Impact of Prior Biologic or Janus Kinase Inhibitor Therapy on Efficacy and Safety of Etrasimod in the ELEVATE UC 52 and ELEVATE UC 12 Trials.

BACKGROUND AND AIMS: Etrasimod is an oral, once daily, selective sphingosine 1-phosphate [S1P]1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis [UC]. This subgroup analysis evaluated the efficacy and safety of etrasimod 2 mg once daily vs placebo by prior biologic/Janus kinase inhibitor [bio/JAKi] exposure in ELEVATE UC 52 and ELEVATE UC 12. METHODS: Pre-defined efficacy endpoints were assessed at Weeks 12 and 52 in ELEVATE UC 52 and Week 12 in ELEVATE UC 12 in bio/JAKi-naïve and -experienced patients, and at Week 12 [pooled] based on prior advanced therapy exposure mechanism. RESULTS: In the ELEVATE UC 52 and ELEVATE UC 12 analysis populations, 80/274 [29.2%] and 74/222 [33.3%] patients receiving etrasimod and 42/135 [31.1%] and 38/112 [33.9%] patients receiving placebo, respectively, were bio/JAKi-experienced. In both bio/JAKi-naïve and -experienced patients, a significantly greater proportion receiving etrasimod vs placebo achieved clinical remission (p<0.05) in ELEVATE UC 52 at Weeks 12 [naïve: 30.9% vs 9.7%; experienced: 17.5% vs 2.4%] and 52 [naïve: 36.6% vs 7.5%; experienced: 21.3% vs 4.8%]; in ELEVATE UC 12, this was observed only for bio/JAKi-naïve patients [naïve: 27.7% vs 16.2%, p=0.033; experienced: 18.9% vs 13.2%, p=0.349]. Similar patterns were observed for most efficacy endpoints. Among patients with prior anti-integrin exposure [N=90], a significantly greater proportion achieved clinical response [54.1% vs 27.6%, p=0.030], but not clinical remission [9.8% vs 3.4%, p=0.248], with etrasimod vs placebo. CONCLUSIONS: Bio/JAKi-naïve and -experienced patients had clinically meaningful induction and maintenance treatment benefits with etrasimod vs placebo.

The Effect of Etrasimod on Fecal Calprotectin and High-sensitivity C-reactive Protein: Results From the ELEVATE UC Clinical Program.

BACKGROUND: Biomarkers offer potential alternatives to endoscopies in monitoring ulcerative colitis (UC) progression and therapeutic response. This post hoc analysis of the ELEVATE UC clinical program assessed potential predictive values of fecal calprotectin (fCAL) and high-sensitivity C-reactive protein (hsCRP) as biomarkers and associated responses to etrasimod, an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active UC, in 2 phase 3 clinical trials. METHODS: In ELEVATE UC 52 and ELEVATE UC 12, patients were randomized 2:1 to 2 mg of etrasimod once daily or placebo for 52 or 12 weeks, respectively. Fecal calprotectin/hsCRP differences between responders and nonresponders for efficacy end points (clinical remission, clinical response, endoscopic improvement-histologic remission [EIHR]) were assessed by Wilcoxon P-values. Sensitivity and specificity were presented as receiver operating characteristics (ROC) curves with area under the curve (AUC). RESULTS: In ELEVATE UC 52 and ELEVATE UC 12, 289 and 238 patients received etrasimod and 144 and 116 received placebo, respectively. Baseline fCAL/hsCRP concentrations were generally balanced. Both trials had lower week-12 median fCAL levels in week-12 responders vs nonresponders receiving etrasimod for clinical remission, clinical response, and EIHR (all P < .001), with similar trends for hsCRP levels (all P < .01). For etrasimod, AUCs for fCAL/hsCRP and EIHR were 0.85/0.74 (week 12; ELEVATE UC 52), 0.83/0.69 (week 52; ELEVATE UC 52), and 0.80/0.65 (week 12; ELEVATE UC 12). CONCLUSIONS: Fecal calprotectin/hsCRP levels decreased with etrasimod treatment; ROC analyses indicated a prognostic correlation between fCAL changes during induction and short-/long-term treatment response.

We show associations between fecal calprotectin (fCAL) and high-sensitivity C-reactive protein (hsCRP) levels with efficacy outcomes among patients receiving 2 mg of etrasimod once daily, and that fCAL levels may be an early indicator of the achievement of long-term efficacy end point achievement.

