Comparative analysis of US real-world dosing patterns and direct infusion-related costs for matched cohorts of rheumatoid arthritis patients treated with infliximab or intravenous golimumab.

Purpose: The objectives of this study were to evaluate and compare treatment patterns and infusion-related health care resource expenditures for rheumatoid arthritis (RA) patients initiating golimumab for intravenous use (GLM-IV) and infliximab (IFX) therapy and to assess cost implications from the commercial perspective. Methods: Adult RA patients with a new episode of GLM-IV or IFX treatment between January 1, 2014 and March 31, 2016 were identified from MarketScan databases and evaluated for maintenance infusion intervals and related costs of treatment. IFX and GLM-IV patients were matched 1:1 on index medication treatment duration, gender, payer type, prior biologic use, and post-index methotrexate use. Paid amounts for drugs and associated administration costs were applied to treatment group dosing patterns. Results: Final matched treatment groups included 547 GLM-IV and 547 IFX patients (mean age = 55-56 years). Mean (SD) follow-up was 609 (161) days for GLM-IV and 613 (163) days for IFX. Treatment duration was 396 (240) days for GLM-IV and 397 (239) days for IFX. Overall, 80% of GLM-IV and 39% of IFX maintenance infusions were given approximately every 8 weeks; and 6% of GLM-IV and 53% of IFX maintenance infusions occurred more frequently than every 8 weeks (P\u3c0.001). When weighting of the maintenance infusion interval was applied, the mean number of induction plus maintenance infusions during the first year of treatment was estimated at 7.03 for GLM-IV and 9.48 for IFX. From the commercial perspective, drug plus administration costs per infusion were $5,846 for GLM-IV and$5,444 for IFX with total annual cost of therapy for GLM-IV patients costing $10,507 less than that for IFX patients in the first year and$6,774 less than that for IFX patients in subsequent years. Conclusion: Annual GLM-IV drug plus administration costs for commercial health plans were significantly less than IFX in RA patients due to differences in real-world dosing and administration. © 2019 Ellis et al

Efficacy of ustekinumab in biologic-naïve patients with psoriatic arthritis by prior treatment exposure and disease duration: data from PSUMMIT 1 and PSUMMIT 2

Objective: To evaluate the efficacy of ustekinumab by prior treatment exposure and disease duration in tumour necrosis factor inhibitor (TNF)-naïve patients with psoriatic arthritis (PsA) in the PSUMMIT 1 and PSUMMIT 2 studies. Methods: In the phase 3, randomised, placebo-controlled PSUMMIT 1 and PSUMMIT 2 studies, adults with active PsA for ≥6 months despite conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and/or non-steroidal anti-inflammatory drugs (NSAIDs) (PSUMMIT 1) or csDMARDs, NSAIDs and/or anti-TNF agents (PSUMMIT 2) were enrolled. Patients were randomised to subcutaneous injections of placebo, ustekinumab 45 mg or ustekinumab 90 mg at weeks 0 and 4 and every 12 weeks. Efficacy was assessed at week 24 using the American College of Rheumatology criteria and 28-joint count disease activity score using C reactive protein (DAS28-CRP); radiographical progression, enthesitis, and dactylitis were also assessed in this post hoc analysis. Results: A total of 747 patients were included; all 747 were TNF-naïve, of which, 179 were methotrexate-naïve and TNF-naïve, and 146 were all csDMARD-naïve and TNF-naïve. At week 24, greater proportions of ustekinumab-treated patients had ≥20%/50%/70% improvement in American College of Rheumatology criteria (ACR20/ACR50/ACR70) responses, DAS28-CRP response and DAS28-CRP remission versus placebo in all three prior-treatment populations, with similar differences between treatment groups. Greater proportions of ustekinumab-treated patients also had complete resolution of enthesitis and dactylitis at week 24 across the three prior-treatment populations. Mean changes from baseline in total van der Heijde-Sharp Score at week 24 were generally smaller for ustekinumab-treated patients versus placebo but were statistically significant only in the full TNF-naïve population. Response rates for ACR20/ACR50/ACR70 were similar for TNF-naïve patients with PsA durations of <1 year, ≥1 to <3 years, and ≥3 years. Conclusion: Ustekinumab-treated patients demonstrated greater clinical response at week 24 compared with placebo regardless of prior treatment exposure and PsA disease duration

