Olokizumab versus Placebo or Adalimumab in Rheumatoid Arthritis.

BACKGROUND: The cytokine interleukin-6 is involved in the pathogenesis of rheumatoid arthritis. Olokizumab, a humanized monoclonal antibody targeting the interleukin-6 cytokine directly, is being tested for the treatment of rheumatoid arthritis. METHODS: In a 24-week, phase 3, multicenter, placebo- and active-controlled trial, we randomly assigned (in a 2:2:2:1 ratio) patients with rheumatoid arthritis and an inadequate response to methotrexate to receive subcutaneous olokizumab at a dose of 64 mg every 2 or 4 weeks, adalimumab (40 mg every 2 weeks), or placebo; all patients continued methotrexate therapy. The primary end point was an American College of Rheumatology 20 (ACR20) response (≥20% fewer tender and swollen joints and ≥20% improvement in three of five other domains) at week 12, with each olokizumab dose tested for superiority to placebo. We also tested the noninferiority of each olokizumab dose to adalimumab with respect to the percentage of patients with an ACR20 response (noninferiority margin, -12 percentage points in the lower boundary of the 97.5% confidence interval for the difference between groups). RESULTS: A total of 464 patients were assigned to receive olokizumab every 2 weeks, 479 to receive olokizumab every 4 weeks, 462 to receive adalimumab, and 243 to receive placebo. An ACR20 response at week 12 occurred in 44.4% of the patients receiving placebo, in 70.3% receiving olokizumab every 2 weeks (difference vs. placebo, 25.9 percentage points; 97.5% confidence interval [CI], 17.1 to 34.1), in 71.4% receiving olokizumab every 4 weeks (difference vs. placebo, 27.0 percentage points; 97.5% CI, 18.3 to 35.2), and in 66.9% receiving adalimumab (difference vs. placebo, 22.5 percentage points; 95% CI, 14.8 to 29.8) (P<0.001 for the superiority of each olokizumab dose to placebo). Both olokizumab doses were noninferior to adalimumab with respect to the percentage of patients with an ACR20 response at week 12 (difference, 3.4 percentage points [97.5% CI, -3.5 to 10.2] with olokizumab every 2 weeks and 4.5 percentage points [97.5% CI, -2.2 to 11.2] with olokizumab every 4 weeks). Adverse events, most commonly infections, occurred in approximately 70% of the patients who received olokizumab. Antibodies against olokizumab were detected in 3.8% of the patients receiving the drug every 2 weeks and in 5.1% of those receiving it every 4 weeks. CONCLUSIONS: In patients with rheumatoid arthritis who were receiving maintenance methotrexate, olokizumab was superior to placebo and noninferior to adalimumab in producing an ACR20 response at 12 weeks. Larger and longer trials are required to determine the efficacy and safety of olokizumab in patients with rheumatoid arthritis. (Supported by R-Pharm; CREDO2 ClinicalTrials.gov number, NCT02760407.).

Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis.

BACKGROUND: Increases in lipid levels and cancers with tofacitinib prompted a trial of major adverse cardiovascular events (MACE) and cancers in patients with rheumatoid arthritis receiving tofacitinib as compared with a tumor necrosis factor (TNF) inhibitor. METHODS: We conducted a randomized, open-label, noninferiority, postauthorization, safety end-point trial involving patients with active rheumatoid arthritis despite methotrexate treatment who were 50 years of age or older and had at least one additional cardiovascular risk factor. Patients were randomly assigned in a 1:1:1 ratio to receive tofacitinib at a dose of 5 mg or 10 mg twice daily or a TNF inhibitor. The coprimary end points were adjudicated MACE and cancers, excluding nonmelanoma skin cancer. The noninferiority of tofacitinib would be shown if the upper boundary of the two-sided 95% confidence interval for the hazard ratio was less than 1.8 for the combined tofacitinib doses as compared with a TNF inhibitor. RESULTS: A total of 1455 patients received tofacitinib at a dose of 5 mg twice daily, 1456 received tofacitinib at a dose of 10 mg twice daily, and 1451 received a TNF inhibitor. During a median follow-up of 4.0 years, the incidences of MACE and cancer were higher with the combined tofacitinib doses (3.4% [98 patients] and 4.2% [122 patients], respectively) than with a TNF inhibitor (2.5% [37 patients] and 2.9% [42 patients]). The hazard ratios were 1.33 (95% confidence interval [CI], 0.91 to 1.94) for MACE and 1.48 (95% CI, 1.04 to 2.09) for cancers; the noninferiority of tofacitinib was not shown. The incidences of adjudicated opportunistic infections (including herpes zoster and tuberculosis), all herpes zoster (nonserious and serious), and adjudicated nonmelanoma skin cancer were higher with tofacitinib than with a TNF inhibitor. Efficacy was similar in all three groups, with improvements from month 2 that were sustained through trial completion. CONCLUSIONS: In this trial comparing the combined tofacitinib doses with a TNF inhibitor in a cardiovascular risk-enriched population, risks of MACE and cancers were higher with tofacitinib and did not meet noninferiority criteria. Several adverse events were more common with tofacitinib. (Funded by Pfizer; ORAL Surveillance ClinicalTrials.gov number, NCT02092467.).

