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ObjectivesTo elucidate the mechanism of action of baricitinib, a Janus kinase (JAK) 1/2 inhibitor, and describe immunological pathways related to disease activity in adults with systemic lupus erythematosus (SLE) receiving standard background therapy in a phase II trial.MethodsPatients with SLE were treated with baricitinib 2 mg or 4 mg in a phase II randomised, placebo-controlled study. Sera from 239 patients (baricitinib 2 mg: n=88; baricitinib 4 mg: n=82; placebo: n=69) and 49 healthy controls (HCs) were collected at baseline and week 12 and analysed using a proximity extension assay (Target 96 Inflammation Panel (Olink)). Interferon (IFN) scores were determined using an mRNA panel. Analytes were compared in patients with SLE versus HCs and in changes from baseline at week 12 between baricitinib 2 mg, 4 mg and placebo groups using a restricted maximum likelihood-based mixed models for repeated measures. Spearman correlations were computed for analytes and clinical measurements.ResultsAt baseline, SLE sera had strong cytokine dysregulation relative to HC sera. C-C motif chemokine ligand (CCL) 19, C-X-C motif chemokine ligand (CXCL) 10, tumour necrosis factor alpha (TNF-α), TNF receptor superfamily member (TNFRSF)9/CD137, PD-L1, IL-6 and IL-12β were significantly reduced in patients treated with baricitinib 4 mg versus placebo at week 12. Inflammatory biomarkers indicated correlations/associations with type I IFN (CCL19, CXCL10, TNF-α and PD-L1), anti-double stranded DNA (dsDNA) (TNF-α, CXCL10) and Systemic Lupus Erythematosus Disease Activity Index-2000, tender and swollen joint count and worst joint pain (CCL19, IL-6 and TNFRSF9/CD137).ConclusionThese results suggest that baricitinib 4 mg downregulated key cytokines that are upregulated in patients with SLE and may play a role in a multitargeted mechanism beyond the IFN signature although clinical relevance remains to be further delineated.Trial registration numberNCT02708095.

The severity of coronavirus disease 2019 (COVID-19) ranges from mild to death, with high morbidity and mortality rates reported amongst a vulnerable subset of patients termed high risk. While vaccines remain the primary option for COVID-19 prevention, neutralizing monoclonal antibodies (mAbs), such as bamlanivimab and etesevimab, have been shown to benefit certain subpopulations after exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Unlike vaccine-derived immunity that develops over time, administration of neutralizing mAbs is an immediate and passive immunotherapy, with the potential to reduce disease progression, emergency room visits, hospitalizations, and death. Bamlanivimab alone and together with etesevimab hold emergency use authorizations in several countries globally, with countries increasingly transitioning to the use of bamlanivimab and etesevimab together and other authorized mAbs on the basis of their evolving variant landscape, regulatory authorizations, and access to drugs. The current guidelines for the administration of bamlanivimab alone or together with etesevimab are informed by an iterative process of testing and development. Herein the rationale for these guidelines is provided by sharing the learnings that have been gathered throughout the development process of these mAbs. In addition, this review addresses the most common clinical questions received from health care professionals (HCPs) and patients regarding indicated population, dose, use with other medications and vaccines, duration of protection, and variants in clinical practice. As prevalence of SARS-CoV-2 variants can differ by country and state, prescribing HCPs should consider the prevalence of bamlanivimab and etesevimab resistant variants in their area, where data are available, regarding potential efficacy impact when considering treatment options. Trial Registration: ClinicalTrials.gov identifier: NCT04427501; NCT04411628; NCT04497987; NCT04634409.

Introduction In the SPIRIT-H2H (ClinicalTrials.gov: NCT03151551) trial in biologic-naïve patients with active psoriatic arthritis (PsA), ixekizumab (IXE) was superior to adalimumab (ADA) at week 24 in terms of achieving a combined endpoint of ≥ 50% improved response in the American College of Rheumatology scale score (ACR50) and 100% improvement in the Psoriasis Areas and Severity Index (PASI100), and was non-inferior in terms of achieving ACR50. IXE resulted in similar improvements of PsA manifestations irrespective of the use of concomitant conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), while ADA response was higher with concomitant csDMARD use. The aim of this study was to determine the efficacy and safety of treatment with IXE and ADA with or without methotrexate (MTX), the most commonly use csDMARD, through week 52 in patients with PsA. Methods In the open-label, rater-blinded, head-to-head SPIRIT-H2H trial, randomization of patients was stratified by concomitant use of csDMARD and moderate-to-severe plaque psoriasis involvement. In the post-hoc subgroup analysis presented here, subgroups were defined as with/without concomitant MTX use at baseline. Treatment group effects within subgroups were tested using Fisher’s exact test. Missing data were imputed using non-responder imputation. Results By week 52, IXE provided similar improvements in the combined ACR50 and PASI100 endpoint, ACR50, and other PsA-related domains regardless of whether IXE was used with or without MTX, while ADA efficacy appeared to be improved with concomitant MTX use. When used without concomitant MTX, IXE resulted in significantly higher response versus ADA in terms of the combined ACR50 and PASI100 (p = 0.002) endpoint, minimal disease activity (p = 0.016), and very low disease activity (p = 0.037). The safety of both agents was consistent with their known safety profiles regardless of concomitant MTX use. Conclusion In PsA patients with inadequate control of the disease, IXE delivers consistent efficacy in several clinical domains of the disease regardless of concomitant MTX use. The efficacy of ADA is increased by the concomitant use of MTX. These findings can inform treatment decisions when considering the need for concomitant MTX use with IXE or ADA at initiation or for long-term maintenance. Electronic supplementary material The online version of this article (10.1007/s40744-020-00250-3) contains supplementary material, which is available to authorized users.

ObjectivesSPIRIT head-to-head (H2H) is a 52-week (Wk) trial comparing ixekizumab (IXE) with adalimumab (ADA) for simultaneous American College of Rheumatology (ACR)50 and Psoriasis Area and Severity Index (PASI)100 responses in 566 patients (distributed evenly across both groups) with psoriatic arthritis (PsA). IXE was superior to ADA for this primary end point at Wk24. We aimed to determine the final efficacy and safety results through Wk52 including a prespecified subgroup analysis of concomitant conventional synthetic disease-modifying anti-rheumatic drugs (csDMARD) use.MethodsSPIRIT-H2H is a Wk52 multicentre, open-label, blinded-assessor study comparing IXE and ADA in bionaïve patients with PsA. Patients were randomised 1:1 to IXE or ADA with stratification by concomitant csDMARD use and presence of moderate-to-severe plaque psoriasis. Prespecified end points at Wk24 and Wk52 included musculoskeletal, psoriasis, quality-of life outcomes, subgroup analyses and safety.ResultsA significantly higher proportion of patients treated with IXE versus ADA simultaneously achieved ACR50 and PASI100 (39% vs 26%, pConclusionsIXE provided significantly greater simultaneous joint and skin improvement than ADA through Wk52 in bionaïve patients with PsA. IXE showed better efficacy on psoriasis and performed at least as well as ADA on musculoskeletal manifestations. IXE efficacy was consistent irrespective of concomitant csDMARD use.Trial registration numberNCT03151551.

