Disease activity and biologic use in patients with psoriatic arthritis or rheumatoid arthritis.

To compare disease burden and biologic use among psoriatic arthritis (PsA) or rheumatoid arthritis (RA) patients recruited to the Corrona registry. Retrospective study of patients with PsA or RA enrolled in Corrona between January 2002 and March 2013 and grouped in 2-year intervals. Clinical outcomes and biologic use were assessed. Biologic use increased over time in both cohorts, with 62 and 52% of patients with PsA and RA, respectively, receiving biologics by 2012-2013. However, 25 and 35% of patients with PsA and RA, respectively, continued to experience moderate/high disease activity. Overall, the progressive increase in biologic use accompanied progressive decreases in Clinical Disease Activity Index (from 14.2 to 10.4 for RA, and 12.4 to 8.1 for PsA) and mean Health Assessment Questionnaire score (from 0.36 to 0.34, and 0.3 to 0.24). Mean patient pain, the proportion of patients reporting morning stiffness, and the mean duration of morning stiffness remained similar for both cohorts. PsA and RA treated in the rheumatology setting had a comparable impact on patient quality of life and functional ability. Disease burden improved with increased biologic utilization in both groups; however, moderate/severe disease remains in a significant proportion of PsA and RA patients

Discontinuation and switching patterns of tumour necrosis factor inhibitors (TNFis) in TNFi-naive and TNFi-experienced patients with psoriatic arthritis: an observational study from the US-based Corrona registry.

Objective: To examine patterns of tumour necrosis factor inhibitor (TNFi) use in TNFi-naive and TNFi-experienced patients with psoriatic arthritis (PsA) in the USA. Methods: All patients aged ≥18 years with PsA enrolled in the Corrona Psoriatic Arthritis/Spondyloarthritis Registry who initiated a TNFi (index therapy) between March 2013 and January 2017 and had ≥1 follow-up visit were included. Times to and rates of discontinuation/switch of the index TNFi were compared between TNFi-naive and TNFi-experienced cohorts. Patient demographics and disease characteristics at the time of TNFi initiation (baseline) were compared between cohorts and between patients who continued versus discontinued their index TNFi by the first follow-up visit within each cohort. Results: This study included 171 TNFi-naive and 147 TNFi-experienced patients (total follow-up, 579.2 person-years). Overall, 75 of 171 TNFi-naive (43.9%) and 80 of 147 TNFi-experienced (54.4%) patients discontinued their index TNFi; 33 of 171 (19.3%) and 48 of 147 (32.7%), respectively, switched to a new biologic. TNFi-experienced patients had a shorter time to discontinuation (median, 20 vs 27 months) and were more likely to discontinue (p=0.03) or switch (p Conclusions: The results of this real-world study can help inform treatment decisions when selecting later lines of therapy for patients with PsA

Long-Term Effectiveness of Adalimumab in Patients with Rheumatoid Arthritis: An Observational Analysis from the Corrona Rheumatoid Arthritis Registry

INTRODUCTION: Current recommendations for the management of rheumatoid arthritis (RA) focus on a treat-to-target approach with the objective of maximizing long-term health-related quality-of-life in patients with RA. Published studies from randomized clinical trials have reported limited data regarding the long-term efficacy and safety of adalimumab in patients with RA. This study aims to evaluate the long-term (10+ years) persistency and effectiveness of adalimumab in patients with RA in a real-world setting. METHODS: Included in this study were biologic-naive adults with RA initiating adalimumab during follow-up enrolled in the Corrona RA registry. More than 10 years of data on persistency of adalimumab and rheumatologist-supplied reasons for discontinuation were examined. Among patients who persisted on adalimumab over the years, clinical [e.g., clinical disease activity index scores (CDAI), physician global assessment, tender joint count, and swollen joint count] and patient-reported outcomes (PRO), such as physical function, pain, fatigue, and morning stiffness, were examined. RESULTS: Of 1791 biologic-naive patients treated with adalimumab who had \u3e /=1 follow-up registry visit, 64.1% were still on therapy at 1 year and 10.2% were still on therapy by the end of year 12. Among patients who persisted on adalimumab for at least 1 year (77.1% female, mean age 53.9 years), 67.0% were in low disease activity (LDA)/remission (CDAI \u3c /=10) and had clinically meaningful improvements from baseline in all clinical assessments and PROs. Initial improvements in LDA/remission and in clinical and PRO assessments observed at year 1 were sustained in those patients who remained on adalimumab over 10 years of follow-up. Among patients who discontinued adalimumab, 61.6% were not in LDA/remission and 41.9% switched to another biologic within 12 months after discontinuing adalimumab. CONCLUSIONS: Real-world data demonstrate a sustained effectiveness of adalimumab in the treatment of RA for patients who remained on therapy for 10 years. FUNDING: Corrona, LLC and AbbVie