Resolution of enthesitis by guselkumab and relationships to disease burden: 1-year results of two phase 3 psoriatic arthritis studies

Objective: To further characterize the effect of guselkumab, a selective IL-23p19-subunit inhibitor approved for PsA, on enthesitis and assess relationships between enthesitis resolution and patient status/outcomes. Methods: Adults with active PsA despite standard therapies in the phase 3 DISCOVER-1 and DISCOVER-2 studies were randomized 1:1:1 to guselkumab 100 mg every 4 weeks (Q4W); guselkumab 100 mg at week 0, week 4, Q8W; or placebo through week 20 followed by guselkumab 100 mg Q4W. Independent assessors evaluated enthesitis using the Leeds Enthesitis Index (LEI; total score 0–6). Enthesitis findings through week 24 were pre-specified to be pooled across studies; post hoc and week 52 analyses also employed pooled data. Results: Among 1118 randomized, treated patients in DISCOVER-1 and 2 who had ≥1 LEI site evaluated, 65% had enthesitis at baseline. These patients exhibited numerically more swollen and tender joints, systemic inflammation and impaired physical function than patients without enthesitis. Guselkumab Q4W and Q8W were superior to placebo in resolving pre-existing enthesitis at week 24 (45 and 50% vs 29%; both adjusted P = 0.0301). Enthesitis resolution rates continued to rise; 58% of guselkumab-randomized patients achieved resolution at week 52, including patients with mild (LEI = 1; 70–75%), moderate (LEI = 2; 69–73%) or severe (LEI = 3–6; 42–44%) enthesitis at baseline. Among guselkumab-randomized patients with resolved enthesitis at week 24, 42% achieved minimal disease activity at week 52, vs 17% of patients with unresolved enthesitis. Conclusion: Guselkumab resulted in higher proportions of PsA patients with resolved enthesitis by week 24, with maintenance of resolution rates through 1 year. As enthesitis confers greater disease burden, sustained resolution could portend better patient outcomes. Clinical trial registration: DISCOVER 1 (NCT03162796) and DISCOVER 2 (NCT03158285)

LKB1 Destabilizes Microtubules in Myoblasts and Contributes to Myoblast Differentiation

Background: Skeletal muscle myoblast differentiation and fusion into multinucleate myotubes is associated with dramatic cytoskeletal changes. We find that microtubules in differentiated myotubes are highly stabilized, but premature microtubule stabilization blocks differentiation. Factors responsible for microtubule destabilization in myoblasts have not been identified. Findings: We find that a transient decrease in microtubule stabilization early during myoblast differentiation precedes the ultimate microtubule stabilization seen in differentiated myotubes. We report a role for the serine-threonine kinase LKB1 in both microtubule destabilization and myoblast differentiation. LKB1 overexpression reduced microtubule elongation in a Nocodazole washout assay, and LKB1 RNAi increased it, showing LKB1 destabilizes microtubule assembly in myoblasts. LKB1 levels and activity increased during myoblast differentiation, along with activation of the known LKB1 substrates AMPactivated protein kinase (AMPK) and microtubule affinity regulating kinases (MARKs). LKB1 overexpression accelerated differentiation, whereas RNAi impaired it. Conclusions: Reduced microtubule stability precedes myoblast differentiation and the associated ultimate microtubule stabilization seen in myotubes. LKB1 plays a positive role in microtubule destabilization in myoblasts and in myoblast differentiation. This work suggests a model by which LKB1-induced microtubule destabilization facilitates the cytoskeleta

Pooled safety results through 1 year of 2 phase iii trials of guselkumab in patients with psoriatic arthritis