Background/Objectives: This article compares the effectiveness of baricitinib (BARI) 4 mg (oral, Janus kinase [JAK] 1/2 inhibitor) versus other targeted synthetic/biologic disease-modifying antirheumatic drugs, in combination with methotrexate (MTX), in moderate-to-severe rheumatoid arthritis patients with inadequate response (IR) to MTX. Methods: A systematic literature review was conducted to identify randomized controlled trials (RCTs) of the interventions of interest. Bayesian network meta-analyses (NMA) were used to compare American College of Rheumatology (ACR) responses at 24 weeks. A series of prespecified sensitivity analyses addressed the potential impact of, among others, baseline risk, treatment effect modifiers, and trial design on treatment response. Results: Nineteen RCTs were included in the NMA (primary analysis). For ACR20, BARI 4 mg + MTX was found to be more effective than adalimumab (ADA) 40 mg + MTX (Odds Ratio [OR] 1.33), abatacept (ABA) 10 mg + MTX (IV/4 weeks) (OR 1.45), infliximab (IFX) 3 mg + MTX (IV/8 wks) (OR 1.63), and rituximab (RTX) 1000 mg + MTX (OR 1.63). No differences were found on ACR50. For ACR70, BARI 4 mg + MTX was more effective than ADA 40 mg + MTX (OR 1.37), ABA 10 mg + MTX (OR 1.86), and RTX 1000 mg + MTX (OR 2.26). Sensitivity analysis including 10 additional RCTs with up to 20% of patients with prior biologic use showed BARI 4 mg + MTX to be more effective than tocilizumab (TCZ) 8 mg + MTX on ACR20 (OR 1.44). Results for all sensitivity analyses were consistent with the direction and magnitude of the primary results. Key limitations include the time span in which trials were conducted (1999–2017), during which patient characteristics and treatment approaches might have changed. Conclusion: This NMA suggests that BARI 4 mg + MTX is an efficacious treatment option in the MTX-IR population as evidenced by the robustness of results.

Background In the phase 2/3 BLAZE-1 trial, bamlanivimab and etesevimab together reduced coronavirus disease 2019 (COVID-19)–related hospitalizations and any-cause mortality in ambulatory patients. Herein, we assess the impact of bamlanivimab and etesevimab treatment on the severity and length of symptoms and health outcomes among patients at increased risk for severe COVID-19. Methods In the phase 3 portion of BLAZE-1 (NCT04427501), symptomatic patients with increased risk for severe COVID-19 were randomized (2:1) to a single infusion of 700 mg bamlanivimab and 1400 mg etesevimab or placebo. Hospitalization events, vital signs, and symptomatology were monitored throughout the trial. Results Overall, 769 patients were randomized to bamlanivimab and etesevimab together (n = 511) or placebo (n = 258). The time to sustained symptom resolution was significantly shorter among patients who received bamlanivimab and etesevimab compared with placebo (8 vs 10 days; P Conclusions Patients receiving bamlanivimab and etesevimab together resolved their symptoms more rapidly than those receiving placebo. Bamlanivimab and etesevimab treatment was associated with reduced rates of hospitalizations and shorter hospital stays. Clinical Trials Registration NCT04427501.

Introduction Improvements in both musculoskeletal and non-musculoskeletal manifestations are important treatment goals in psoriatic arthritis (PsA). Objective These post hoc analyses determined whether additional benefits related to various PsA domains are observed in patients simultaneously achieving 50% improvement in American College of Rheumatology criteria (ACR50) and 100% improvement in Psoriasis Area Severity Index (PASI100), the primary endpoint of the SPIRIT-H2H study. Methods Patients with active PsA and psoriasis in SPIRIT-H2H (N = 566) were categorised into two sets of four response groups irrespective of treatment allocation (approved dosages of ixekizumab or adalimumab): patients who simultaneously achieved ACR50 and PASI100 response, achieved ACR50 response only, achieved PASI100 response only, or did not achieve ACR50 or PASI100 response after 24 and 52 weeks of treatment. Patients achieving simultaneous ACR50 and PASI100 response were compared with the other patient response groups at the corresponding time point for efficacy and health-related quality of life (HRQoL) outcomes. Results Patients simultaneously achieving ACR50 and PASI100 responses at week 24 or 52 showed higher rates of ACR70 response, minimal disease activity, Disease Activity in Psoriatic Arthritis ≤ 4, resolution of enthesitis and dactylitis, and HRQoL improvement at weeks 24 and 52, respectively, than the other corresponding response groups at both time points. Conclusion High levels of disease control, such as those obtained with simultaneous achievement of ACR50 and PASI100 response, were linked to better outcomes across a wide range of endpoints that are important for patients with PsA. Patients meeting this combined endpoint showed more comprehensive and thus greater control of disease activity. Trial registration NCT03151551 Key Points• Treatment goals for patients with psoriatic arthritis emphasise the importance of improving both musculoskeletal and non-musculoskeletal manifestations of the disease.• A combined endpoint considering both these manifestations, achievement of at least 50% improvement in American College of Rheumatology criteria and 100% improvement in Psoriasis Area Severity Index, was linked with achievement of a number of other endpoints relevant to psoriatic arthritis, including health-related quality of life that are important to patients with psoriatic arthritis.• Patients meeting the combined endpoint were more likely to achieve a disease state of remission, which is the stated aim of treatment for psoriasis.

ObjectivesTo evaluate if baricitinib, a Janus kinase inhibitor, further enhances disease-modifying effects by uncoupling the link between disease activity and structural damage progression in patients with rheumatoid arthritis (RA) using two phase III randomised, double-blinded trials.MethodsIn RA-BEAM, patients with established RA and inadequate response to methotrexate (MTX-IR) received placebo (PBO), baricitinib 4 mg or adalimumab 40 mg on background MTX. In RA-BEGIN, conventional synthetic disease-modifying antirheumatic drug (csDMARD)-naïve patients received MTX, baricitinib 4 mg or baricitinib 4 mg plus MTX. Using linear regression analyses, joint damage progression (assessed by change from baseline in van der Heijde modification of the Total Sharp Score) was compared between treatment groups for patients achieving certain disease activity states by the Clinical Disease Activity Index. Time-averaged postbaseline responses were used to week 24 (RA-BEAM) and week 52 (RA-BEGIN).ResultsFor MTX-IR patients, structural damage progression was reduced regardless of disease activity states in baricitinib-treated patients (p=0.6), whereas in PBO patients there was a clear dependence on disease activity states, being significantly lower in those who achieved remission/low disease activity (REM/LDA) compared with moderate/high disease activity (MDA/HDA) (p=0.02). Furthermore, the baricitinib MDA/HDA group had less damage progression than the PBO MDA/HDA group (p5 mg/L) sensitivity analyses supported the primary findings.ConclusionsBaricitinib reduces structural damage progression versus PBO with background MTX and/or MTX, even in patients with MDA/HDA, showing a disease-modifying effect across all disease activity states.