Impact of rituximab on patient-reported outcomes in patients with rheumatoid arthritis from the US Corrona Registry

To evaluate the impact of rituximab on patient-reported outcomes (PROs) in a US-based observational cohort of patients with rheumatoid arthritis (RA). Patients with active RA, prior exposure to \u3e /=1 tumor necrosis factor inhibitor (TNFi) and who newly initiated rituximab were identified. Changes in PROs were assessed 1 year after rituximab initiation. PRO measures included Clinical Disease Activity Index (CDAI); patient global disease activity, pain and fatigue (visual analog score; 0-100); morning stiffness (hours); modified Health Assessment Questionnaire (mHAQ; 0-3); and EuroQoL EQ-5D. Of the 667 patients who newly initiated rituximab, baseline PRO and clinical measures indicated that patients were substantially impacted by their RA disease and quality of life; 54% of patients had high disease activity. One year after rituximab initiation, 49.0, 47.1, 49.8, and 23.2% of patients reported clinically meaningful improvements in patient global, pain, fatigue, and mHAQ, respectively. Morning stiffness and EuroQol EQ-5D domains improved in 48 and 19-32% of patients, respectively. These real-world registry data demonstrated that patients with long-standing, refractory RA experienced improvements in PROs 1 year after initiating rituximab

Baseline patient characteristics associated with response to biologic therapy in patients with psoriatic arthritis enrolled in the Corrona Psoriatic Arthritis/Spondyloarthritis Registry.

Objectives: To compare baseline characteristics between patients with psoriatic arthritis (PsA) who achieved and did not achieve minimal disease activity (MDA) with biologic therapy in the US-based Corrona Psoriatic Arthritis/Spondyloarthritis Registry. Methods: Patients with PsA aged ≥18 years enrolled between March 2013 and March 2016 who were receiving biologics at enrolment (baseline), not in MDA and had ≥2 follow-up visits were included. Patients were classified as those who remained on their index biologic and achieved MDA at the second follow-up visit (MDA achievers (MDA-A)) and those who did not (MDA non-achievers (MDA-NA)). Demographics, clinical characteristics, patient-reported outcomes and medication history were compared between groups. Results: Of 148 patients with PsA who met the inclusion criteria, 34 (23.0%) and 114 (77.0%) were classified as MDA-A and MDA-NA, respectively. At baseline, most patients (96.6%) were receiving tumour necrosis factor inhibitors, and both groups were similar in age, sex, race, medication history, enthesitis and dactylitis counts, disease duration and comorbidities. Compared with MDA-A, MDA-NA had significantly worse mean tender joint count (7.2 vs 3.4), patient-reported pain (51.2 vs 35.7), patient-reported fatigue (54.1 vs 42.4), physical function (Health Assessment Questionnaire, 1.0 vs 0.6), Bath Ankylosing Disease Activity Index (5.0 vs 3.4) and Bath Ankylosing Spondylitis Functional Index (4.0 vs 2.0) scores (all p\u3c0.05). Conclusions: Approximately one in four patients achieved MDA with their index biologic at the time of the second follow-up visit. Both groups were similar in several baseline demographic and clinical features; however, patients who did not achieve MDA generally had worse tender joint counts and patient-reported outcomes

Risk of Infection Associated With Subsequent Biologic Agent Use After Rituximab: Results From a National Rheumatoid Arthritis Patient Registry