Olokizumab plus methotrexate: safety and efficacy over 106 weeks of treatment.

OBJECTIVE: To report long-term safety and tolerability of olokizumab (OKZ) in combination with methotrexate (MTX) in subjects with active rheumatoid arthritis (RA), using pooled data from three randomised clinical trials (RCT) followed by open-label extension (OLE) study. METHODS: Cumulative data from three phase 3 core trials and their OLE were analysed. Safety variables assessed included treatment-emergent adverse events (AEs), serious AEs (SAEs), AEs of special interest and laboratory results. Efficacy assessments included ACR20/50/70 responses, Disease Activity Score 28 (C-reactive protein) <3.2, CDAI remission and low disease activity (LDA), SDAI remission and LDA, HAQ-DI decrease of 0.22 unit and Boolean 2.0 remission. RESULTS: A total of 2304 patients received OKZ in combination with MTX either once every 2 weeks or once every 4 weeks. Event rates per 100 patient-years in OKZ every 2 weeks and OKZ every 4 weeks, respectively, were 9.57 and 9.13 for SAEs; 2.95 and 2.34 for serious infections; 0.09 and 0.05 for gastrointestinal perforations; 0.58 and 0.83 for major adverse cardiovascular events; and 0.45 and 0.50 for malignancies. No increase in the rate of any AE was observed over 106 weeks of treatment. The evaluation of laboratory variables demonstrated the expected changes, like neutropenia, elevation of liver enzymes and blood lipids. Clinical response rates remained stable during the OLE. CONCLUSION: The long-term safety and tolerability of OKZ in combination with MTX remained stable. The efficacy of OKZ was maintained through week 106. These findings support OKZ as a treatment option for patients with active RA.

Safety profile of upadacitinib in patients at risk of cardiovascular disease: integrated post hoc analysis of the SELECT phase III rheumatoid arthritis clinical programme.

OBJECTIVE: Increased risk of serious adverse events (AEs) was reported for tofacitinib relative to tumour necrosis factor inhibitor therapy in patients with rheumatoid arthritis (RA) aged ≥50 years enriched for cardiovascular (CV) risk (ORAL Surveillance). We assessed post hoc the potential risk of upadacitinib in a similar RA population. METHODS: Pooled safety data from six phase III trials were evaluated post hoc for AEs in patients receiving upadacitinib 15 mg once a day (with or without conventional synthetic disease-modifying antirheumatic drugs), adalimumab 40 mg every other week with concomitant methotrexate (MTX), or MTX monotherapy in the overall trial population and in a subset of patients with higher CV risk (aged ≥50 years, ≥1 CV risk factor). Higher-risk patients from a head-to-head study of upadacitinib 15 mg versus adalimumab (SELECT-COMPARE) were assessed in parallel. Exposure-adjusted incidence rates for treatment-emergent AEs were summarised based on exposure to upadacitinib or comparators. RESULTS: A total of 3209 patients received upadacitinib 15 mg, 579 received adalimumab and 314 received MTX monotherapy; ~54% of the patients were included in the overall and SELECT-COMPARE higher-risk populations. Major adverse cardiovascular events (MACE), malignancy (excluding non-melanoma skin cancer (NMSC)) and venous thromboembolism (VTE) were more frequent in the higher-risk cohorts versus the overall population but were generally similar across treatment groups. Rates of serious infections in higher-risk populations and herpes zoster (HZ) and NMSC in all populations were higher with upadacitinib 15 mg than comparators. CONCLUSIONS: An increased risk of MACE, malignancy (excluding NMSC) and VTE was observed in higher-risk populations with RA, yet risk was comparable between upadacitinib-treated and adalimumab-treated patients. Higher rates of NMSC and HZ were observed with upadacitinib versus comparators across all populations, and increased rates of serious infections were detected in upadacitinib-treated patients at higher CV risk. TRIAL REGISTRATION NUMBERS: NCT02706873, NCT02675426, NCT02629159, NCT02706951, NCT02706847 and NCT03086343.

Anti-GM-CSF otilimab versus tofacitinib or placebo in patients with active rheumatoid arthritis and an inadequate response to conventional or biologic DMARDs: two phase 3 randomised trials (contRAst 1 and contRAst 2).

OBJECTIVES: To investigate the efficacy and safety of otilimab, an antigranulocyte-macrophage colony-stimulating factor antibody, in patients with active rheumatoid arthritis. METHODS: Two phase 3, double-blind randomised controlled trials including patients with inadequate responses to methotrexate (contRAst 1) or conventional synthetic/biologic disease-modifying antirheumatic drugs (cs/bDMARDs; contRAst 2). Patients received background csDMARDs. Through a testing hierarchy, subcutaneous otilimab (90/150 mg once weekly) was compared with placebo for week 12 endpoints (after which, patients receiving placebo switched to active interventions) or oral tofacitinib (5 mg two times per day) for week 24 endpoints. PRIMARY ENDPOINT: proportion of patients achieving an American College of Rheumatology response ≥20% (ACR20) at week 12. RESULTS: The intention-to-treat populations comprised 1537 (contRAst 1) and 1625 (contRAst 2) patients. PRIMARY ENDPOINT: proportions of ACR20 responders were statistically significantly greater with otilimab 90 mg and 150 mg vs placebo in contRAst 1 (54.7% (p=0.0023) and 50.9% (p=0.0362) vs 41.7%) and contRAst 2 (54.9% (p<0.0001) and 54.5% (p<0.0001) vs 32.5%). Secondary endpoints: in both trials, compared with placebo, otilimab increased the proportion of Clinical Disease Activity Index (CDAI) low disease activity (LDA) responders (not significant for otilimab 150 mg in contRAst 1), and reduced Health Assessment Questionnaire-Disability Index (HAQ-DI) scores. Benefits with tofacitinib were consistently greater than with otilimab across multiple endpoints. Safety outcomes were similar across treatment groups. CONCLUSIONS: Although otilimab demonstrated superiority to placebo in ACR20, CDAI LDA and HAQ-DI, improved symptoms, and had an acceptable safety profile, it was inferior to tofacitinib. TRIAL REGISTRATION NUMBERS: NCT03980483, NCT03970837.