OBJECTIVE: To retrospectively compare the long-term clinical, functional, and cost outcomes for early RA patients (symptoms

Improvements in both musculoskeletal and non-musculoskeletal manifestations are important treatment goals in psoriatic arthritis (PsA).These post hoc analyses determined whether additional benefits related to various PsA domains are observed in patients simultaneously achieving 50% improvement in American College of Rheumatology criteria (ACR50) and 100% improvement in Psoriasis Area Severity Index (PASI100), the primary endpoint of the SPIRIT-H2H study.Patients with active PsA and psoriasis in SPIRIT-H2H (N = 566) were categorised into two sets of four response groups irrespective of treatment allocation (approved dosages of ixekizumab or adalimumab): patients who simultaneously achieved ACR50 and PASI100 response, achieved ACR50 response only, achieved PASI100 response only, or did not achieve ACR50 or PASI100 response after 24 and 52 weeks of treatment. Patients achieving simultaneous ACR50 and PASI100 response were compared with the other patient response groups at the corresponding time point for efficacy and health-related quality of life (HRQoL) outcomes.Patients simultaneously achieving ACR50 and PASI100 responses at week 24 or 52 showed higher rates of ACR70 response, minimal disease activity, Disease Activity in Psoriatic Arthritis ≤ 4, resolution of enthesitis and dactylitis, and HRQoL improvement at weeks 24 and 52, respectively, than the other corresponding response groups at both time points.High levels of disease control, such as those obtained with simultaneous achievement of ACR50 and PASI100 response, were linked to better outcomes across a wide range of endpoints that are important for patients with PsA. Patients meeting this combined endpoint showed more comprehensive and thus greater control of disease activity. Trial registration NCT03151551 Key Points • Treatment goals for patients with psoriatic arthritis emphasise the importance of improving both musculoskeletal and non-musculoskeletal manifestations of the disease. • A combined endpoint considering both these manifestations, achievement of at least 50% improvement in American College of Rheumatology criteria and 100% improvement in Psoriasis Area Severity Index, was linked with achievement of a number of other endpoints relevant to psoriatic arthritis, including health-related quality of life that are important to patients with psoriatic arthritis. • Patients meeting the combined endpoint were more likely to achieve a disease state of remission, which is the stated aim of treatment for psoriasis.

Several neutralizing monoclonal antibodies (mAbs) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed and are now under evaluation in clinical trials. With the US Food and Drug Administration recently granting emergency use authorizations for neutralizing mAbs in non-hospitalized patients with mild-to-moderate COVID-19, there is an urgent need to discuss the broader potential of these novel therapies and to develop strategies to deploy them effectively in clinical practice, given limited initial availability. Here, we review the precedent for passive immunization and lessons learned from using antibody therapies for viral infections such as respiratory syncytial virus, Ebola virus and SARS-CoV infections. We then focus on the deployment of convalescent plasma and neutralizing mAbs for treatment of SARS-CoV-2. We review specific clinical questions, including the rationale for stratification of patients, potential biomarkers, known risk factors and temporal considerations for optimal clinical use. To answer these questions, there is a need to understand factors such as the kinetics of viral load and its correlation with clinical outcomes, endogenous antibody responses, pharmacokinetic properties of neutralizing mAbs and the potential benefit of combining antibodies to defend against emerging viral variants., Peter Taylor and colleagues provide an overview of the neutralizing monoclonal antibody therapies that have been developed to target severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and discuss the clinical utility of these antibodies.

Objectives Interstitial lung disease (ILD) occurs in up to 30% of patients with rheumatoid arthritis (RA), resulting in increased morbidity and death in the absence of proven therapies. The aim of this study is to estimate the number of incident ILD cases reported through development studies with baricitinib in patients with RA. Methods Estimates were based on 3770 patients with RA from eight randomized clinical trials (four phase 3, three phase 2, one phase 1b) and one long-term extension study on baricitinib for which ILD was not an exclusion criterion with 12,358 patient-years of exposure (PYE). Results Twenty-one non-infectious cases of ILD were reported with an exposure-adjusted incidence rate (EAIR) of 0.17 per 100 PYE. Of the 21 cases, six were reported as serious and 15 as non-serious resulting in an incidence rate of 0.05 per 100 PYE and 0.12 per 100 PYE, respectively. There were also 11 cases caused by an infectious agent: seven serious (IR: 0.06 per 100 PYE) and four non-serious cases (IR: 0.03 per 100 PYE). Conclusions The findings of this analysis in patients with RA treated with baricitinib are consistent with a low risk to develop non-infectious ILD during baricitinib treatment, similar to that observed with other Janus kinase inhibitors.

ObjectiveTo characterise changes in selected haematological parameters following once-daily oral baricitinib dosing.MethodsData were pooled from eight randomised clinical trials (four phase 3, three phase 2, one phase 1b) and one long-term extension. Changes in haematological parameters were evaluated up to 128 weeks (N=2387); overall safety of baricitinib was assessed up to 6 years (N=3492).ResultsMean absolute neutrophil counts decreased (−1.36×109/L) within 1 month, followed by stabilisation within the normal reference range through week 128. The incidence of serious infections was not elevated in patients with neutropenia during the 24-week placebo-controlled period. Mean lymphocyte counts increased (+0.30×109/L) within 1 month, then decreased to baseline (weeks 12–24). Mean platelet counts increased at week 2 (+51×109/L), then decreased towards baseline. Overall, mean haemoglobin concentrations decreased (−0.12 mmol/L), then returned to baseline; however, reduced baseline haemoglobin concentrations observed in the highest baseline high-sensitivity C reactive protein quartile increased over time. Permanent drug discontinuation occurred due to laboratory abnormalities related to neutrophil count in 8 (0.2%), lymphocyte counts in 6 (0.2%), platelet counts in 8 (0.2%), and haemoglobin levels in 16 (0.5%) of all baricitinib-treated patients (N=3492 with 7993 total person-years of exposure).ConclusionsModerate decreases in neutrophils were seen during baricitinib treatment; however, serious infection was uncommon in patients with neutropenia. Transient increases were observed in lymphocytes and platelets, which returned to baseline over time. Changes in haemoglobin concentration were generally small. Haematological abnormalities seldom led to drug discontinuation.