Histological Outcomes And Jak-Stat Signalling In Ulcerative Colitis Patients Treated With Tofacitinib.

BACKGROUND AND AIMS: Histological outcomes and JAK-STAT signaling were assessed in a prospective ulcerative colitis (UC) patient cohort after 8 weeks treatment with tofacitinib, an oral Janus kinase (JAK) inhibitor. METHODS: Forty UC patients received tofacitinib 10 mg twice daily for 8 weeks. Treatment response was defined as histo-endoscopic mucosal improvement (HEMI). Histological remission was defined as a Robarts Histopathology Index (RHI) ≤3 points and histological response as 50% decrease in RHI. Mucosal expression of JAK1-3, Tyrosine kinase 2 (TYK2) and total signal transducer and activator of transcription (STAT) 1-6 were assessed using immunohistochemistry (IHC). RESULTS: At baseline, the median RHI was 14 (interquartile range (IQR) 10-19). Twenty-six of 40 (65%) patients had severe endoscopic disease (endoscopic Mayo score 3) and 31/40 (78%) failed prior anti-TNF treatment. At week 8, 15 patients (38%) had HEMI, 23 patients (58%) histological remission and 34 (85%) histological response. RHI decreased by a median of 14 points (IQR 9-21) in responders (p<0.001) and by 6 points (IQR 0-13) in non-responders (p=0.002). STAT1, STAT3 and STAT5 expression levels decreased significantly in the whole cohort. Responders had lower week 8 STAT1 expression levels compared to non-responders (0.2%, IQR 0.1-2.8 vs 4.3%, IQR 1.2-11.9, p=0.001), suggesting more profound STAT1 blockade. A trend of higher baseline JAK2 expression was observed in tofacitinib non-responders (2.7%, IQR 0.1-7.7) compared to responders (0.4%, IQR 0.1-2.1). CONCLUSIONS: Tofacitinib treatment resulted in histological improvement in the majority of UC patients and a substantial decrease of STAT1, STAT3 and STAT5 expression. HEMI was associated with more profound suppression of STAT1.

Risk of Venous Thromboembolism With Tofacitinib Versus Tumor Necrosis Factor Inhibitors in Cardiovascular Risk-Enriched Rheumatoid Arthritis Patients.

OBJECTIVE: The ORAL Surveillance trial found a dose-dependent increase in venous thromboembolism (VTE) and pulmonary embolism (PE) events with tofacitinib versus tumor necrosis factor inhibitors (TNFi). We aimed to assess VTE incidence over time and explore risk factors of VTE, including disease activity, in ORAL Surveillance. METHODS: Patients with rheumatoid arthritis (RA) aged 50 years or older with at least one additional cardiovascular risk factor received tofacitinib 5 or 10 mg twice daily (BID) or TNFi. Post hoc, cumulative probabilities and incidence rates (patients with first events/100 patient-years) by 6-month intervals were estimated for adjudicated VTE, deep vein thrombosis, and PE. Cox regression models identified risk factors. Clinical Disease Activity Index leading up to the event was explored in patients with VTE. RESULTS: Cumulative probabilities for VTE and PE were higher with tofacitinib 10 mg BID, but not 5 mg BID, versus TNFi. Incidence rates were consistent across 6-month intervals within treatments. Across treatments, risk factors for VTE included prior VTE, body mass index greater than or equal to 35 kg/m2, older age, and history of chronic lung disease. At the time of the event, most patients with VTE had active disease as defined by Clinical Disease Activity Index. CONCLUSION: Incidences of VTE and PE were higher with tofacitinib (10 > 5 mg BID) versus TNFi and were generally consistent over time. Across treatments, VTE risk factors were aligned with previous studies in the general RA population. These data highlight the importance of assessing VTE risk factors, including age, body mass index, and VTE history, when considering initiation of tofacitinib or TNFi in patients with active RA.

An Insight into Patients' Perspectives of Ulcerative Colitis Flares via Analysis of Online Public Forum Posts.