Objective: Evaluate the safety of guselkumab (monoclonal antibody targeting interleukin [IL]-23p19) in patients with psoriatic arthritis (PsA) through 1 year (1Y) of the phase III DISCOVER-1 and DISCOVER-2 trials. Methods: Patients with active PsA (n = 1120; biologic-naïve except 118 patients treated with tumor necrosis factor inhibitors in DISCOVER-1) were randomized to subcutaneous guselkumab 100 mg every 4 weeks (Q4W) or at Week 0, Week 4, then every 8 weeks (Q8W); or placebo. At Week 24, patients in the placebo group switched to guselkumab 100 mg Q4W. Treatment continued through 1Y and 2 years for DISCOVER-1 and DISCOVER-2, respectively. In this pooled analysis, patients with ≥ 1 adverse event (AE) through 1Y were standardized for 100 patient-years [100 PYs] of follow-up. Results: Through Week 24, adverse events (AEs) were consistent between patients treated with placebo and guselkumab (Q4W + Q8W). AEs were 142.8/100 PYs and 150.6/100 PYs, serious AEs were 7.1/100 PYs and 4.4/100 PYs, and AEs leading to study agent discontinuation were 4.1/100 PYs and 3.8/100 PYs, respectively. Through 1Y in patients treated with guselkumab, no uveitis, active tuberculosis, opportunistic infections, or inflammatory bowel disease were observed, and low rates of malignancy and major adverse cardiovascular (CV) events were observed. Injection-site reactions occurred in 1.7%, and antibodies to guselkumab in 4.5% of patients treated with guselkumab through 1Y; the vast majority of antibodies to guselkumab were nonneutralizing. Serum hepatic transaminase elevations (more common with Q4W than Q8W dosing) and decreased neutrophil counts were generally mild, transient, and did not require treatment discontinuation, with minimal change from Week 24 to 1Y. Conclusion: Guselkumab 100 mg Q4W and Q8W were well tolerated in patients with PsA, with no new safety concerns through 1Y of the phase III DISCOVER trials. Guselkumab safety through 1Y in patients with PsA is consistent with that established in patients with psoriasis who were treated with guselkumab. [ClinicalTrials.gov: NCT03162796 and NCT03158285]

Efficacy and safety of intravenous golimumab plus methotrexate in patients with rheumatoid arthritis aged \u3c 65 years and those ≥ 65 years of age.

OBJECTIVE: To evaluate the safety and efficacy of intravenous golimumab + methotrexate (MTX) in patients with active rheumatoid arthritis (RA) aged \u3c 65 years and those ≥ 65 years who were enrolled in the GO-FURTHER study. METHODS: In the phase III, double-blind, randomized, placebo-controlled GO-FURTHER trial, patients with active RA were randomized to intravenous (IV) golimumab 2 mg/kg + MTX or placebo + MTX at weeks 0 and 4, then every 8 weeks thereafter (with crossover to golimumab at week 16 [early escape] or week 24 [per-protocol]). The final golimumab infusion was at week 100. Assessments included American College of Rheumatology (ACR) 20/50/70 response criteria. Efficacy and adverse events (AEs) were monitored through 2 years. Efficacy and AEs were summarized for patients aged \u3c 65 years or ≥ 65 years; AEs were also summarized for patients \u3c or ≥ 70 years and patients \u3c or ≥ 75 years. RESULTS: In GO-FURTHER, 592 patients were randomized to receive placebo (n = 197) or golimumab (n = 395), 515 were aged \u3c 65 years and 77 were ≥ 65 years. At week 24, ACR20 response rates were greater for golimumab + MTX patients compared with placebo + MTX for patients \u3c 65 years (61.6% vs 31.3%, p \u3c 0.001) and those ≥ 65 years (69.5% vs 33.3%; p \u3c 0.01). Infections were the most common AE through week 112 (51.6% in patients \u3c 65 years; 55.3% in patients ≥ 65 years); upper respiratory infections were the most common infection in patients \u3c 65 years (13.2%) and those ≥ 65 years (11.8%). Serious AEs occurred in 17.7% in patients \u3c 65 years and 25.0% of patients ≥ 65 years and included malignancies, pneumonia, fractures, acute pancreatitis, cellulitis, and bacterial arthritis. CONCLUSIONS: In GO-FURTHER, ACR response rates were similar between patients \u3c 65 years and patients ≥ 65 years within each treatment group. AEs in elderly patients were similar to the known safety profile of IV golimumab. Immunosenescence is known to increase the risk of infections in the elderly. Elderly patients had a numerically higher incidence of serious infections. Six malignancies occurred in golimumab-treated patients, all in patients \u3c 65 years. TRIAL REGISTRATION: clinicaltrials.gov: NCT00973479 . Registered September 9, 2009