Background In RA, disease activity correlates with physical function and there is a link between joint damage and functional disability. In many countries, RA patients with inadequate response (IR) to MTX or other conventional DMARDs (cDMARDs) are not eligible for potentially more effective treatments, such as biologic or targeted synthetic DMARDs (tsDMARDs), unless they have high disease activity (HDA). Thus, managing RA patients with persistent moderate disease activity (MDA) despite cDMARD treatment poses a problem. Baricitinib (BARI) is a tsDMARD approved for the treatment of moderate to severe RA in adults. This post-hoc analysis assessed if RA patients with MDA benefit from improved physical function with BARI treatment to the same extent as patients with HDA. Methods Patients analysed were from the modified intention-to-treat populations in the BARI phase 3 studies RA-BEAM (MTX-IR) and RA-BUILD (cDMARD-IR) with moderate to severe disability (HAQ-Disability Index [HAQ-DI] score ≥1), MDA (Simplified Disease Activity Index [SDAI] score 11.1-26.0) or HDA (SDAI score>26.0) and non-missing SDAI data at baseline. All patients fulfilled ACR criteria for RA. Patients from RA-BEAM received BARI 4 mg + MTX once daily (n = 396), adalimumab 40 mg every 2 weeks + MTX (n = 270) or placebo (PBO) + MTX (n = 390); patients from RA-BUILD received BARI 4 mg (n = 189) or 2 mg (n = 186) or PBO (n = 185). Multivariable linear regression (MLR) models were used to estimate mean HAQ-DI scores at baseline and week 24 (W24) for the treatment arms stratified by baseline disease activity (MDA or HDA SDAI). Age, RA duration, BMI, high-sensitivity CRP, baseline SDAI disease activity (MDA/HDA), treatment and treatment-by-baseline SDAI interaction were included as covariates. The MLR model for HAQ-DI at (W24) was further adjusted by baseline HAQ-DI. Results In patients from RA-BEAM with MDA at baseline, the mean adjusted HAQ-DI score at W24 was greater in PBO (1.314) than in BARI 4 mg (0.843) patients (Δ = 0.472; p = 0.001). A similar pattern of improved physical function with BARI was seen in RA-BUILD, but the adjusted mean difference in HAQ-DI score between PBO (1.376) and BARI 4 mg (1.113) was not statistically significant (Δ = 0.263; p = 0.109). In patients with HDA at baseline, the W24 mean adjusted HAQ-DI score was 0.443 points greater (p < 0.001) with PBO (1.387) than with BARI 4 mg (0.944) in RA-BEAM, and 0.257 points greater (p < 0.001) in RA-BUILD. Conclusion MTX-IR and/or cDMARD-IR RA patients with MDA and moderate to severe disability at baseline treated with BARI showed a similar pattern of improvement in physical function vs. PBO-treated patients to that seen in patients with HDA, supporting early use of BARI in MDA patients. As for those with HDA, patients with persistent MDA despite MTX and/or other cDMARD treatment could benefit from access to biologic and tsDMARDs to prevent disability progression. Disclosures B. Kirkham: Consultancies; AbbVie, Eli Lilly, Gilead, Janssen, Novartis, Pfizer. Grants/research support; Eli Lilly, Novartis. E. Nikiphorou: Honoraria; Pfizer, Sanofi, Gilead, Celltrion, Eli Lilly. P. López-Romero: Shareholder/stock ownership; Eli Lilly. Other; Full time employee of Eli Lilly. I. Kouris: Shareholder/stock ownership; Eli Lilly. Other; Full time employee of Eli Lilly. T. Holzkaemper: Shareholder/stock ownership; Eli Lilly. Other; Full time employee of Eli Lilly. L. Zaremba-Pechmann: Other; contractor for Eli Lilly and Company. I. de la Torre: Shareholder/stock ownership; Eli Lilly. Other; Full time employee of Eli Lilly. P.C. Taylor: Consultancies; AbbVie, Biogen, Galapagos, Gilead, GlaxoSmithKline, Janssen, Eli Lilly, Pfizer, Roche, Sanofi, Nordic Pharma, Fresenius, UCB. Grants/research support; Celgene, Galapagos, Janssen, Eli Lilly.

ObjectivesThis study investigated the effects of dose step-down in patients with rheumatoid arthritis (RA) who achieved sustained disease control with baricitinib 4 mg once a day.MethodsPatients who completed a baricitinib phase 3 study could enter a long-term extension (LTE). In the LTE, patients who received baricitinib 4 mg for ≥15 months and maintained CDAI low disease activity (LDA) or remission (REM) were blindly randomised to continue 4 mg or taper to 2 mg. Patients could rescue (to 4 mg) if needed. Efficacy and safety were assessed through 48 weeks.ResultsPatients in both groups maintained LDA (80% 4 mg; 67% 2 mg) or REM (40% 4 mg; 33% 2 mg) over 48 weeks. However, dose reduction resulted in small, statistically significant increases in disease activity at 12, 24 and 48 weeks. Dose reduction also produced earlier and more frequent relapse (loss of step-down criteria) over 48 weeks compared with 4 mg maintenance (23% 4 mg vs 37% 2 mg, p=0.001). Rescue rates were 10% for baricitinib 4 mg and 18% for baricitinib 2 mg. Dose reduction was associated with a numerically lower rate of non-serious infections (30.6 for baricitinib 4 mg vs 24.9 for 2 mg). Rates of serious adverse events and adverse events leading to discontinuation were similar across groups.ConclusionsIn a large randomised, blinded phase 3 study, maintenance of RA control following induction of sustained LDA/REM with baricitinib 4 mg was greater with continued 4 mg than after taper to 2 mg. Nonetheless, most patients tapered to 2 mg could maintain LDA/REM or recapture with return to 4 mg if needed.

Current guidelines for the management of rheumatoid arthritis (RA) recommend early treatment and a treat-to-target goal of remission or low disease activity. Over the past decade, this approach has been extremely successful in reducing disease activity and joint damage in patients with RA. At the same time, however, overall patient perception of well-being appears to have decreased with respect to outcome measures considered important by patients themselves, such as pain, fatigue, physical function and quality of life. The timely and effective use of patient-reported outcomes (PROs) should encourage healthcare professionals (HCPs) to focus more on the impact of RA on patients and how patients are feeling. This would facilitate shared decision making between patients and HCPs, ultimately leading to a more patient-centered approach, improved patient care and optimal health outcomes. Importantly, PROs provide information about individual patients that complements information provided by physical assessment and composite scores, and can also be used to guide patient care, such as determining whether a clinic visit is needed or whether management modifications are necessary. This is particularly important for patients who do not achieve the target of remission or low disease activity with pharmacological treatment. A number of validated PRO questionnaires are available, but how and which PROs should be incorporated into rheumatology clinical practice as part of the decision-making process is still controversial. Combining PROs with digital technology, such as computer adaptive tests, electronic PRO systems, web-based platforms and patient dashboards, could further aid PRO integration into daily rheumatology clinical practice.

This expert opinion article explores the strategy of adopting a holistic approach to the management of rheumatoid arthritis (RA) by incorporating the wellness practices of exercise, optimised sleep, optimised nutrition, mindfulness, social connectedness and positive emotions into the management plan. The aim is to attain optimal health for each patient beyond that achievable by limiting disease management to pharmacological treatment to attain the lowest achievable composite scores of disease activity, as recommended with the current treat-to-target approach, and addressing the recent recognition of pain control as a key patient-reported outcome. Incorporating wellness practices into a busy clinical setting requires creativity and customisation based on the individual practice setting and the individual needs of each patient. Such practices can help people living with RA to achieve optimum wellness through the introduction of measures—according to individual need—designed to improve the aspects of life most impacted for that person, thereby complementing treat-to-target and pain control strategies with pharmacological agents. Clinicians must consider wellness practices in addition to treat-to-target pharmacological agents for the holistic management of people with RA.