Anti-GM-CSF otilimab versus sarilumab or placebo in patients with rheumatoid arthritis and inadequate response to targeted therapies: a phase III randomised trial (contRAst 3).

OBJECTIVES: To investigate the efficacy and safety of otilimab, an anti-granulocyte-macrophage colony-stimulating factor antibody, in patients with active rheumatoid arthritis and an inadequate response to conventional synthetic (cs) and biologic disease-modifying antirheumatic drugs (DMARDs) and/or Janus kinase inhibitors. METHODS: ContRAst 3 was a 24-week, phase III, multicentre, randomised controlled trial. Patients received subcutaneous otilimab (90/150 mg once weekly), subcutaneous sarilumab (200 mg every 2 weeks) or placebo for 12 weeks, in addition to csDMARDs. Patients receiving placebo were switched to active interventions at week 12 and treatment continued to week 24. The primary end point was the proportion of patients achieving an American College of Rheumatology ≥20% response (ACR20) at week 12. RESULTS: Overall, 549 patients received treatment. At week 12, there was no significant difference in the proportion of ACR20 responders with otilimab 90 mg and 150 mg versus placebo (45% (p=0.2868) and 51% (p=0.0596) vs 38%, respectively). There were no significant differences in Clinical Disease Activity Index, Health Assessment Questionnaire-Disability Index, pain Visual Analogue Scale or Functional Assessment of Chronic Illness Therapy-Fatigue scores with otilimab versus placebo at week 12. Sarilumab demonstrated superiority to otilimab in ACR20 response and secondary end points. The incidence of adverse or serious adverse events was similar across treatment groups. CONCLUSIONS: Otilimab demonstrated an acceptable safety profile but failed to achieve the primary end point of ACR20 and improve secondary end points versus placebo or demonstrate non-inferiority to sarilumab in this patient population. TRIAL REGISTRATION NUMBER: NCT04134728.

Consensus statement on blocking interleukin-6 receptor and interleukin-6 in inflammatory conditions: an update.

BACKGROUND: Targeting interleukin (IL)-6 has become a major therapeutic strategy in the treatment of immune-mediated inflammatory disease. Interference with the IL-6 pathway can be directed at the specific receptor using anti-IL-6Rα antibodies or by directly inhibiting the IL-6 cytokine. This paper is an update of a previous consensus document, based on most recent evidence and expert opinion, that aims to inform on the medical use of interfering with the IL-6 pathway. METHODS: A systematic literature research was performed that focused on IL-6-pathway inhibitors in inflammatory diseases. Evidence was put in context by a large group of international experts and patients in a subsequent consensus process. All were involved in formulating the consensus statements, and in the preparation of this document. RESULTS: The consensus process covered relevant aspects of dosing and populations for different indications of IL-6 pathway inhibitors that are approved across the world, including rheumatoid arthritis, polyarticular-course and systemic juvenile idiopathic arthritis, giant cell arteritis, Takayasu arteritis, adult-onset Still's disease, Castleman's disease, chimeric antigen receptor-T-cell-induced cytokine release syndrome, neuromyelitis optica spectrum disorder and severe COVID-19. Also addressed were other clinical aspects of the use of IL-6 pathway inhibitors, including pretreatment screening, safety, contraindications and monitoring. CONCLUSIONS: The document provides a comprehensive consensus on the use of IL-6 inhibition to treat inflammatory disorders to inform healthcare professionals (including researchers), patients, administrators and payers.

Long-term safety and efficacy of sarilumab with or without background csDMARDs in rheumatoid arthritis.