BACKGROUND: The knowledge of patients' perceptions of factors contributing to ulcerative colitis (UC) flares is limited; however, online patient communications could offer insight. This analysis aimed to identify the most frequent patient-reported triggers and symptoms of UC flares, which could highlight potential interventions for outcome improvement. METHODS: Online posts written pre- and postflare by patients with UC on 8 public forums in 6 countries between January 1, 2019, and February 14, 2021, were identified using flare-related keywords. Flare-related posts were captured and Netbase Quid™ artificial intelligence text analytics and natural language processing software were used to semantically map and identify commonly discussed themes and topics (subsets of themes). RESULTS: Of >27 000 patient posts, 12 900 were identified as flare related. The most frequent themes were treatment experiences and side effects (28.5% of posts), followed by flare symptoms (22.9% of posts). The most frequent topic was emotional/peer support (9.4% of posts), followed by experiences with mesalamine (and other oral/rectal formulations; 8.0% of posts), and dietary recommendations (6.0% of posts). Stress and anxiety were the most frequently reported flare triggers (37.9% of posts), followed by diet (28.4% of posts). Stress and anxiety were frequently identified as both triggers for, and general symptoms of, flare. Blood in the stool was the most discussed flare indicator (57.8% of posts). CONCLUSIONS: Frequently discussed patient-perceived triggers of UC flares included diet, stress, and anxiety. These results suggest that physicians could incorporate a broader and more holistic approach to UC monitoring and management than is currently practiced.

The patient-reported triggers of flares that were most frequently discussed in online forum posts are not routinely monitored during ulcerative colitis management, emphasizing the need for physicians to incorporate a broader, more holistic approach to ulcerative colitis management than currently practiced.

Presence of risk factors associated with colectomy among patients with ulcerative colitis: a post hoc analysis of data from the tofacitinib OCTAVE ulcerative colitis clinical program.

Background: Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Objective: To assess colectomy incidence rates (IRs) and baseline characteristics for the presence of identified colectomy risk factors among patients in the tofacitinib OCTAVE UC clinical program. Design: This post hoc analysis evaluated patients in the 8-week OCTAVE Induction 1 and 2, 52-week OCTAVE Sustain, and OCTAVE Open (open-label, long-term extension) studies. Methods: IRs [95% confidence interval (CI)] for colectomy were analyzed. Baseline risk factors based on clinical guidelines: aged <40 years at diagnosis, extensive colitis, severe endoscopic disease [Mayo endoscopic subscore (MES) = 3], hospitalization for UC within 12 months, C-reactive protein (CRP) >3 mg/L, and serum albumin <3.5 g/dL. Baseline risk factors were evaluated in patients who underwent colectomy by study and summarized descriptively. Results: Over a maximum of 7.8 years of tofacitinib exposure, 14 patients underwent colectomy: 3/1139 (0.3%) in OCTAVE Induction 1 and 2 [tofacitinib 10 mg twice daily (BID): n = 2; placebo: n = 1], 3/593 (0.5%) in OCTAVE Sustain (placebo: n = 3), and 8/944 (0.8%) in OCTAVE Open (tofacitinib 10 mg BID: n = 8). Colectomy IR per 100 patient-years for all patients who received ⩾1 tofacitinib dose was 0.34 (95% CI: 0.16-0.63). All patients who underwent colectomy had ⩾1 risk factor and prior tumor necrosis factor inhibitor (TNFi) failure, among which the most common risk factors were a MES of 3 (n = 13), CRP >3 mg/L (n = 11), and aged <40 years at diagnosis (n = 9). Conclusions: Among patients with moderate to severe UC receiving tofacitinib, colectomies were infrequent; all patients undergoing colectomy had prior TNFi failure, and most had multiple additional risk factors. This provides important information to discuss with patients and inform management decisions. Registration: NCT01465763; NCT01458951; NCT01458574; and NCT01470612.

Improvements in Disease Activity Partially Mediate the Effect of Tofacitinib Treatment on Generic and Disease-Specific Health-Related Quality of Life in Patients with Ulcerative Colitis: Data from the OCTAVE Program.

