respective phase IIb trial baselines. Conclusion Among 319 patients who completed this 2-year extension of two global phase IIb studies, peficitinib 100 mg once daily demonstrated a stable safety profile and sustained effectiveness in patients with moderate-to-severe RA. Trial Registration ClinicalTrials.gov identifier, NCT01711814. Registered 19 October 2012. Funding Astellas Pharma Global Development, Inc. Electronic Supplementary Material The online version of this article (10.1007/s40744-019-00167-6) contains supplementary material, which is available to authorized users.

Objective To evaluate the efficacy and safety of orally administered once-daily peficitinib in combination with limited conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in patients with moderate-to-severe rheumatoid arthritis (RA). Methods In this randomized, double-blind, phase IIb trial, patients with RA (n = 289) were treated with peficitinib 25 mg, 50 mg, 100 mg, or 150 mg or matching placebo once daily for 12 weeks. The primary end point was the percentage of patients who met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at week 12. Results ACR20 response rates at week 12 were 22.0%, 36.8%, 48.3% (P

Patients who have had inadequate response to tumour necrosis factor inhibitors have fewer treatment options and are generally more treatment refractory to subsequent therapeutic interventions than previously untreated patients. We report the efficacy and safety of ixekizumab, a monoclonal antibody that selectively targets interleukin-17A, in patients with active psoriatic arthritis and previous inadequate response to tumour necrosis factor inhibitors.In this double-blind, multicentre, randomised, placebo-controlled, phase 3 study (SPIRIT-P2), patients were recruited from 109 centres across ten countries in Asia, Australia, Europe, and North America. Patients were aged 18 years or older, had a confirmed diagnosis of psoriatic arthritis for at least 6 months, and had a previous inadequate response, distinguished by being refractory to therapy or had loss of efficacy, or were intolerant to tumour necrosis factor inhibitors. Patients were randomly assigned (1:1:1) by a computer-generated random sequence to receive a subcutaneous injection of 80 mg ixekizumab every 4 weeks or every 2 weeks after a 160 mg starting dose or placebo. The primary endpoint was the proportion of patients who attained at least 20% improvement in the American College of Rheumatology response criteria (ACR-20) at week 24. This study is registered with ClinicalTrials.gov, number NCT02349295.Between March 3, 2015, to March 22, 2016, 363 patients were randomly assigned to placebo (n=118), ixekizumab every 4 weeks (n=122), or ixekizumab every 2 weeks (n=123). At week 24, a higher proportion of patients attained ACR-20 with ixekizumab every 4 weeks (65 [53%] patients; effect size vs placebo 33·8% [95% CI 22·4-45·2]; p0·0001) and ixekizumab every 2 weeks (59 [48%] patients; 28.5% [17·1-39.8]; p0·0001) than did patients with placebo (23 [20%] patients). Up to week 24, serious adverse events were reported in three (3%) patients with ixekizumab every 4 weeks, eight (7%) with ixekizumab every 2 weeks, and four (3%) with placebo; no deaths were reported. Infections were reported in 47 (39%) patients with ixekizumab every 4 weeks, 47 (38%) with ixekizumab every 2 weeks, and 35 (30%) with placebo. Three (2%) serious infections, all in patients in the ixekizumab every 2 weeks group, were reported.Both the 2-week and 4-week ixekizumab dosing regimens improved the signs and symptoms of patients with active psoriatic arthritis and who had previously inadequate response to tumour necrosis factor inhibitors, with a safety profile consistent with previous studies investigating ixekizumab.Eli Lilly and Company.

Objective.To evaluate the longer-term safety and efficacy of secukinumab, a fully human monoclonal antiinterleukin-17A antibody, in patients with rheumatoid arthritis.Methods.In this 52-week, double-blind, placebo-controlled (up to Week 20) study (NCT00928512), patients responding inadequately to disease-modifying antirheumatic drugs (DMARD) or biologics were randomized to receive monthly subcutaneous injections of secukinumab (25, 75, 150, or 300 mg), or placebo. The efficacy and safety results up to Week 20 have been reported previously. Here, efficacy results from Week 20 to 52 and safety results from Week 20 to 60 are presented.Results.Of 237 patients randomized, 174 (73.4%) completed the study. Patients with improved American College of Rheumatology (ACR) and 28-joint Disease Activity Score (DAS28) C-reactive protein (CRP) responses at Week 16 sustained their responses through Week 52. In patients taking 150 mg of secukinumab, responses were improved through Week 52 (ACR50: Week 16 = 45%, Week 52 = 55%; DAS28-CRP ≤ 2.6: Week 16 = 25%, Week 52 = 40%). The rate of adverse events (AE) from weeks 20 to 60 was 64.8%, with most AE being mild to moderate in severity. The overall rate of infections was 31.9%, most being mild. The most predominant infection was nasopharyngitis, and was not associated with dose or concurrent neutropenia. Serious AE were reported in 21 patients (8.9%). There were 3 reports of malignancies (ovarian, lung, basal cell), and no deaths between weeks 20 and 60.Conclusion.Patients with active RA who failed to respond to DMARD and other biologics showed an improvement after longterm treatment with 150 mg of secukinumab. The frequency of AE remained stable over time and secukinumab had a consistent safety profile over 60 weeks.