OBJECTIVE: To evaluate the long-term safety and efficacy of sarilumab with/without conventional synthetic (cs)DMARDs in RA. METHODS: The analyses evaluated two open-label extensions (OLEs): EXTEND and MONARCH OLE, which included patients from six randomized trials. Patients received sarilumab 200 mg once every 2 weeks (q2w) for at least 264 weeks up to 516 weeks (EXTEND: Sarilumab Monotherapy and Sarilumab + csDMARD groups) or for 276 weeks (MONARCH OLE: Continuation and Switch groups). Primary endpoints included safety, immunogenicity and changes in laboratory parameters. Secondary endpoints included clinical signs and symptoms along with health-related quality-of-life (HRQOL) questionnaires. RESULTS: The Sarilumab Monotherapy (n = 111), Continuation (n = 165) and Switch (n = 155) groups received sarilumab monotherapy, while the Sarilumab + csDMARD group (n = 1910) received sarilumab in combination with csDMARDs. Incidence of one or more treatment-emergent adverse events was 126 (Sarilumab Monotherapy group), 169 (Sarilumab + csDMARD group), 159 (Continuation group) and 159 (Switch group) events/100 patient-years. Neutropenia was the most common adverse event. Neutropenia was not associated with an increased incidence of infections. Most neutropenia cases normalized on-treatment. Adverse events of special interests, such as malignancies, major adverse cardiovascular events, venous thromboembolism and gastrointestinal perforations, were rare. Immunogenicity was low and not associated with hypersensitivity reactions or discontinuations due to lack or loss of efficacy. Improvements in clinical signs and symptoms and HRQOL, observed during the initial blinded trials, were maintained throughout the OLE assessment period. CONCLUSIONS: Long-term sarilumab treatment with/without csDMARDs in patients with RA revealed no new safety findings. Efficacy and HRQOL were maintained or further increased over the open-label assessment period. TRIAL REGISTRATION: EXTEND, ClinicalTrials.gov, https://www.clinicaltrials.gov/ct2/show/NCT01146652, NCT01146652; MONARCH OLE, ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT02332590, NCT02332590.

Impact of initial therapy with upadacitinib or adalimumab on achievement of 48-week treatment goals in patients with rheumatoid arthritis: post hoc analysis of SELECT-COMPARE.

OBJECTIVES: Evaluate the importance of treatment sequencing in SELECT-COMPARE, assessing potential differences between starting upadacitinib or adalimumab therapy following inadequate MTX response. METHODS: Patients from SELECT-COMPARE were randomized to upadacitinib 15 mg once daily, placebo or adalimumab 40 mg. Per protocol, patients with <20% improvement in tender or swollen joint counts (weeks 14, 18, 22) or failure to achieve Clinical Disease Activity Index (CDAI) low disease activity (LDA) at week 26 were blindly switched from upadacitinib to adalimumab or vice versa. Treatment outcomes, including clinical remission/LDA, physical function, pain and a novel combined endpoint for deep response, were evaluated through 48 weeks and corresponding time-averaged response rates determined. Data were analysed by initial randomized group regardless of any subsequent switch in therapy. RESULTS: This post hoc analysis included 651 patients initially randomized to upadacitinib (of whom 252 switched to adalimumab) and 327 patients initially randomized to adalimumab (of whom 159 switched to upadacitinib). At week 48, patients randomized to either therapy demonstrated similar achievement of most treatment endpoints. Greater improvements in the total time spent in a lower disease state were observed for initial upadacitinib vs initial adalimumab therapy across most clinical and patient-reported outcomes through 48 weeks, and the median time to DAS28(CRP) <2.6/≤3.2 occurred 6-8 weeks earlier among those randomized to upadacitinib. CONCLUSION: Following a modified treat-to-target strategy, rates of CDAI remission/LDA and DAS28(CRP) <2.6/≤3.2 at 48 weeks were similar, regardless of starting therapy. However, patients initially receiving upadacitinib reached treatment targets more quickly and spent more time in clinical targets over the initial 48 weeks of treatment. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT02629159.

Olokizumab, a monoclonal antibody against interleukin-6, in combination with methotrexate in patients with rheumatoid arthritis inadequately controlled by tumour necrosis factor inhibitor therapy: efficacy and safety results of a randomised controlled phase III study.

OBJECTIVES: To assess the efficacy and safety of olokizumab (OKZ), a monoclonal antibody against the interleukin-6 (IL-6) cytokine, versus placebo (PBO) in patients with prior inadequate response to tumour necrosis factor inhibitors (TNFi-IRs). METHODS: In this 24-week multicentre, placebo-controlled, double-blind study, the patients were randomised in a 2:2:1 ratio to receive subcutaneously administered OKZ 64 mg once every 2 weeks (q2w), OKZ 64 mg once every 4 weeks (q4w) or PBO plus methotrexate. At week 16, the patients on PBO were randomised to receive either OKZ regime. The primary endpoint was the proportion of patients achieving an American College of Rheumatology 20% (ACR20) response at week 12. Disease Activity Score 28-joint count C-reactive protein (DAS28 (CRP))<3.2 at week 12 was the major secondary efficacy endpoint. Safety and immunogenicity were assessed. RESULTS: In 368 patients randomised, ACR20 response rates were 60.9% in OKZ q2w, 59.6% in OKZ q4w and 40.6% in PBO (p<0.01 for both comparisons). Achievement of DAS28 (CRP) <3.2 was significantly different, favouring the OKZ arms. Improvements in efficacy and patient-reported outcomes were maintained throughout 24 weeks and were noted after week 16 in patients who switched from PBO.Dose-related treatment-emergent serious adverse events were 7% in OKZ q2w, 3.2% in OKZ q4w and none in the PBO group. CONCLUSIONS: Direct inhibition of IL-6 with OKZ resulted in significant improvements in the signs and symptoms of rheumatoid arthritis compared with PBO in TNF-IR patients with a similar safety profile as observed for monoclonal antibodies to the IL-6 receptor. TRIAL REGISTRATION NUMBER: NCT02760433.