BACKGROUND: Patients with ulcerative colitis (UC) often report impaired health-related quality of life (HRQoL). Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of UC. In addition to previous demonstrations of improved clinical measures (e.g., Mayo score), tofacitinib has been shown to improve HRQoL in patients with UC. This analysis explored the interrelationships among tofacitinib treatment, HRQoL, and disease activity (measured using Mayo subscores) using mediation modeling. METHODS: Data were collected from two 8-week induction studies (OCTAVE Induction 1 and 2) in patients with moderate to severe UC treated with tofacitinib or placebo. Two mediation models were specified. First, Mayo subscores were mediators between the binary treatment variable (tofacitinib vs. placebo) and the eight Short Form-36 Health Survey (SF-36) domain scores as outcomes. Second, the four Inflammatory Bowel Disease Questionnaire (IBDQ) domain scores served as outcomes. Both models used data collected at week 8. RESULTS: Overall, 1,073 and 1,079 patients were included in the SF-36- and IBDQ-based models, respectively. For all SF-36 domains, improvements in Mayo subscores were estimated to explain 65.6% (bodily pain) to 92.9% (mental health) of the total treatment effect on SF-36 domain scores (all p < 0.05). For all IBDQ domains, improvements in Mayo subscores explained 71.6% (systemic symptoms) to 84.7% (emotional function) of the total treatment effect (all p < 0.05). CONCLUSION: Mayo scores and Mayo subscores are significant but incomplete contributors to tofacitinib's effect on HRQoL in patients with moderate to severe UC. CLINICALTRIALS: gov: NCT01465763; NCT01458951.

Clostridium difficile Infection in Patients with Ulcerative Colitis Treated with Tofacitinib in the Ulcerative Colitis Program.

BACKGROUND: Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Patients with inflammatory bowel disease are susceptible to Clostridium difficile infection (CDI). Here, we evaluate CDI in the tofacitinib UC clinical program. METHODS: Events from 4 randomized, placebo-controlled studies (phase [P] 2 or P3 induction [NCT00787202; NCT01465763; NCT01458951], P3 maintenance [NCT01458574]) and an open-label, long-term extension (OLE) study (NCT01470612), were analyzed as 3 cohorts: Induction (P2/P3 induction), Maintenance (P3 maintenance), and Overall (patients receiving tofacitinib 5 or 10 mg twice daily [BID] in P2, P3, and OLE studies; including final data from the OLE study, as of August 24, 2020). Proportions and incidence rates (unique patients with events per 100 patient-years of exposure) of CDI were evaluated. RESULTS: The overall cohort comprised 1157 patients who received ≥1 dose of tofacitinib 5 or 10 mg BID, with a total of 2814.4 patient-years of tofacitinib exposure and up to 7.8 years of treatment. A total of 82.6% of patients received predominantly tofacitinib 10 mg BID. In the induction, maintenance, and overall cohorts, 3 (2 tofacitinib treated, 1 placebo treated), 3 (all placebo treated), and 9 patients had CDI, respectively; the overall cohort incidence rate was 0.31 (95% confidence interval, 0.14-0.59). CDI were all mild-moderate in severity and resolved with treatment in 8 patients. Six of 9 patients continued tofacitinib treatment without interruption. Two patients had events reported as serious due to hospitalization. Two patients were receiving corticosteroids when the CDI occurred. CONCLUSION: CDIs among patients with UC receiving tofacitinib were infrequent, cases were mild-moderate in severity, and most resolved with treatment.

The incidence of Clostridium difficile infection in the tofacitinib ulcerative colitis clinical program was evaluated. C. difficile infection among patients with ulcerative colitis receiving tofacitinib were infrequent; cases were mild­moderate in severity, and most resolved with treatment.

Effectiveness and Safety of Tofacitinib in Canadian Patients With Rheumatoid Arthritis: Primary Results From a Prospective Observational Study.