Introduction and objectives Nonischemic sudden cardiac death (SCD) is predominantly caused by cardiomyopathies and channelopathies. There are many diagnostic tests, including some complex techniques. Our aim was to analyze the diagnostic yield of a systematic diagnostic protocol in a specialized unit. Methods The study included 56 families with at least 1 index case of SCD (resuscitated or not). Survivors were studied with electrocardiogram, advanced cardiac imaging, exercise testing, familial study, genetic testing and, in some cases, pharmacological testing. Families with deceased probands were studied using the postmortem findings, familial evaluation, and molecular autopsy with next-generation sequencing (NGS). Results A positive diagnosis was obtained in 80.4% of the cases, with no differences between survivors and nonsurvivors ( P = .53). Cardiac channelopathies were more prevalent among survivors than nonsurvivors (66.6% vs 40%, P = .03). Among the 30 deceased probands, the definitive diagnosis was given by autopsy in 7. A diagnosis of cardiomyopathy tended to be associated with a higher event rate in the family. Genetic testing with NGS was performed in 42 index cases, with a positive result in 28 (66.6%), with no differences between survivors and nonsurvivors ( P = .21). Conclusions There is a strong likelihood of reaching a diagnosis in SCD after a rigorous protocol, with a more prevalent diagnosis of channelopathy among survivors and a worse familial prognosis in cardiomyopathies. Genetic testing with NGS is useful and its value is increasing with respect to the Sanger method.

Resumen Introduccion y objetivos La muerte subita cardiaca (MSC) de origen no isquemico esta causada predominantemente por miocardiopatias y canalopatias. La bateria de test diagnosticos es amplia e incluye pruebas complejas. El objetivo de nuestro estudio es analizar la rentabilidad diagnostica del estudio etiologico sistematizado de la MSC. Metodos Se estudio a 56 familias con al menos 1 caso indice con MSC (reanimada o no). En los supervivientes se exploro con electrocardiograma, imagen cardiaca avanzada, ergometria, estudio familiar, estudio genetico y, puntualmente, test farmacologicos. En los fallecidos se examino la necropsia, asi como la autopsia molecular con next generation sequencing (NGS), junto con estudio clinico familiar. Resultados El diagnostico se alcanzo en el 80,4% de los casos, sin diferencias entre supervivientes y fallecidos (p = 0,53). Entre los supervivientes, el diagnostico de canalopatia fue mas frecuente que entre los fallecidos (el 66,6 frente al 40%; p = 0,03). De los 30 sujetos fallecidos, en 7 la autopsia aporto un hallazgo concluyente. El diagnostico de miocardiopatia tendia a asociarse con mayor tasa de eventos en la familia. El test genetico con NGS se realizo en 42 de los casos; se obtuvo resultado positivo en 28 (66,6%), sin diferencias entre supervivientes y fallecidos (p = 0,21). Conclusiones La probabilidad de alcanzar el diagnostico en la MSC tras un protocolo exhaustivo es alta, con mayor prevalencia de canalopatias en los supervivientes y un aparente peor pronostico en las miocardiopatias. El test genetico mediante NGS muestra utilidad en casos de MSC e incrementa la rentabilidad respecto al estudio con Sanger.

A comprehensive review was performed to investigate the effect of route of administration on medication adherence and persistence in rheumatoid arthritis (RA) and to compare adherence/persistence with oral medications between RA and a non-painful disease (dyslipidemia).Comprehensive database searches were performed to identify studies investigating medication adherence and/or persistence in adults with RA receiving conventional synthetic or biologic agents. Similar searches were performed for studies of patients with dyslipidemia receiving statins. Studies had to be published after 1998 in English and involve ≥6 months' follow up.Adherence and persistence were compared between the different routes of drug administration in RA, and between the two diseases for oral medications.A total of 35 and 28 papers underwent data extraction for RA and dyslipidemia, respectively. Within the constraints of the analysis, adherence and persistence rates appeared broadly similar for the different routes of drug administration in RA. Adherence to oral medications was also broadly similar across the two diseases, but persistence was lower in dyslipidemia. Poor adherence has clinical consequences in both diseases: greater disease activity and risk of flare in RA, and increased serum cholesterol levels and risk of heart and cerebrovascular disease in dyslipidemia. Over 1-3 years, poor adherence to biologic RA medications led to increased resource use and medical costs but lower total direct costs due to reduced biologic drug costs. Conversely, poor adherence to dyslipidemia medications resulted in increased total direct costs. In both diseases, adherence improved with patient education/support.The route of drug administration and the symptomatic (pain) nature of the disease do not appear to be dominant factors for drug adherence or persistence in RA.The wide range of adherence and persistence values and definitions across studies made comparisons between drug formulations and diseases difficult.

Celine J Van De Laar,1 Martijn AH Oude Voshaar,1,2 Walid KH Fakhouri,3 Liliana Zaremba-Pechmann,3 Francesco De Leonardis,3 Inmaculada De La Torre,3 Mart AFJ Van De Laar1,2 1Transparency in Healthcare BV, Hengelo, the Netherlands; 2Department of Psychology and Communication of Health and Risk, Institute for Behavioural Research, University of Twente, Enschede, the Netherlands; 3Eli Lilly & Company, Indianapolis, IN, USACorrespondence: Celine J Van De Laar Tel +31 74-43032645Email c.vandelaar@tihealthcare.nlBackground: Baricitinib is a janus kinase (JAK1/JAK2) inhibitor developed for the treatment of patients suffering from rheumatoid arthritis (RA). Treating RA to the target of remission is current common practice. Cost-effectiveness of different treat-to-target (T2T) strategies, especially ones including new treatments is important for development and preference policy for treatment centers. European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) guidelines are currently unclear about preference between a JAK1/JAK2 versus a biological disease-modifying antirheumatic drug (bDMARD).Objective: The main goal of this paper was to evaluate the cost-effectiveness of baricitinib versus first biological for methotrexate inadequate responders in a T2T strategy using a Markov model that incorporates hospital costs as well as societal costs. Costs and utilities over five years were compared between the two strategies.Methods: A Monte Carlo simulation model was developed to conduct cost–utility analysis from the societal perspective over 5 years. Health states were based on the DAS28-erythrocyte sedimentation rate (ESR) categories. Effectiveness of baricitinib was retrieved from randomized controlled trials. Effectiveness of all other treatments, health state utilities, medical costs, and productivity loss were retrieved from the Dutch RhEumatoid Arthritis Monitoring (DREAM) cohorts. Annual discount rates of 1.5% for utility and 4% for costs were used. Probabilistic sensitivity analysis was employed to incorporate uncertainty and assess robustness of the results.Results: Probabilistic sensitivity analysis results showed the baricitinib strategy yielded lower costs and higher utility over a 5-year period. Scenario analyses showed the baricitinib strategy to be cost-effective in both the moderate and severe RA populations.Conclusion: Results suggest that the use of a JAK1/JAK2 inhibitor instead of a bDMARD in a T2T approach is cost-effective in csDMARD refractory RA patients.Keywords: Markov model, rheumatoid arthritis, baricitinib, cost-effectiveness, health economic model, treat-to-target