OBJECTIVE: To assess whether the time between the last rituximab infusion and initiation of a different biologic agent influenced infection risk in patients with rheumatoid arthritis (RA). METHODS: Patients with RA who newly initiated rituximab within the Consortium of Rheumatology Researchers of North America registry were included if they switched to a nonrituximab biologic agent and had \u3e /=1 followup visit within 12 months of switching. Patients were categorized by duration of time between their last rituximab infusion and initiation of a subsequent biologic agent (\u3c /=5 months, 6-11 months, and \u3e /=12 months). The primary outcome was time to first infectious event. Adjusted Cox regression models estimated the association between time to starting a subsequent biologic agent and infection. RESULTS: A total of 44 overall infections (7 serious, 37 nonserious) were reported during the 12-month followup in the 215 patients included in this analysis (104 switched at \u3c /=5 months, 67 at 6-11 months, and 44 at \u3e /=12 months). Median (interquartile range) time to infection was 4 (2-5) months. Infection rates per patient-year in the \u3c /=5-month, 6-11-month, and \u3e /=12-month groups were 0.34 (95% confidence interval [95% CI] 0.22-0.52), 0.30 (95% CI 0.17-0.52), and 0.41 (95% CI 0.22-0.77), respectively. After adjustment, time to switch to a subsequent biologic agent was not associated with infection, which remained unchanged when number and rate of rituximab retreatments were included in the models. CONCLUSION: In this real-world cohort of patients with RA, infection rates ranged from 0.30 to 0.41 per patient-year, with no significant difference in the rate between patients who initiated a subsequent biologic agent earlier versus later after rituximab treatment

Impact of Tocilizumab Monotherapy on Clinical and Patient-Reported Quality-of-Life Outcomes in Patients with Rheumatoid Arthritis

INTRODUCTION: Tocilizumab (TCZ) monotherapy has been proven as an effective treatment for rheumatoid arthritis (RA) in clinical trials. However, there are limited data available regarding the effectiveness of TCZ monotherapy in real-world clinical settings in the United States. The objective of this study was to evaluate the impact of TCZ monotherapy on disease activity and patient-reported outcomes (PROs) in a US-based observational cohort of patients with RA seen in routine clinical practice. METHODS: Eligible patients had active RA, no prior use of TCZ, and initiated TCZ as monotherapy. Changes in disease activity and PROs were assessed 1 year after TCZ initiation for the overall cohort and stratified by number of prior tumor necrosis factor inhibitors (TNFis; 0, 1, or \u3e /=2). Primary outcomes were change in Clinical Disease Activity Index (CDAI); change in patient global disease activity, pain, fatigue; and the proportions of patients with improvement in modified Health Assessment Questionnaire (mHAQ), morning stiffness, and EQ-5D. RESULTS: Of 255 eligible TCZ monotherapy initiators, 9.4% were TNFi naive, 36.5% had one prior TNFi, and 54.1% had \u3e /=2 prior TNFis. Clinical and PRO measures indicated that patients were substantially impacted by their disease at baseline. The median decrease in CDAI from baseline to 1 year was 9.8 and median patient global and pain scores improved by 10 mm, indicative of clinically meaningful improvement; the median fatigue score improved by 5 mm. Approximately 26% of patients reported clinically meaningful improvement in mHAQ, 54% experienced improvement in morning stiffness, and 20% to 36% experienced improvement in EQ-5D domains (walking, self-care, usual activities, pain/discomfort, and anxiety/depression). Improvements were similar across TNFi groups. CONCLUSIONS: Patients with active, refractory RA who initiated TCZ monotherapy experienced improvements in both composite disease activity scores and PROs at 1 year, regardless of prior TNFi exposure. FUNDING: Corrona, LLC and Genentech

Synthesis and Biological Evaluation of Some Novel Substituted N-Benzylideneaniline Derivatives