OBJECTIVE: The Canadian Tofacitinib for Rheumatoid Arthritis Observational (CANTORAL) is the first Canadian prospective, observational study assessing tofacitinib. The objective was to assess effectiveness and safety for moderate to severe rheumatoid arthritis (RA). Coprimary and secondary outcomes are reported from an interim analysis. METHODS: Patients initiating tofacitinib from October 2017 to July 2020 were enrolled from 45 Canadian sites. Coprimary outcomes (month 6) included the Clinical Disease Activity Index (CDAI)-defined low disease activity (LDA) and remission. Secondary outcomes (to month 18) included the CDAI and the 4-variable Disease Activity Score in 28 joints (DAS28) using the erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP) level to define LDA and remission; the proportions of patients achieving mild pain (visual analog scale <20 mm), and moderate (≥30%) and substantial (≥50%) pain improvements; and the proportions of patients achieving a Health Assessment Questionnaire disability index (HAQ DI) score greater or equal to normative values (≤0.25) and a HAQ DI score greater or equal to minimum clinically important difference (MCID) (≥0.22). Safety was assessed to month 36. RESULTS: Of 504 patients initiating tofacitinib, 44.4% received concomitant methotrexate. At month 6, 52.9% and 15.4% of patients were in CDAI-defined LDA and remission, respectively; a similar proportion of patients achieved outcomes by month 3 (first post-baseline assessment). By month 3, 27.2% and 41.7% of patients, respectively, were in DAS28-ESR-defined LDA and DAS28-CRP <3.2; 14.7% and 25.8% achieved DAS28-ESR remission and DAS28-CRP <2.6. By month 3, mild pain and moderate and substantial pain improvements occurred in 29.6%, 55.6%, and 42.9% of patients, respectively; 19.9% and 53.7% of patients achieved a HAQ DI score greater than or equal to normative values and a HAQ DI score greater than or equal to MCID, respectively. Outcomes were generally maintained to month 18. Incidence rates (events per 100 patient-years) for treatment-emergent adverse events (AEs), serious AEs, and discontinuations due to AEs were 126.8, 11.9, and 14.5, respectively, and AEs of special interest were infrequent. CONCLUSION: Tofacitinib was associated with early and sustained improvement in RA signs and symptoms in real-world patients. Effectiveness and safety were consistent with the established tofacitinib clinical profile.

Influenza Adverse Events in Patients with Rheumatoid Arthritis, Ulcerative Colitis, or Psoriatic Arthritis in the Tofacitinib Clinical Development Programs.

INTRODUCTION: This post hoc analysis evaluated influenza adverse events (AEs) across rheumatoid arthritis (RA), ulcerative colitis (UC), and psoriatic arthritis (PsA) tofacitinib clinical programs. METHODS: Available data from phase 1, randomized phase 2/3/3b/4 clinical trials (completed by 2018), and long-term extension (LTE) studies (up to May 2019) in patients with RA, UC, and PsA were included [randomized or Overall (phase 1-3b/4 and LTE studies) tofacitinib cohorts]. Incidence rates (IRs; events per 100 patient-years) of combined influenza AEs (seasons 2004/2005 to 2018/2019) were analyzed, including by tofacitinib dose [5 or 10 mg twice daily (BID)] and age (< 65 versus ≥ 65 years). Logistic regression models evaluated risk factors for influenza AEs in the RA Overall tofacitinib cohort. RESULTS: In randomized cohorts, combined influenza AE IRs were generally similar across tofacitinib, adalimumab, methotrexate, and placebo groups, across indications. Among Overall tofacitinib cohorts, combined influenza AE IRs with tofacitinib 5/10 mg BID, respectively, were higher in the UC (3.66/5.09) versus RA (2.38/2.19) and PsA (1.74/1.29) cohorts. IRs were generally similar across tofacitinib dose and age groups. Most influenza AEs were nonserious and did not require changes to tofacitinib treatment. Significant risk factors for influenza AEs in patients with RA were geographic region, baseline oral corticosteroid and methotrexate use, and tofacitinib dose. CONCLUSIONS: In the RA, UC, and PsA clinical programs, combined influenza AE IRs were highest in UC, while in each indication they were generally similar across tofacitinib, placebo, and comparator groups. Influenza AEs were predominantly nonserious and not associated with changes to tofacitinib treatment. TRIAL REGISTRATION NUMBERS: NCT01262118, NCT01484561, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT02147587, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT02281552, NCT02187055, NCT02831855, NCT00413699, NCT00661661, NCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612, NCT01877668, NCT01882439, NCT01976364.

Long-Term Improvement in the Patient-Reported Outcomes of Rectal Bleeding, Stool Frequency, and Health-Related Quality of Life with Tofacitinib in the Ulcerative Colitis OCTAVE Clinical Program.