Filgotinib or lanraplenib in moderate to severe cutaneous lupus erythematosus: a phase 2, randomized, double-blind, placebo-controlled study.

OBJECTIVES: To explore the safety and efficacy of filgotinib (FIL), a Janus kinase 1 inhibitor, and lanraplenib (LANRA), a spleen kinase inhibitor, in cutaneous lupus erythematosus (CLE). METHODS: This was a phase 2, randomized, double-blind, placebo-controlled, exploratory, proof-of-concept study of LANRA (30 mg), FIL (200 mg) or placebo (PBO) once daily for 12 weeks in patients with active CLE. At week 12, PBO patients were rerandomized 1:1 to receive LANRA or FIL for up to 36 additional weeks. RESULTS: Of 47 randomized patients, 45 were treated (PBO, n = 9; LANRA, n = 19; FIL, n = 17). The primary endpoint [change from baseline in Cutaneous Lupus Erythematosus Disease Area and Severity Index Activity (CLASI-A) score at week 12] was not met. The least squares mean CLASI-A score change from baseline was -5.5 (s.e. 2.56) with PBO, -4.5 (1.91) with LANRA and -8.7 (1.85) with FIL. Numerical differences between FIL and PBO were greater in select subgroups. A ≥5-point improvement in the CLASI-A score at week 12 was achieved by 50.0%, 56.3% and 68.8% in the PBO, LANRA and FIL arms, respectively. A numerically greater proportion of patients in the FIL arm (50%) also achieved ≥50% improvement in the CLASI-A score at week 12 (37.5% PBO, 31.3% LANRA). Most adverse events (AEs) were mild or moderate in severity. Two serious AEs were reported with LANRA and one with FIL. CONCLUSION: The primary endpoint was not met. Select subgroups displayed a numerically greater treatment response to FIL relative to PBO. LANRA and FIL were generally well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03134222.

Switching between Janus kinase inhibitor upadacitinib and adalimumab following insufficient response: efficacy and safety in patients with rheumatoid arthritis.

OBJECTIVES: To evaluate efficacy and safety of immediate switch from upadacitinib to adalimumab, or vice versa, in patients with rheumatoid arthritis with non-response or incomplete-response to the initial therapy. METHODS: SELECT-COMPARE randomised patients to upadacitinib 15 mg once daily (n=651), placebo (n=651) or adalimumab 40 mg every other week (n=327). A treat-to-target study design was implemented, with blinded rescue occurring prior to week 26 for patients who did not achieve at least 20% improvement in both tender and swollen joint counts ('non-responders') and at week 26 based on Clinical Disease Activity Index (CDAI) >10 ('incomplete-responders') without washout. RESULTS: A total of 39% (252/651) and 49% (159/327) of patients originally randomised to upadacitinib and adalimumab were rescued to the alternate therapy. In both switch groups (adalimumab to upadacitinib and vice versa) and in non-responders and incomplete-responders, improvements in disease activity were observed at 3 and 6 months following rescue. CDAI low disease activity was achieved by 36% and 47% of non-responders and 45% and 58% of incomplete-responders switched to adalimumab and upadacitinib, respectively, 6 months following switch. Overall, approximately 5% of rescued patients experienced worsening in disease activity at 6 months postswitch. The frequency of adverse events was similar between switch groups. CONCLUSIONS: These observations support a treat-to-target strategy, in which patients who fail to respond initially (or do not achieve sufficient response) are switched to a therapy with an alternate mechanism of action and experience improved outcomes. No new safety findings were observed despite immediate switch without washout.

Points to consider for the treatment of immune-mediated inflammatory diseases with Janus kinase inhibitors: a consensus statement.

OBJECTIVES: Janus kinase inhibitors (JAKi) have been approved for use in various immune-mediated inflammatory diseases. With five agents licensed, it was timely to summarise the current understanding of JAKi use based on a systematic literature review (SLR) on efficacy and safety. METHODS: Existing data were evaluated by a steering committee and subsequently reviewed by a 29 person expert committee leading to the formulation of a consensus statement that may assist the clinicians, patients and other stakeholders once the decision is made to commence a JAKi. The committee included patients, rheumatologists, a gastroenterologist, a haematologist, a dermatologist, an infectious disease specialist and a health professional. The SLR informed the Task Force on controlled and open clinical trials, registry data, phase 4 trials and meta-analyses. In addition, approval of new compounds by, and warnings from regulators that were issued after the end of the SLR search date were taken into consideration. RESULTS: The Task Force agreed on and developed four general principles and a total of 26 points for consideration which were grouped into six areas addressing indications, treatment dose and comedication, contraindications, pretreatment screening and risks, laboratory and clinical follow-up examinations, and adverse events. Levels of evidence and strengths of recommendations were determined based on the SLR and levels of agreement were voted on for every point, reaching a range between 8.8 and 9.9 on a 10-point scale. CONCLUSION: The consensus provides an assessment of evidence for efficacy and safety of an important therapeutic class with guidance on issues of practical management.

Long-term safety and efficacy of sarilumab over 5 years in patients with rheumatoid arthritis refractory to TNF inhibitors.