Objectives The interleukin-6 receptor (IL-6R) blocker tocilizumab (TCZ) reduces inflammatory disease activity in rheumatoid arthritis (RA) but elevates lipid concentrations in some patients. We aimed to characterise the impact of IL-6R inhibition on established and novel risk factors in active RA.\ud \ud Methods Randomised, multicentre, two-part, phase III trial (24-week double-blind, 80-week open-label), MEASURE, evaluated lipid and lipoprotein levels, high-density lipoprotein (HDL) particle composition, markers of coagulation, thrombosis and vascular function by pulse wave velocity (PWV) in 132 patients with RA who received TCZ or placebo.\ud \ud Results Median total-cholesterol, low-density lipoprotein-cholesterol (LDL-C) and triglyceride levels increased in TCZ versus placebo recipients by week 12 (12.6% vs 1.7%, 28.1% vs 2.2%, 10.6% vs −1.9%, respectively; all p\ud \ud Conclusions These data provide the first detailed evidence for the modulation of lipoprotein particles and other surrogates of vascular risk with IL-6R inhibition. When compared with placebo, TCZ induced elevations in LDL-C but altered HDL particles towards an anti-inflammatory composition and favourably modified most, but not all, measured vascular risk surrogates. The net effect of such changes for cardiovascular risk requires determination.

ObjectiveTo assess the safety and efficacy of secukinumab, a fully human monoclonal anti-interleukin-17A antibody, in patients with rheumatoid arthritis (RA).MethodsPatients (n=237) with inadequate response to methotrexate were randomly assigned to receive monthly subcutaneous injections of secukinumab 25 mg, 75 mg, 150 mg, 300 mg or placebo. The primary endpoint was the American College of Rheumatology 20% response (ACR20) at week 16.ResultsDemographics and baseline characteristics were comparable across all treatment groups. The primary efficacy endpoint was not achieved: the proportion of ACR20 responders at week 16 with secukinumab 25–300 mg was 36.0–53.7% versus placebo (34%). Disease activity score in 28 joints (DAS28)–C-reactive protein (CRP) was a secondary endpoint and clinically relevant decreases with secukinumab 75–300 mg were reported versus placebo. Serum high sensitivity CRP levels at week 16 were significantly reduced with secukinumab 75 mg, 150 mg and 300 mg doses versus placebo. The safety profile of secukinumab was consistent with that seen with other biological agents. Most adverse events (AE) were mild to moderate in severity. Infections were slightly more frequent with secukinumab than placebo. Six serious AE were reported: secukinumab 75 mg (one), secukinumab 300 mg (four) and placebo (one).ConclusionsACR20 response rates differed between secukinumab 75 mg, 150 mg and 300 mg doses and placebo; however, the primary efficacy endpoint was not achieved. Greater decreases in DAS28 were observed with secukinumab 75 mg, 150 mg and 300 mg than placebo. There were no unexpected safety signals and no specific organ-related toxicities. Further trials with secukinumab in the treatment of RA are warranted.