BACKGROUND: Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). The tofacitinib OCTAVE clinical program included phase III induction (OCTAVE Induction 1 and 2) and maintenance (OCTAVE Sustain) studies, and an open-label, long-term extension study (OCTAVE Open). OBJECTIVE: This post hoc analysis assessed selected long-term, disease-specific patient-reported outcome (PRO) and health-related quality-of-life (HRQoL) measurements in patients with UC receiving tofacitinib in the OCTAVE clinical program. METHODS: Analyses included patients from OCTAVE Open assigned to tofacitinib 5 mg twice daily (subpopulation in remission at Week 52 of OCTAVE Sustain). OCTAVE Open data from the final analyses are shown to Month 48. Endpoints included rectal bleeding subscore (RBS) = 0, stool frequency subscore (SFS) ≤ 1, and HRQoL measure, Inflammatory Bowel Disease Questionnaire (IBDQ) remission (IBDQ total score ≥ 170); with non-responder imputation for missing data at all visits, and last observation carried forward for visits after a patient advanced to the next study (NRI-LOCF). Observed cases were also assessed. RESULTS: At Month 48, of 175 patients, 95 (54.3%) and 96 (54.9%) achieved/maintained RBS = 0 and SFS ≤ 1, respectively (NRI-LOCF). Additionally, 93 (53.1%) patients achieved/maintained IBDQ remission at Month 48 (NRI-LOCF). CONCLUSIONS: Among patients who entered OCTAVE Open in remission, most maintained normalization of rectal bleeding and improvement in stool frequency for ≤ 4 years of follow-up in OCTAVE Open. IBDQ remission was also generally maintained in OCTAVE Open. These data show robust maintenance of key UC PROs and durability of response with tofacitinib 5 mg twice daily. TRIAL REGISTRATION: http://www. CLINICALTRIALS: gov (NCT01465763 [21/10/2011]; NCT01458951 [21/10/2011]; NCT01458574 [21/10/2011]; NCT01470612 [21/10/2011]).

Predictors of Sustained Response With Tofacitinib Therapy in Patients With Ulcerative Colitis.

BACKGROUND: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis. We evaluate baseline characteristics as predictors of sustained response and remission in patients with ulcerative colitis receiving tofacitinib maintenance therapy. METHODS: Patients with clinical response following OCTAVE Induction 1 and 2 entered OCTAVE Sustain and were rerandomized to receive tofacitinib 5 or 10 mg twice daily or placebo. Baseline characteristics were stratified by week 52 efficacy endpoints (remission, sustained remission, clinical response, sustained clinical response). Associations between baseline characteristics and efficacy endpoints were evaluated using logistic regression analyses. RESULTS: Overall, 170 of 487 (34.9%) patients were in remission at week 52. In multivariable modeling, endoscopic subscore at baseline of OCTAVE Induction 1 and 2 (2 vs 3; odds ratio [OR], 1.60; 95% confidence interval [CI], 1.06-2.44]), partial Mayo score (<2 vs ≥2; OR, 1.92; 95% CI, 1.27-2.90), and age (per 10-years; OR, 1.19; 95% CI, 1.02-1.39) at baseline of OCTAVE Sustain (following 8 weeks' tofacitinib induction therapy) were associated with higher odds of remission at week 52. Oral corticosteroid use (OR, 0.63; 95% CI, 0.42-0.96) and C-reactive protein (per unit; OR, 0.94; 95% CI, 0.89-0.99) at baseline of OCTAVE Sustain were associated with reduced likelihood of remission at week 52. In general, opposite associations were observed for time to loss of response. CONCLUSION: Patients with greater clinical improvement after 8 weeks of tofacitinib induction therapy are more likely to maintain response or remission with tofacitinib regardless of dose received during maintenance, highlighting the importance of a robust response to induction therapy.

Identification of Distinct Disease Activity Trajectories in Methotrexate-Naive Patients With Rheumatoid Arthritis Receiving Tofacitinib Over Twenty-Four Months.

OBJECTIVE: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). To better understand tofacitinib treatment responses, we used group-based trajectory modeling to investigate distinct disease activity trajectories and associated baseline variables in patients with active RA. METHODS: This post hoc analysis used data from a phase III study of methotrexate-naive patients receiving tofacitinib 5 mg twice daily. Changes in the 4-variable Disease Activity Score in 28 joints, using the erythrocyte sedimentation rate (DAS28-ESR) from baseline to month 24 were used in group-based trajectory modeling to identify distinct disease activity trajectories. Patient and disease characteristics, changes in radiographic progression and patient-reported outcomes, and safety up to month 24 were compared among trajectory groups. RESULTS: From 346 methotrexate-naive patients, 5 disease trajectory groups, defined by DAS28-ESR scores, were identified, which progressed from high disease activity (HDA) to remission (group 1, n = 28), to low disease activity (LDA) rapidly (group 2, n = 107), to moderate disease activity (group 3, n = 98), to LDA gradually (group 4, n = 46), or remained in HDA (group 5, n = 67), at month 24. At baseline, groups 1 and 2 generally had lower disease activity and more favorable patient-reported outcomes, compared with other groups. Improvements in radiographic progression and patient-reported outcomes over 24 months were generally consistent with DAS28-ESR-predicted disease activity trajectories. Adverse event rates were generally comparable across groups. CONCLUSION: Distinct phenotypic subgroups identified heterogeneity in patients with RA normally analyzed as a single population. Trajectory modeling may enable separation of clinically meaningful subsets of patients with RA, and may help optimize treatment outcomes.