OBJECTIVE: The objective of this study was to evaluate the long-term safety and efficacy of sarilumab over 5 years in patients with RA refractory to TNF inhibitors (TNFis). METHODS: Patients in the 24-week randomized controlled trial (RCT) TARGET (NCT01709578) who received double-blind placebo or sarilumab 150 or 200 mg every 2 weeks (q2w), plus conventional synthetic DMARDs (csDMARDs), were eligible to receive open-label sarilumab 200 mg q2w plus csDMARDs in the open-label extension (OLE), EXTEND (NCT01146652). OLE dose reduction to 150 mg q2w was permitted per investigators' judgement or protocol-mandated safety concerns. Safety and efficacy were assessed through treatment-emergent adverse events (AEs), laboratory abnormalities and clinical DASs. All statistics are descriptive. RESULTS: Of 546 patients, 454 (83%) were treated with sarilumab in the OLE. The cumulative observation period was 1654.8 patient-years (PY; n = 521); 268 patients (51%) had ≥4 years' exposure. Incidence rates per 100 PY of AEs, and AEs leading to discontinuation, infection and serious infection were 160.4, 8.1, 57.8 and 3.9, respectively. Neutropenia was the most common AE (15.3 per 100 PY). An absolute neutrophil count of <1000 cells/mm3 (Grade 3/4 neutropenia) was observed in 74 patients (14.2%) and normalized on treatment in 48. Clinical efficacy was sustained through 5 years' follow-up. Efficacy was similar for patients with 1 and >1 TNFi failure, and similar for patients who either remained on 200 mg or reduced to 150 mg. CONCLUSION: In patients with RA refractory to TNFi, sarilumab's long-term term safety profile was consistent with previous clinical studies and post-marketing reports. Efficacy was sustained over 5 years. TRIAL REGISTRATION: TARGET, ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01709578, NCT01709578; EXTEND, ClinicalTrials.gov, https://www.clinicaltrials.gov/ct2/show/NCT01146652, NCT01146652.

Upadacitinib improves patient-reported outcomes vs placebo or adalimumab in patients with rheumatoid arthritis: results from SELECT-COMPARE.

OBJECTIVE: To evaluate the impact of upadacitinib vs placebo and adalimumab treatment, on patient-reported outcomes (PROs) in SELECT-COMPARE in an active RA population with inadequate responses to MTX (MTX-IR). METHODS: PROs in patients receiving upadacitinib (15 mg QD), placebo, or adalimumab (40 mg EOW) while on background MTX were evaluated over 48 weeks. PROs included Patient Global Assessment of Disease Activity (PtGA) and pain by visual analogue scale (VAS), the HAQ Disability Index (HAQ-DI), the 36-Item Short Form Survey (SF-36), morning (AM) stiffness duration and severity, the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), and work instability. Least squares mean (LSM) changes and proportions of patients reporting improvements ≥ minimal clinically important differences (MCIDs) and scores ≥ normative values were evaluated. RESULTS: Upadacitinib and adalimumab resulted in greater LSM changes from baseline vs placebo across all PROs (P < 0.05) at week 12, and pain and AM stiffness severity (P < 0.05) at week 2. More upadacitinib- vs placebo-treated (P < 0.05) and similar percentages of upadacitinib- vs adalimumab-treated patients reported improvements ≥ MCID across all PROs at week 12. Upadacitinib vs adalimumab resulted in greater LSM changes from baseline in PtGA, pain, HAQ-DI, stiffness severity, FACIT-F, and the SF-36 Physical Component Summary (PCS) (all P < 0.05) at week 12. More upadacitinib- vs adalimumab-treated patients reported scores ≥ normative values in HAQ-DI and SF-36 PCS (P < 0.05) at week 12. More upadacitinib- vs adalimumab-treated patients maintained clinically meaningful improvements in PtGA, pain, HAQ-DI, FACIT-F, and AM stiffness through 48 weeks. CONCLUSION: In MTX-IR patients with RA, treatment with upadacitinib resulted in statistically significant and clinically meaningful improvements in PROs equivalent to or greater than with adalimumab. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT02629159.

Infections in baricitinib clinical trials for patients with active rheumatoid arthritis.

OBJECTIVES: To evaluate the incidence of infection in patients with active rheumatoid arthritis (RA) treated with baricitinib, an oral selective Janus kinase (JAK)1 and JAK2 inhibitor. METHODS: Infections are summarised from an integrated database (8 phase 3/2/1b clinical trials and 1 long-term extension (LTE)) with data to 1 April 2017. The 'all-bari-RA' analysis set included patients who received any baricitinib dose. Placebo comparison was based on six studies with 4 mg and placebo to week 24, including four trials with 2 mg (placebo-controlled set). Dose-response assessment was based on four studies with 2 mg and 4 mg, including LTE data (2-4 mg extended set). RESULTS: There were 3492 patients who received baricitinib for 7860 patient-years (PY) of exposure (median 2.6 years, maximum 6.1 years). Treatment-emergent infections were higher for baricitinib versus placebo (exposure-adjusted incidence rate (IR)/100 PY: placebo 75.9, 2 mg 84.0 (p not significant), 4 mg 88.4 (p≤0.001)). The IR of serious infection was similar for baricitinib versus placebo and stable over time (all-bari-RA IR 3.0/100 PY). There were 11 cases of tuberculosis (all-bari-RA IR 0.1/100 PY); all occurred with 4 mg in endemic regions. Herpes zoster (HZ) IR/100 PY was higher for baricitinib versus placebo (placebo 1.0, 2 mg 3.1 (p not significant), 4 mg 4.3 (p≤0.01)); rates remained elevated and stable over time (all-bari-RA 3.3). Opportunistic infections, including multidermatomal HZ, were infrequent in the baricitinib programme (all-bari-RA IR 0.5/100 PY). CONCLUSIONS: Increased rates of treatment-emergent infections including HZ were observed in patients with RA treated with baricitinib, consistent with baricitinib's immunomodulatory mode of action.