Objective To examine immunization responses in patients with rheumatoid arthritis (RA) treated with rituximab and to investigate the effects of rituximab-induced CD20+ B cell depletion on immune responses to tetanus toxoid (T cell–dependent antigen), pneumococcal polysaccharide (T cell–independent antigen), and keyhole limpet hemocyanin (KLH) (neoantigen) and on delayed-type hypersensitivity (DTH). Methods In a controlled trial, we enrolled 103 patients with active RA receiving a stable dose of methotrexate (MTX). Tetanus toxoid, pneumococcal polysaccharide, and KLH vaccines as well as a Candida albicans skin test were administered to 1 group of patients receiving rituximab plus MTX (called rituximab-treated patients) for 36 weeks and to 1 group of patients receiving MTX alone for 12 weeks. The primary end point was the proportion of patients with a ≥4-fold rise in antitetanus IgG levels. Antitetanus, antipneumococcal, and anti-KLH serum IgG levels were measured prior to and 4 weeks following vaccine administration. The DTH response to C albicans was measured 2–3 days following placement. Results Responses to tetanus toxoid vaccine (≥4-fold rise) were similar in both groups (39.1% of rituximab-treated patients and 42.3% of patients treated with MTX alone). The ability to maintain a positive DTH response to the C albicans skin test was comparable in both groups (77.4% of rituximab-treated patients and 70% of patients treated with MTX alone), showing no effect of rituximab treatment. Rituximab-treated patients had decreased responses to pneumococcal polysaccharide vaccine (57% of patients had a 2-fold rise in titer in response to ≥1 serotype, compared with 82% of patients treated with MTX alone) and to KLH vaccine (47% of patients had detectable anti-KLH IgG, compared with 93% of patients treated with MTX alone). Conclusion Recall responses to the T cell–dependent protein antigen tetanus toxoid as well as DTH responses were preserved in rituximab-treated RA patients 24 weeks after treatment. Responses to neoantigen (KLH) and T cell–independent responses to pneumococcal vaccine were decreased, but many patients were able to mount responses. These data suggest that polysaccharide and primary immunizations should be administered prior to rituximab infusions to maximize responses.

Objective To assess the efficacy and safety of abatacept in biological-naive patients with rheumatoid arthritis and an inadequate response to methotrexate treated in the long-term extension (LTE) of the ATTEST trial. Methods Patients randomly assigned to abatacept, placebo or infliximab completing the 1-year double-blind period were eligible to receive abatacept ∼10 mg/kg in the open-label LTE. Efficacy to year 2 is presented for patients randomly assigned to abatacept or infliximab who switched to open-label abatacept. Safety data are presented for all patients entering LTE regardless of double-blind treatment. Results Of 431 patients randomly assigned, 79.8% remained on abatacept at year 2. At years 1 and 2, 19.7% and 26.1% of abatacept and 13.3% and 28.6% of infliximab-to-abatacept patients achieved disease activity score 28-defined remission (

Background A key goal in rheumatoid arthritis (RA) therapy is to achieve remission or at least very low disease activity 1 . Secukinumab, a fully human anti-IL-17A monoclonal antibody has been shown to improve signs and symptoms of patients with active RA in this phase II trial 2 . Objectives To report the effect of secukinumab treatment on disease activity in patients with active RA despite stable methotrexate (MTX) treatment. Methods Adult RA patients (n=237) on MTX were randomized equally to receive monthly s.c injections of secukinumab 25mg, 75mg, 150mg, 300mg or placebo. After Week (wk) 16, responders on secukinumab remained on the same dose whereas doses were escalated in non-responders at wk20 (except patients initially on 300mg who remained on the same dose). At wk20, all placebo patients were switched to secukinumab 150mg. All patients were followed up to wk52. Primary endpoint was the proportion of patients achieving American College of Rheumatology (ACR) 20 at wk16. Secondary efficacy endpoints are presented here using ACR50, Health Assessment Questionnaire (HAQ-DI) and EULAR remission rate (DAS28-CRP≤2.6). Results Demographics and baseline characteristics were comparable across treatment groups. The primary endpoint ACR 20 at wk16 was not achieved. ACR50 responses at wk24 and wk52 were highest in patients who remained on secukinumab 150mg for the entire study (ACR50: wk24=50%; wk52=55%). HAQ scores improved over time in responders on secukinumab 150mg (wk24=-0.6; wk52=-0.8). At wk16, the proportion of patients achieving EULAR remission response was 11.3% for 25mg, 6.1% for 75mg, 11.6% for 150mg, 14.6% for 300mg and 6% for placebo. The percentage of patients achieving EULAR remission increased overtime and were highest in patients on secukinumab 150mg (wk24=30%, wk52=40%). Additionally, patients who responded on placebo but switched to secukinumab 150mg at wk20 achieved similar EULAR remission rates that patients receiving secukinumab 150mg for the entire study (wk24=29.4%; wk52=38.9%). Non-responders did not gain much additional efficacy benefit after dose escalation as assessed by ACR50, HAQ and EULAR remission criteria. The safety data for this cohort has been previously described 2 . Overall rates of adverse events (AEs) at wk52 was comparable to data up to wk20 and most AEs were mild to moderate in severity and did not lead to study discontinuation. Conclusions The primary efficacy endpoint was not achieved in this study. Analysis of secondary endpoints suggest that a substantial proportion of patients achieved a consistent ACR50, HAQ-DI and EULAR remission rates improvements through Wk52 in patients with active RA despite stable MTX treatmentwho either remained on or escalated to secukinumab 150mg were observed. These results provide potential evidence for the role of secukinumab in the treatment of RA and support further exploration of secukinumab in RA. References Sesin CA, Bingham CO 3rd. Semin Arthritis Rheum. 2005;35(3):185–96. Genovese M., et al. Arthritis Rheum. 2011;63(10[suppl]):S149–S150. Disclosure of Interest M. Genovese Grant/Research support from: Novartis, H. Kellner: None Declared, P. Durez: None Declared, C. Codding: None Declared, G. Ligozio Employee of: Novartis Pharmaceuticals Corporation, H. Richards Employee of: Novartis Pharma AG, C. Escrig Shareholder of: Novartis Pharma AG, Employee of: Novartis Pharma AG, S. Mpofu Shareholder of: Novartis Pharma AG, Employee of: Novartis Pharma AG