Cost-utility analysis of a multidisciplinary strategy to manage osteoarthritis of the knee: economic evaluation of a cluster randomized controlled trial study.

OBJECTIVE: To determine if a pharmacist-initiated multidisciplinary strategy provides value for money compared to usual care in participants with previously undiagnosed knee osteoarthritis. METHODS: Pharmacies were randomly allocated to provide either 1) usual care and a pamphlet or 2) intervention care, which consisted of education, pain medication management by a pharmacist, physiotherapy-guided exercise, and communication with the primary care physician. Costs and quality-adjusted life-years (QALYs) were determined for patients assigned to each treatment and incremental cost-effectiveness ratios (ICERs) were determined. RESULTS: From the Ministry of Health perspective, the average patient in the intervention group generated slightly higher costs compared with usual care. Similar findings were obtained when using the societal perspective. The intervention resulted in ICERs of $232 (95% confidence interval [95% CI] -1,530, 2,154) per QALY gained from the Ministry of Health perspective and $14,395 (95% CI 7,826, 23,132) per QALY gained from the societal perspective, compared with usual care. CONCLUSION: A pharmacist-initiated, multidisciplinary program was good value for money from both the societal and Ministry of Health perspectives.

Does physical activity reduce seniors' need for healthcare?: a study of 24 281 Canadians.

OBJECTIVES: Physical inactivity has been associated with significant increases in disease morbidity and mortality. This study assessed the association between physical activity and (1) health resource use and (2) health resource use costs. DESIGN AND PARTICIPANTS: The responses from 24 281 respondents >65 years to the Canadian Community Health Survey Cycle 1.1 were used to find activity levels and determine health resource use and costs. Logistic regression models were used to assess risks of hospitalisation. RESULTS: Physical inactivity was associated with statistically significant increases to hospitalisations, lengths of stay and healthcare visits (p<0.01). Average healthcare costs (based on the 2007 value of the Canadian dollar) for the physically inactive were $C1214.15 higher than the healthcare costs of the physically active ($C2005.27 vs $C791.12, p<0.01). CONCLUSION: Among those >65 years, physical activity is strongly associated with reduced health resource use and costs.

Meta-analysis of the impact of 9 medication classes on falls in elderly persons.

BACKGROUND: There is increasing recognition that the use of certain medications contributes to falls in seniors. Our objective was to update a previously completed meta-analysis looking at the association of medication use and falling to include relevant drug classes and new studies that have been completed since a previous meta-analysis. METHODS: Studies were identified through a systematic search of English-language articles published from 1996 to 2007. We identified studies that were completed on patients older than 60 years, looking at the association between medication use and falling. Bayesian methods allowed us to combine the results of a previous meta-analysis with new information to estimate updated Bayesian odds ratios (ORs) and 95% credible intervals (95% CrIs) RESULTS: Of 11 118 identified articles, 22 met our inclusion criteria. Meta-analyses were completed on 9 unique drug classes, including 79 081 participants, with the following Bayesian unadjusted OR estimates: antihypertensive agents, OR, 1.24 (95% CrI, 1.01-1.50); diuretics, OR, 1.07 (95% CrI, 1.01-1.14); beta-blockers, OR, 1.01 (95% CrI, 0.86-1.17); sedatives and hypnotics, OR, 1.47 (95% CrI, 1.35-1.62); neuroleptics and antipsychotics, OR, 1.59 (95% CrI, 1.37-1.83); antidepressants, OR, 1.68 (95% CrI, 1.47-1.91); benzodiazepines, OR, 1.57 (95% CrI, 1.43-1.72); narcotics, OR, 0.96 (95% CrI, 0.78-1.18); and nonsteroidal anti-inflammatory drugs, OR, 1.21 (95% CrI, 1.01-1.44). The updated Bayesian adjusted OR estimates for diuretics, neuroleptics and antipsychotics, antidepressants, and benzodiazepines were 0.99 (95% CrI, 0.78-1.25), 1.39 (95% CrI, 0.94-2.00), 1.36 (95% CrI, 1.13-1.76), and 1.41 (95% CrI, 1.20-1.71), respectively. Stratification of studies had little effect on Bayesian OR estimates, with only small differences in the stratified ORs observed across population (for beta-blockers and neuroleptics and antipsychotics) and study type (for sedatives and hypnotics, benzodiazepines, and narcotics). An increased likelihood of falling was estimated for the use of sedatives and hypnotics, neuroleptics and antipsychotics, antidepressants, benzodiazepines, and nonsteroidal anti-inflammatory drugs in studies considered to have "good" medication and falls ascertainment. CONCLUSION: The use of sedatives and hypnotics, antidepressants, and benzodiazepines demonstrated a significant association with falls in elderly individuals.