Ixekizumab treatment of biologic-naïve patients with active psoriatic arthritis: 3-year results from a phase III clinical trial (SPIRIT-P1).

OBJECTIVE: The aim was to assess the safety and efficacy of up to 156 weeks of ixekizumab (an IL-17A antagonist) treatment in PsA patients. METHODS: In a phase III study, patients naïve to biologic treatment were randomized to placebo, adalimumab 40 mg every 2 weeks (ADA; active reference) or ixekizumab 80 mg every 2 weeks (IXEQ2W) or every 4 weeks (IXEQ4W) after an initial dose of 160 mg. At week 24 (week 16 for inadequate responders), ADA (after 8-week washout) and placebo patients were re-randomized to IXEQ2W or IXEQ4W. Outcomes were evaluated using a modified non-responder imputation [linear extrapolation for radiographic progression (modified total Sharp score = 0)] during extended treatment until week 156. RESULTS: Of 417 patients, 381 entered the extension, and 243 of 381 (63.8%) completed the 156-week study. Incidence rates of treatment-emergent and serious adverse events, respectively, were 38.0 and 5.2 with IXEQ2W (n = 189) and 38.1 and 8.0 with IXEQ4W (n = 197). One death occurred (IXEQ4W). With IXEQ2W and IXEQ4W, respectively, the response rates persisted to week 156 as measured by the ACR response ≥20% (62.5 and 69.8%), ≥50% (56.1 and 51.8%) and ≥70% (43.8 and 33.4%), psoriasis area and severity index (PASI) 75 (69.1 and 63.5%), PASI 90 (64.5 and 51.2%) and PASI 100 (60.5 and 43.6%). Inhibition of radiographic progression also persisted to week 156 in 61% of IXEQ2W and 71% of IXEQ4W patients. CONCLUSION: In this 156-week study of ixekizumab, the safety profile remained consistent with previous reports, and improvements in signs and symptoms of PsA were observed, including persistent low rates of radiographic progression. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT01695239, EudraCT 2011-002326-49.

Long-term safety of sarilumab in rheumatoid arthritis: an integrated analysis with up to 7 years' follow-up.

OBJECTIVE: Sarilumab is a human monoclonal antibody that blocks IL-6 from binding to membrane-bound and soluble IL-6 receptor-α. We assessed the long-term safety of sarilumab in patients from eight clinical trials and their open-label extensions. METHODS: Data were pooled from patients with rheumatoid arthritis who received at least one dose of sarilumab in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs; combination group) or as monotherapy (monotherapy group). Treatment-emergent adverse events (AEs) and AEs and laboratory values of special interest were assessed. RESULTS: 2887 patients received sarilumab in combination with csDMARDs and 471 patients received sarilumab monotherapy, with mean exposure of 2.8 years and 1.7 years, maximum exposure 7.3 and 3.5 years, and cumulative AE observation period of 8188 and 812 patient-years, respectively. Incidence rates per 100 patient-years in the combination and monotherapy groups, respectively, were 9.4 and 6.7 for serious AEs, 3.7 and 1.0 for serious infections, 0.6 and 0.5 for herpes zoster (no cases were disseminated), 0.1 and 0 for gastrointestinal perforations, 0.5 and 0.2 for major adverse cardiovascular events, and 0.7 and 0.6 for malignancy. Absolute neutrophil counts <1000 cells/mm3 were recorded in 13% and 15% of patients, respectively. Neutropenia was not associated with increased risk of infection or serious infection. Analysis by 6-month interval showed no signal for increased rate of any AE over time. CONCLUSION: The long-term safety profile of sarilumab, either in combination with csDMARDs or as monotherapy, remained stable and consistent with the anticipated profile of a molecule that inhibits IL6 signalling.

Tofacitinib in combination with methotrexate in patients with rheumatoid arthritis: patient-reported outcomes from the 24-month Phase 3 ORAL Scan study.