Efficacy of ustekinumab in biologic-naïve patients with psoriatic arthritis by prior treatment exposure and disease duration: data from PSUMMIT 1 and PSUMMIT 2

ObjectiveTo evaluate the efficacy of ustekinumab by prior treatment exposure and disease duration in tumour necrosis factor inhibitor (TNF)-naïve patients with psoriatic arthritis (PsA) in the PSUMMIT 1 and PSUMMIT 2 studies.MethodsIn the phase 3, randomised, placebo-controlled PSUMMIT 1 and PSUMMIT 2 studies, adults with active PsA for ≥6 months despite conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and/or non-steroidal anti-inflammatory drugs (NSAIDs) (PSUMMIT 1) or csDMARDs, NSAIDs and/or anti-TNF agents (PSUMMIT 2) were enrolled. Patients were randomised to subcutaneous injections of placebo, ustekinumab 45 mg or ustekinumab 90 mg at weeks 0 and 4 and every 12 weeks. Efficacy was assessed at week 24 using the American College of Rheumatology criteria and 28-joint count disease activity score using C reactive protein (DAS28-CRP); radiographical progression, enthesitis, and dactylitis were also assessed in this post hoc analysis.ResultsA total of 747 patients were included; all 747 were TNF-naïve, of which, 179 were methotrexate-naïve and TNF-naïve, and 146 were all csDMARD-naïve and TNF-naïve. At week 24, greater proportions of ustekinumab-treated patients had ≥20%/50%/70% improvement in American College of Rheumatology criteria (ACR20/ACR50/ACR70) responses, DAS28-CRP response and DAS28-CRP remission versus placebo in all three prior-treatment populations, with similar differences between treatment groups. Greater proportions of ustekinumab-treated patients also had complete resolution of enthesitis and dactylitis at week 24 across the three prior-treatment populations. Mean changes from baseline in total van der Heijde-Sharp Score at week 24 were generally smaller for ustekinumab-treated patients versus placebo but were statistically significant only in the full TNF-naïve population. Response rates for ACR20/ACR50/ACR70 were similar for TNF-naïve patients with PsA durations of &lt;1 year, ≥1 to &lt;3 years, and ≥3 years.ConclusionUstekinumab-treated patients demonstrated greater clinical response at week 24 compared with placebo regardless of prior treatment exposure and PsA disease duration.</jats:sec

Machine Learning Applied to Patient‐Reported Outcomes to Classify Physician‐Derived Measures of Rheumatoid Arthritis Disease Activity

Objective Patient‐reported outcome (PRO) data have assumed increasing importance in the care of patients with rheumatoid arthritis (RA), yet physician‐derived disease activity measures, such as Clinical Disease Activity Index (CDAI), remain the most accepted metrics to assess disease activity. The possibility that newer longitudinal PRO data might be used as a proxy for the CDAI has not been evaluated. Methods Using data from a large pragmatic trial, we evaluated patients with RA initiating golimumab intravenous or infliximab. The classification target was low disease activity (LDA) (CDAI ≤10) at the first visit between months 3 and 12. Data were randomly partitioned into training (80%) and test (20%) data sets. Multiple machine learning (ML) methods (eg, random forests, gradient boosting, support vector machines) were used to classify CDAI disease activity category, conduct feature selection, and assess feature importance. Model performance evaluated cross‐validated error, comparing different ML approaches using both training and test data. Results A total of 494 patients were analyzed, and 36.4% achieved LDA. The most important classification features included several Patient‐Reported Outcomes Measurement Information System measures (social participation, pain interference, pain intensity, and physical function), patient global, and baseline CDAI. Among all ML methods, random forests performed best. Overall model accuracy and positive predictive values for all ML methods were approximately 80%. Conclusion ML methods coupled with longitudinal PRO data appear useful and can achieve reasonable accuracy in classifying LDA among patients starting a new biologic. This approach has promise for real‐world evidence generation in the common circumstance when physician‐derived disease activity data are not available yet PRO measures are