Patients with rheumatoid arthritis (RA) may experience residual pain and functional impairment despite good control of disease activity. This study compared improvements in pain and physical function in patients with well-controlled RA after 24 weeks’ treatment with baricitinib, adalimumab or placebo in the 52-week RA-BEAM phase III study. Adults with active RA and inadequate response to methotrexate received baricitinib 4 mg once daily, adalimumab 40 mg every two weeks or placebo, with background methotrexate. Patients (N = 1010) were categorised as in remission, in remission or low disease activity, or not in remission or low disease activity at week 24. For patients in remission or low disease activity (n = 310), improvements in mean pain and physical function scores at week 24 were significantly greater with baricitinib than placebo (p &lt, 0.001 and p &lt, 0.01, respectively) and adalimumab (p &lt, 0.05 for both). For both outcomes, differences between adalimumab and placebo were not significant. The proportions of patients in remission or low disease activity with minimal or no pain and with normalised physical function were numerically greater with baricitinib than placebo. Baricitinib 4 mg once daily provided enhanced improvement in pain and physical function in patients with well-controlled RA, suggesting it may produce effects beyond immunomodulation.

Patients with rheumatoid arthritis (RA) have a high prevalence of comorbidities.1 This post-hoc analysis investigated the effect of select comorbidities (depression, osteoporosis, hepatic, cardiovascular or pulmonary disorders) on the efficacy and safety of baricitinib 4 mg once daily in patients with moderate-to-severe active RA and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). Data from the placebo-controlled periods of five baricitinib studies2–6 were pooled for baricitinib 4 mg; data for baricitinib 2 mg were not analysed due to low (n=302) patient numbers. Additional data for all baricitinib-treated patients with a median exposure of 2 years were derived from an ongoing open-label, long-term extension (LTE) study that included patients from phase II and III studies (RA-BEYOND; NCT01885078).7 Efficacy outcomes were evaluated at week 12 (vs placebo). Interaction of comorbidity-by-treatment was analysed using logistic regression or analysis of covariance. Safety observations up to week 16 (vs placebo) and during the LTE were summarised by the Medical Dictionary for Regulatory Activities preferred term. Data from 1684 patients (803, baricitinib 4 mg; 881, placebo) from the placebo-controlled periods were analysed. The mean (SD) age was 52.7 (12.1) years, with only 38 (2.3%) patients aged ≥75 years; most patients (1506, 89.4%) were receiving background methotrexate, alone or in combination with another csDMARD. The numbers of patients receiving placebo and baricitinib 4 mg combined (with or without each comorbidity, respectively) were 133/1551 for depression, 247/1437 for osteoporosis, 424/1260 for hepatic disorders, 731/953 for cardiovascular disorders, and 166/1518 for pulmonary disorders. Demographic and clinical characteristics within each comorbidity subgroup were similar between patients randomised to baricitinib or placebo. Higher …

Background The aim of this retrospective study was to examine the longitudinal association between disease activity and radiographic damage in a cohort of patients with early RA (symptom onset Methods Baseline to 3-year follow-up data were used from patients included in the DREAM remission induction cohort. Patients received protocolized T2T treatment, aimed at 28-joint disease activity score-erythrocyte sedimentation rate (DAS28-ESR) remission. Disease activity (DAS28-ESR and C-reactive protein, CRP) were assessed at least every 3 months; X-rays of the hand and feet at inclusion, 6 months, and 1, 2, and 3 years were scored using modified Sharp/van der Heijde scoring (SHS). Between and within-person associations between time-integrated disease activity and radiographic progression over time were examined. Results A subset of 229 out of 534 included patients were available for analysis. At the between-patient level, time-integrated DAS28-ESR scores were not significantly correlated with progression at the 6 month and 2-year follow-up and only weakly at the 1-year (Pearson’s correlation coefficient r = 0.17, P r = 0.21, P r between 0.39 and 0.59; P values Conclusions In early RA patients treated according to T2T, radiographic progression appears to be an individually determined disease process, driven by factors other than consistent high disease activity. For individual patients, the intra-patient relation between disease activity and cumulative radiographic damage during the first 6 months is a good indicator for this relation in later years. Trial registration Netherlands Trial Register NTR578, 12 January 2006.

Background: Treating Rheumatoid Arthritis (RA) to an a priori defined disease activity target (T2T) is recommended in EULAR guidelines. This involves a step-up approach in which it is first attempted to achieve the target with a combination of conventional synthetic (cs) DMARDs. Baricitinib is a JAK1/JAK2-inhibitor approved for treatment of patients suffering from RA. EULAR and ACR guidelines currently position JAK1/JAK2-inhibitors and bDMARDs at the same level in the therapeutic treatment sequence for csDMARD Inadequate Responders (IR). Cost-effectiveness assessment of different T2T strategies, especially ones including new treatments, and integrating health economic considerations is of importance to the decision-making process as it incorporates the societal perspective in the longer run. Objectives: To compare the cost-effectiveness of the previously evaluated DREAM T2T strategy csDMARD combination therapy (csDMARDs)→ first bDMARD (adalimumab)→ next bDMARD (TNFi/non-TNFi) with the comparable strategy in which baricitinib is placed instead of adalimumab in csDMARDs IR using a Markov model. All analyses were performed from the societal perspective. Costs and effects over five years were compared between the two strategies to provide insight into the differences in economic considerations between treating patients with strategies including either JAK1/JAK2-inhibitor (baricitinib) or 1st bDMARD (adalimumab). Methods: A Monte Carlo microsimulation model was developed to conduct cost-utility analysis from the societal perspective over 5 years. Health states were based on the DAS28-ESR categories. Effectiveness of baricitinib was retrieved from clinical trials (1) and corrected for differences between RCT and real-world setting. Effectiveness of all other treatments, health state utilities, medical costs, and productivity loss were retrieved from DREAM cohorts (2) and the Dutch Institute for Health. Annual discount rates of 1.5% for utility and 4% for costs were used, as advised in Dutch guidelines. All analyses were run using probabilistic sensitivity analysis (PSA) to incorporate uncertainty around all parameters and assess result robustness. Results: PSA results showed the baricitinib strategy yielded lower costs and higher utility over a 5-year period and is cost-effective and dominant over the DREAM T2T strategy. Scenario analyses showed the baricitinib strategy to be cost-effective in both the moderate and severe at baseline RA populations analysed together and separately. CI= 95% Confidence Interval, QALY = Quality-Adjusted Life Year, ΔC = Cost difference, ΔE = Effect Difference, ICER = Incremental Cost-Effectiveness Ratio Conclusion: Results suggest the use of a JAK1/JAK2-inhibitor (baricitinib) instead of a 1st bDMARD (adalimumab) in a T2T strategy is cost-effective in treating RA patients. References: [1] Taylor, P. C., Keystone, E. C., van der Heijde, D., Weinblatt, M. E., del Carmen Morales, L., ... & Arora, V. (2017). Baricitinib versus placebo or adalimumab in rheumatoid arthritis. New England Journal of Medicine, 376(7), 652-662. [2] M., Versteeg, G. A., Vonkeman, H. E., Ten Klooster, P. M., Kuper, H. H., ... & van de Laar, M. A. (2016). Initial combination therapy versus step-up therapy in treatment to the target of remission in daily cl. Steunebrink, L. inical practice in early rheumatoid arthritis patients: results from the DREAM registry. Arthritis Research & Therapy, 18(1), 60. Disclosure of Interests: Celine van de Laar: None declared, Martijn Oude Voshaar: None declared, WALID FAKHOURI Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Liliana Zaremba-Pechmann Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Francesco de Leonardis Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Inmaculada De La Torre Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Mart van de Laar Grant/research support from: Eli Lilly, Pfizer, Merck, AbbVie and Janssen Cilag, Consultant for: Sanofi Genzym, Eli Lilly, Pfizer, Merck, Abbvie and Janssen Cilag, Speakers bureau: Eli Lilly, Pfizer and Janssen Cilag