Potential cost-effectiveness of annual influenza immunization for infants and toddlers: experience from Canada.

BACKGROUND: In 2004, expert groups in North America recommended annual influenza immunization for healthy infants and toddlers aged 6-23 months with a goal of reducing high hospitalization rates (HR). We assess cost-effectiveness of this program in Canada. METHODS: Analysis was from third-party payer and societal perspectives in preventing hospitalization and other outcomes among 500,000 vaccinated or non-vaccinated infants/toddlers. Base-case assumptions include: 25% attack rate (AR), 1% case hospitalization rate (HR), 0.002% case fatality, vaccine effectiveness (VE) of 66%, CDN dollar 15 per dose for vaccine and administration, half of mothers requiring 2h from work per dose to immunize and two doses required by 100% (first year) or 33% (subsequent years) of infants/toddlers immunized. RESULTS: After the first year, infant/toddler influenza immunization costs the third-party approximately CDN dollar 9 per day of illness averted, CDN dollar 120 per physician visit averted, CDN dollar 7000 per hospitalization averted, CDN dollar 3 million per death averted and CDN dollar 450,000 per life year gained. Corresponding costs from societal perspective are approximately CDN dollar 3, CDN dollar 45, CDN dollar 2500, CDN dollar 1 million and CDN dollar 170,000. The program becomes cost-saving from the third-party perspective at AR>55%, HR>4%, or cost per dose (for vaccine and its administration) 74%. CONCLUSIONS: In the base case, infant/toddler influenza immunization is not cost-saving but could become more cost-effective in settings of higher attack rate and lower immunization cost. In this context, immunization of children in daycare or other group settings should be preferentially considered. Economic analyses should routinely inform expansions to influenza immunization programs.

A comparison of generic, indirect utility measures (the HUI2, HUI3, SF-6D, and the EQ-5D) and disease-specific instruments (the RAQoL and the HAQ) in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a common, chronic disease where health-related quality of life (HRQL) is one of the main goals of therapy. As such, instruments used to measure HRQL in RA must be able to discriminate across RA severity. The two basic categories of instruments used to measure HRQL are generic instruments and disease-specific instruments. Generic instruments can be further subdivided into preference-based measures which yield both single and multi-attribute utility values anchored at zero (death) and 1.00 (perfect health) as a measure of HRQL. The scores from these types of instruments can be integrated into cost-utility analyses as the weightings for quality adjusted life years. We assessed the construct validity of utility scores from four generic preference-based measures (the Health Utilities Index 2 and 3 (HUI2, HUI3), the EuroQol 5D (EQ-5D), and the Short Form 6-D (SF-6D) and disease specific measures (the Rheumatoid Arthritis Quality of Life Questionnaire (RAQoL) and the Health Assessment Questionnaire (HAQ)) in a sample of 313 RA patients in British Columbia, Canada. We also estimated the minimally important differences (MID) for each of the measures. Generally, as anticipated, the disease-specific measures were better able to discriminate across groups with higher RA severity; however, utility scores from each of the scales also appeared to discriminate well across RA severity categories. The MID values agreed with those previously reported in the literature for the HUI2, SF-6D and the HAQ and provided new information for the HUI3, EQ-5D and the RAQoL. We conclude that the all of the preference-based utility measures that were evaluated appear to adequately discriminate across levels of RA severity.