Background Rheumatoid Arthritis (RA) is a chronic, inflammatory, systemic autoimmune disease of unknown etiology characterized by symmetric synovitis leading to cartilage damage 1 . Chronic and severe RA is associated with a 50% higher risk of death from cardiovascular disease (CVD) compared with healthy controls 2 . Moreover, Active RA is associated with an unfavorable lipid profile resulting in a higher atherogenic index 3 . Secukinumab, a fully human anti-IL-17A monoclonal antibody has shown to improve signs and symptoms of patients with active RA in this phase II trial 4 . Evaluation of the effect of secukinumab on lipids is potentially relevant as current guidelines recommend treatment if hypercholesterolemia is associated with elevated CV risk 5 . Objectives To report the effect of secukinumab on the lipid profile and atherogenic indexes in patients with active RA despite stable methotrexate (MTX) treatment. Methods Adult RA patients (n=237) on MTX were randomized equally to receive monthly s.c injections of secukinumab 25mg, 75mg, 150mg, 300mg or placebo. After Week (wk) 16, responders on secukinumab remained on the same dose whereas doses were escalated in non-responders at wk20 (except patients initially on 300mg who remained on the same dose). All placebo patients were switched to secukinumab 150mg. Patients were followed up to wk52. Primary endpoint was the proportion of patients achieving American College of Rheumatology (ACR) 20 response at wk16. Results Demographics, baseline characteristics and lipid parameters were normal and comparable across all treatment groups. There was no effect of secukinumab on the lipid profile (Total Cholesterol, HDLc, LDLc, TG, Apo A-I and Apo B) during the first 16 wks of treatment in all treatment groups when compared to placebo. Atherogenic indices (TC/HDLc and Apo B/Apo A-I ratio also remained unchanged during first 16 wks of therapy (Table 1). In patients who switched from placebo to secukinumab 150mg at wk20, TC/HDLc and Apo B/Apo A-I ratios remained unchanged throughout the duration of the study (wk0-52). The efficacy and safety of this study group has been reported previously and did not report any CV event 3 . Conclusions Treatment with secukinumab was not associated with changes in the lipid profile or the atherogenic risk in patients with RA. References Voulgari PV. Expert Opin Emerg Drugs. 2009; 13:175-96. Avina-Zubieta JA. Arthritis Rheum. 2008; 59: 1690-7. Myasoedova E et al. Ann Rheum Dis. 2010; 69:1310-4. Mark C. Genovese. Arthritis Rheum. 2011;63(10[suppl]):S149-S150. Peters MJL et al. Int J Clin Prac 2010; 64:1440-3. Disclosure of Interest P. Durez: None Declared, M. Genovese Grant/Research support from: Novartis, H. Kellner: None Declared, C. Codding: None Declared, G. Ligozio Employee of: Novartis Pharmaceuticals Corporation, H. Richards Employee of: Novartis Pharma AG, C. Escrig Shareholder of: Novartis Pharma AG, Employee of: Novartis Pharma AG, S. Mpofu Shareholder of: Novartis Pharma AG, Employee of: Novartis Pharma AG

Vancomycin was used to treat a patient with Staphylococcus aureus endocarditis. After 3 weeks of therapy, the patient developed a diffuse maculopapular rash, which resolved upon stopping the drug. Rechallenge with vancomycin several days later resulted in reappearance of the rash and rapid onset of acute anuric renal failure. Renal biopsy revealed acute granulomatous interstitial nephritis. This is the first report of biopsy-proven vancomycininduced acute interstitial nephritis. Renal function should be monitored closely in patients receiving vancomycin therapy.