Treat-to-target (T2T) and dose tapering after obtaining the therapeutic objective (called “treat-to-budget”-T2B-in this Commentary) are the two most commonly used therapeutic strategies in rheumatoid arthritis. In theory, both strategies could add value to the healthcare system, although they are focused on different objectives: T2T strategy improves outcomes but increases short-term costs, while the cost savings obtained through T2B are associated with higher relapse rates. The systematic implementation of both strategies must be founded on solid evidence of their effectiveness and efficiency. However, the level of evidence between guidelines and individual studies is inconsistent for both strategies and the number and the quality of cost-effectiveness analyses is scarce. Raising the level of evidence requires a move from generalization to individualization by conducting randomized clinical trials that assess each of the many strategies that fall under the umbrella of the overall T2T and T2B concepts. In addition, such studies should consider the therapeutic goals and impact of the disease from the perspective of individual patients, which is only possible by promoting shared decision-making, Fee were funded by Lilly Spain

BackgroundBaricitinib is an oral, reversible, selective Janus kinase 1 and 2 inhibitor.MethodsIn this phase III, double-blind 24-week study, 684 biologic disease-modifying antirheumatic drug (DMARD)-naïve patients with rheumatoid arthritis and inadequate response or intolerance to ≥1 conventional synthetic DMARDs were randomly assigned 1:1:1 to placebo or baricitinib (2 or 4 mg) once daily, stratified by region and the presence of joint erosions. Endpoint measures included American College of Rheumatology 20% response (ACR20, primary endpoint), Disease Activity Score (DAS28) and Simplified Disease Activity Index (SDAI) score ≤3.3.ResultsMore patients achieved ACR20 response at week 12 with baricitinib 4 mg than with placebo (62% vs 39%, p≤0.001). Compared with placebo, statistically significant improvements in DAS28, SDAI remission, Health Assessment Questionnaire-Disability Index, morning joint stiffness, worst joint pain and worst tiredness were observed. In a supportive analysis, radiographic progression of structural joint damage at week 24 was reduced with baricitinib versus placebo. Rates of adverse events during the treatment period and serious adverse events (SAEs), including serious infections, were similar among groups (SAEs: 5% for baricitinib 4 mg and placebo). One patient had an adverse event of tuberculosis (baricitinib 4 mg); one patient had an adverse event of non-melanoma skin cancer (baricitinib 4 mg). Two deaths and three major adverse cardiovascular events occurred (placebo). Baricitinib was associated with a decrease in neutrophils and increases in low-density and high-density lipoprotein.ConclusionsIn patients with rheumatoid arthritis and an inadequate response or intolerance to conventional synthetic DMARDs, baricitinib was associated with clinical improvement and inhibition of progression of radiographic joint damage.Trial registration numberNCT01721057; Results.

Resumen Introduccion y objetivos La heredabilidad y la penetrancia familiar de los trastornos causantes de la parada cardiaca en ausencia de cardiopatia aparente es desconocida. Nuestro objetivo es describir los hallazgos clinicos y los medios para alcanzar el diagnostico en una muestra de familiares de probandos con parada cardiaca en ausencia de cardiopatia aparente. Material y metodos Estudiamos a familiares de primer a tercer grado de pacientes afectados por parada cardiaca de origen incierto. En todos se realizo electrocardiograma y ecocardiograma transtoracico. En los casos con diagnostico cierto en el probando, se realizo ademas estudio dirigido en funcion del mismo para desenmascarar la enfermedad. Resultados Se incluyo a 88 sujetos pertenecientes a 35 familias (media de 2,5 familiares por caso indice, con una edad media de 38,4 anos y 52,8% varones). El 55,6% fueron familiares de primer grado y el resto de segundo y tercer grado. En 18 de los 35 casos indice se alcanzo un diagnostico final. Se obtuvo un diagnostico positivo en 19 familiares (21,5%) consistentes en sindrome de Brugada (10 casos), sindrome de QT largo (3 casos), taquicardia ventricular catecolaminergica polimorfica (5 casos) y un caso de posible Sindrome de QT corto. En 4 familias, el diagnostico del probando se alcanzo exclusivamente mediante el estudio familiar. Conclusiones La prevalencia de canalopatias cardiacas entre los familiares de probandos con parada cardiaca de origen incierto fue alta, con frecuente necesidad de test de desenmascaramiento y genetico para logar un diagnostico cierto.

Digging in 1999 fossa filled in with an archaeological material from the first half of 4th century BC was found; this would be a mean advance to knowledge about Iberic oppidum of Iliberri because of the enlarge of periurban space until the landscape throunght the close relationship between the city and the idea of Darro river. In this paper we show the Iberic and Punic pottery from this context, with a very interesting contributions to quantifying and classification pottery systems in protohistorical archaeology., La excavación en 1999 de una fosa rellena con abundante material datado en la primera mitad del siglo IV a.C. supone un importante avance en el conocimiento de la arqueología ibérica en el oppidum de Iliberri, pues amplia el ámbito periurbano a la relación tan estrecha que mantiene la ciudad con su territorio a través de la imagen del rio Darro. En este trabajo se presenta el estudio del material ibérico y púnico procedente de ese contexto, con interesantes aportaciones acerca de los sistemas de clasificación y cuantificación cerámica en arqueología protohistórica.