ABSTRACT N-benzylideneaniline is a class of important compounds in medicinal and pharmaceutical field. Nbenzylideneaniline represents a model aromatic Schiff base and it is also a classic bioisoster of stilbene and resveratrol. Keeping in view the biological importance of N-benzylideneaniline we have synthesized some novel Nbenzylideneaniline derivatives. The prepared compounds were tested for their in vitro antibacterial, antifungal and antioxidant activity. (4-fluoro-benzylidene)-(3,5-dichloro-phenyl)-amine (5i) showed in vitro antibacterial activity comparable to that of the standard Penicillin against Escherichia coli. The results of the in vitro antifungal activity showed that most of the synthesized derivatives have proven their antifungal potential. The results of the in vitro antioxidant tests showed that most of the synthesized compounds showed moderate (%RSA >50%) to mild (%RSA >40%) radical scavenging activity

INSPECT: A Retrospective Study to Evaluate Long-term Effectiveness and Safety of Darvadstrocel in Patients With Perianal Fistulizing Crohn's Disease Treated in the ADMIRE-CD Trial

Background: The efficacy of a single administration of darvadstrocel (expanded allogeneic adipose-derived mesenchymal stem cells) for treating complex perianal fistulas in patients with Crohn's disease was demonstrated in a randomized, double-blind trial (ADMIRE-CD [Adipose Derived Mesenchymal Stem Cells for Induction of Remission in Perianal Fistulizing Crohn's Disease] trial). The current chart review study (INSPECT [A retrospectIve chart review study evaluatINg the longer-term effectiveneSs of darvadstrocel in PatiEnts who CompleTed ADMIRE-CD]) evaluated the longer-term effectiveness and safety of darvadstrocel. Methods: Eligible patients had completed at least 52 weeks in the ADMIRE-CD trial. Data on clinical remission and fistula relapse outcomes were collected retrospectively at 104 and 156 weeks after treatment. Adverse events of special interest (tumorigenicity and ectopic tissue formation) were collected up to 208 weeks after treatment. Results: Eighty-nine patients were included (43 darvadstrocel patients, 46 control subjects). At 52, 104, and 156 weeks posttreatment, clinical remission was observed in 29 (67.4%) of 43, 23 (53.5%) of 43, and 23 (53.5%) of 43 darvadstrocel-treated patients, compared with 24 (52.2%) of 46, 20 (43.5%) of 46, and 21 (45.7%) of 46 control subjects, respectively. In patients with clinical remission at week 52, this remission was sustained at 104 and 156 weeks after treatment in 19 (65.5%) of 29 and 16 (55.2%) of 29 darvadstrocel-treated patients and in 17 (70.8%) of 24 and 13 (54.2%) of 24 control subjects, respectively. Time to fistula relapse and incidence of fistula relapse or new fistula occurrence were not significantly different between groups. Tumorigenicity was reported for 1 (2.2%) patient in the control group (malignant epidermoid carcinoma). No ectopic tissue formation was reported. Conclusions: Real-world follow-up of patients from the ADMIRE-CD trial indicates that clinical remission of complex perianal fistulas can be sustained in the long term irrespective of whether it is achieved through darvadstrocel administration or maintenance treatment regimens and confirms a favorable long-term safety profile of darvadstrocel

Interaction of Kinesin-5 Motor Domain with Tubulin Dimer

Kinesin-5 in fission yeast also known as Cut7 is a molecular motor essential for separation of spindle fibers during the mitotic cell division. Kinesin-5 crosslinks the spindle microtubules and slides them towards the spindle poles. Molecular dynamics simulation was performed, and various analysis were carried out to study the interaction of kinesin-5 motor domain with alpha and beta tubulins. From electrostatic potential distribution, it is observed that binding interface of kinesin-5 motor domain is mainly positive and tubulin dimer is mainly negative, which shows the stronger interaction between them. Further when electric field lines were plotted, we observed more field lines at kinesin-5 motor and beta tubulin interface. Meaning the interaction of kinesin-5 with beta tubulin is stronger. Moreover, the binding energies, salt-bridges, hydrogen bonds, were analyzed in detail, which again supported the stronger interaction of kinesin-5 motor with beta tubulin. Furthermore, key residues at the binding interfaces of kinesin-5 motor domain and tubulin dimers were identified, which are believed to be useful for developing drug against cancerous cells