OBJECTIVES: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Here we present data from the completed Phase 3 randomised controlled trial (RCT) ORAL Scan (NCT00847613), which evaluated the impact of tofacitinib on patient-reported outcomes (PROs) through 24 months in patients with active RA and inadequate responses to methotrexate (MTX-IR). METHODS: Patients were randomised 4:4:1:1 to receive tofacitinib 5 or 10 mg twice daily (BID), or placebo advanced to tofacitinib 5 or 10 mg, plus background MTX. Patients receiving placebo advanced to tofacitinib at month 3 (non-responders) or month 6 (remaining patients). Mean changes from baseline in PROs, assessed at months 1-24, included Health Assessment Questionnaire-Disability Index, Patient Global Assessment of disease activity (visual analogue scale [VAS]), Patient Assessment of Arthritis Pain (VAS), health-related quality of life (Short Form-36 version 2), Functional Assessment of Chronic Illness Therapy-Fatigue and Medical Outcomes Study-Sleep. RESULTS: Overall, 539/797 (67.6%) patients completed 24 months' treatment. At month 3, tofacitinib-treated patients reported signi cant (p<0.05) mean changes from baseline versus placebo across all PROs, and significantly more patients reported improvements ≥ minimum clinically important differences versus placebo. Improvements in PROs with tofacitinib were sustained to month 24. Following advancement to tofacitinib, placebo-treated patients generally reported changes of similar magnitude to tofacitinib-treated patients. CONCLUSIONS: Patients with RA and MTX-IR receiving tofacitinib 5 or 10 mg BID plus MTX reported significant and clinically meaningful improvements in PROs versus placebo at month 3, which were sustained through 24 months.

Safety and efficacy of upadacitinib in patients with active rheumatoid arthritis refractory to biologic disease-modifying anti-rheumatic drugs (SELECT-BEYOND): a double-blind, randomised controlled phase 3 trial.

BACKGROUND: Phase 2 studies with upadacitinib, a selective Janus kinase 1 (JAK1) inhibitor, have shown safety and efficacy in the treatment of patients with active rheumatoid arthritis. We did this study to further assess the safety and efficacy of upadacitinib in patients with an inadequate response to biologic disease-modifying anti-rheumatic drugs (bDMARDs). METHODS: We did this double-blind, randomised controlled phase 3 trial at 153 sites in 26 countries. Patients were aged 18 years or older, had active rheumatoid arthritis and previous inadequate response or intolerance to bDMARDs, and were receiving concomitant background conventional synthetic DMARDS (csDMARDs). We randomly assigned patients (2:2:1:1) by interactive response technology to receive once-daily oral extended-release upadacitinib 15 mg or 30 mg or placebo for 12 weeks, followed by upadacitinib 15 mg or 30 mg from week 12 onwards. The two separate primary endpoints were the proportions of patients achieving a 20% improvement in American College of Rheumatology criteria (ACR20) at week 12 and the proportion of patients achieving a 28-joint disease activity score using C-reactive protein (DAS28[CRP]) of 3·2 or less at week 12. Efficacy and safety analyses were done in the modified intention-to-treat population of all patients who received at least one dose of study drug. Data are presented up to week 24 of this ongoing study. The trial is registered with ClinicalTrials.gov (NCT02706847). FINDINGS: Between March 15, 2016, and Jan 10, 2017, 499 patients were randomly assigned (n=165 upadacitinib 15 mg; n=165 upadacitinib 30 mg; n=85 placebo then upadacitinib 15 mg; and n=84 placebo then upadacitinib 30 mg) and one patient was withdrawn from the 15 mg upadacitinib group before the start of study treatment. Mean disease duration was 13·2 years (SD 9·5); 235 (47%) of 498 patients had received one previous bDMARD, 137 (28%) had received two, and 125 (25%) had received at least three; 451 (91%) patients completed treatment up to week 12 and 419 (84%) patients completed treatment up to week 24. At week 12, ACR20 was achieved by 106 (65%; 95% CI 57-72) of 164 patients receiving upadacitinib 15 mg and 93 (56%; 49-64) of 165 patients receiving upadacitinib 30 mg compared with 48 (28%; 22-35) of 169 patients receiving placebo (p<0·0001 for each dose vs placebo). DAS28(CRP) of 3·2 or less was achieved by 71 (43%; 95% CI 36-51) of 164 patients receiving upadacitinib 15 mg and 70 (42%; 35-50) of 165 patients receiving upadacitinib 30 mg versus 24 (14%; 9-20) of 169 patients receiving placebo (p<0·0001 for each dose vs placebo). Up to week 12, overall numbers of patients with adverse events were similar for the placebo group (95 [56%] of 169) and the upadacitinib 15 mg group (91 [55%] of 164), but higher in the upadacitinib 30 mg group (111 [67%] of 165). At week 12, the most common adverse events occurring in at least 5% of patients in any treatment group were upper respiratory tract infection (13 [8%] of 169 in the placebo group; 13 [8%] of 164 in the upadacitinib 15 mg group; ten [6%] of 165 in the upadacitinib 30 mg group), nasopharyngitis (11 [7%]; seven [4%]; nine [5%]), urinary tract infection (ten [6%]; 15 [9%]; nine [5%]), and worsening of rheumatoid arthritis (ten [6%]; four [2%]; six [4%]). The number of patients with serious adverse events was higher in the upadacitinib 30 mg group (12 [7%]) than in the upadacitinib 15 mg group (eight [5%]); no serious adverse events were reported in patients receiving placebo. More patients in the upadacitinib 30 mg group had serious infections, herpes zoster, and adverse events leading to discontinuation than in the upadacitinib 15 mg and placebo groups. During the placebo-controlled phase of the study, one case of pulmonary embolism, three malignancies, one major adverse cardiovascular event, and one death were reported in patients receiving upadacitinib; none were reported in patients receiving placebo. INTERPRETATION: Both doses of upadacitinib led to rapid and significant improvements compared with placebo over 12 weeks in patients with refractory rheumatoid arthritis. FUNDING: AbbVie Inc.