Numerous cytokines have been implicated in the pathogenesis of inflammatory diseases, and their dysregulation is a main feature of rheumatoid arthritis (RA). Cytokines stimulate signal transduction through several intracellular pathways, including Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathways, leading to changes in cell activation, proliferation and survival. Consequently, agents that selectively target elements of the JAK/STAT pathways have received significant attention in recent years as potential new treatments for the disease. Baricitinib, an oral selective inhibitor of JAK1 and JAK2, offers an effective treatment for RA in a wide range of patients. The in vitro selectivity of different JAK inhibitors is an important consideration given that key cytokines, growth factors and hormone receptors involved in the pathogenesis of RA signal through specific JAKs. However, it is complex and far from understood how the in vitro effects of JAK inhibitors extrapolate into in vivo and clinical effects in individual patients. This narrative review focuses on the clinical efficacy and safety of baricitinib, but also provides an overview of its mechanism of action in relation to JAK1/JAK2 signalling and discusses the possible clinical implications in patients with RA.

Background: Baricitinib was efficacious in a 24-week phase III study in patients with rheumatoid arthritis (RA) and an inadequate response to conventional synthetic disease-modifying anti rheumatic drugs (DMARDs) (csDMARDs) (RA-BUILD).\ud \ud \ud \ud Objectives: To evaluate radiographic progression of structural joint damage in RA-BUILD patients over 48 weeks of baricitinib treatment in the long-term extension study, RA-BEYOND.\ud \ud \ud \ud Methods: In RA-BUILD, patients were randomised to placebo, baricitinib 2 mg or 4 mg once daily, with rescue possible from week 16. Patients completing RA-BUILD and entering RA-BEYOND continued to receive the baricitinib dose received at the end of RA-BUILD. Patients receiving placebo were switched to baricitinib 4 mg in RA-BEYOND. Joint damage was measured using the van der Heijde modified total Sharp score. To account for missing scores and scores obtained after rescue, switch or discontinuation of study drug, data were analysed using (1) linear extrapolation (LE) and (2) observed/last observation carried forward (LOCF). The observed/LOCF method used all available observed data, including after rescue or switch, with patients analysed according to original treatment assignment.\ud \ud \ud \ud Results: Using LE, radiographic progression at 24 and 48 weeks was statistically significantly lower for both baricitinib 2 or 4 mg compared with placebo. Only baricitinib 4 mg demonstrated statistically significant inhibition of progressive radiographic joint damage compared with patients initially randomised to placebo using observed/LOCF at week 48.\ud \ud \ud \ud Conclusions: Once daily oral baricitinib inhibited radiographic progression of structural joint damage in patients with an inadequate response or intolerance to csDMARDs over 48 weeks. The most robust benefit was seen for the 4 mg dose.

Objective.To assess the safety and efficacy of baricitinib in patients with rheumatoid arthritis (RA) up to 128 weeks in a phase IIb study (NCT01185353).Methods.After a 24-week blinded period, eligible patients entered an initial 52-week open-label extension (OLE); patients receiving 8 mg once daily (QD) continued with that dose and all others received 4 mg QD. Doses could be escalated to 8 mg QD at 28 or 32 weeks at investigator discretion when ≥ 6 tender and ≥ 6 swollen joints were present. Patients completing the first OLE were eligible to enter a second 52-week OLE and receive 4 mg QD regardless of previous dose.Results.In the 4-mg (n = 108) and 8-mg (n = 93) groups, treatment-emergent adverse events (AE) occurred in 63% and 67%, serious AE in 16% and 13%, infections in 35% and 40%, and serious infections in 5% and 3% of patients, respectively. Exposure-adjusted incidence rates for AE for all baricitinib groups in the second OLE were similar to or lower than rates observed in the first OLE. No opportunistic infections, tuberculosis cases, or lymphomas were observed through 128 weeks; 1 death occurred during the first OLE. Among all patients in both OLE, the proportions who achieved disease improvement at Week 24 were similar or increased at weeks 76 and 128.Conclusion.In a phase IIb study in RA, the safety and tolerability profile of baricitinib, up to 128 weeks, remained consistent with earlier observations, without unexpected late signals. Clinical improvements seen in the 24-week blinded period were maintained during the OLE.

Objectives To assess the long term efficacy and optimization of Infliximab (IFX) in refractory Uveitis of Behcet Disease (BD) Methods Multicentre study of Uveitis associated-BD refractory to conventional immunosupressive drug. Ocular inflammation was evaluated with “SUN criteria” (Am J Ophthalmol 2005;140:509–516) and the macular thickening with OCT. Results are expressed as mean±SD or median [IQR] (comparison, Wilcoxon test) Results We studied 100 patients/180 affected eyes (54M/46W), mean age 40.7±10.1. The ocular pattern was panuveitis (n=62), posterior (27) and anterior uveitis (11). Before IFX they received iv MP (28), cyclosporine (75), azathioprine (56), metotrexate (43) and others (33). IFX dose ranged between 3–5mg/kg/4 or 8 weeks. In patients in remission IFX was optimized (n=28) or stopped (n=20). Conclusions IFX is an effective long term-treatment in refractory Uveitis of BD. Optimization and even discontinuation of IFX after remission is possible. Disclosure of Interest None declared

Objectives To evaluate the efficacy of adalimumab (ADA) in short and long term follow-up in refractory uveitis of Behcet9s disease (BD) Methods Multicenter study. Ocular inflammation was evaluated according to “SUN working Group” (Am J Ophthalmol 2005;140:509–516), and the macular thickening with OCT. A comparison was carried out between baseline, and follow-up visits. Results are expressed as mean±SD or median [IQR]. Continuous variables were compared with Wilcoxon test. Results We studied 74 patients/132 affected eyes (39M/35W); mean age 38.7±11.3. The ocular pattern was panuveitis (n=45), posterior uveitis (n=14), anterior uveitis (n=14) and intermediate uveitis (n=1). Before ADA, systemic treatment with corticosteroids, iv metilprednisolone (n=23), Cyclosporin A (58), azathioprine (33), metotrexate (31) and other drugs (28) was used. The dose of ADA was 40 mg/2 weeks/ sc in monotherapy (n=22) or combined (n=52). Most patients showed a rapid and progressive improvement (TABLE). The 24 patients (37 affected eyes) with CME showed a significant improvement. ADA was optimized in 23 (31.1%) that were in remission for 15.3±9 months. Interval of administration was increased to 3 (n=6), 4 (13), 5 (1), 6 (1) and 8 weeks. After a mean follow-up of 13.0±9.7 months after optimization, 21 patients were stable and 2 had a severe flare. In 4 patients ADA was stopped after 35.2±9.3 months in remission. The main adverse effects observed were lymphoma (n=1), pneumonia (1), and 2° bacteriemia by E. Coli (1) Conclusions ADA was effective in short and long-term follow-up in refractory uveitis associated to BD. Optimization or even suspension of ADA is possible. Disclosure of Interest None declared

Background: Baricitinib, an oral JAK1/JAK2 inhibitor, improves disease activity with an acceptable safety profile in patients with active rheumatoid arthritis (RA). We report efficacy and safety data for baricitinib as monotherapy or in combination with methotrexate (MTX), compared with MTX, in[for full text, please go to the a.m. URL]