5-year efficacy and safety of secukinumab in patients with ankylosing spondylitis: end-of-study results from the phase 3 MEASURE 2 trial.

BACKGROUND: Secukinumab, a fully human monoclonal antibody that directly inhibits interleukin 17A, has shown significant and sustained improvement in the signs and symptoms of ankylosing spondylitis over 3 years in the MEASURE 2 study. We report the 5-year (end-of-study) results of subcutaneous secukinumab 150 mg in the MEASURE 2 study. METHODS: MEASURE 2 was a phase 3, double-blind, randomised, placebo-controlled, study done in 13 countries and 53 centres. Patients with ankylosing spondylitis who were 18 years of age or older and fulfilled the modified New York criteria were randomly assigned to receive secukinumab (150 mg or 75 mg) or placebo subcutaneously at baseline and weeks 1, 2, and 3, and then every 4 weeks from week 4. At week 16, patients initially given placebo were randomly assigned again (placebo switchers) to receive secukinumab 150 mg or 75 mg. Efficacy results are reported for patients initially randomised to secukinumab 150 mg and those who switched from placebo to secukinumab 150 mg at week 16. An optional dose escalation from secukinumab 75 mg to 150 mg was initiated beginning week 140. We assessed efficacy endpoints at week 260 (5 years), including Assessment of Spondyloarthritis International Society (ASAS) 20 and ASAS 40, inactive disease according to ankylosing spondylitis disease activity score with C-reactive protein (ASDAS-CRP), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), BASDAI50, Bath Ankylosing Spondylitis Metrology Index, Bath Ankylosing Spondylitis Functional Index, Short Form-36 Physical Component Summary, and ASAS partial remission. Analyses were stratified by anti-tumour necrosis factor (TNF) status (anti-TNF-naive and anti-TNF inadequate response). The safety analysis included all patients who received one dose or more of secukinumab. We report data as observed without accounting for missing data. The MEASURE 2 study was registered with ClinicalTrials.gov, NCT01649375. FINDINGS: 219 patients were randomly assigned during the trial and 150 (68%) completed 5 years of treatment, including 82 (77%) of 106 patients in the secukinumab 150 mg group and 68 (65%) of 105 in the secukinumab 75 mg group. Efficacy analysis in the secukinumab 150 mg group included 53 patients who completed the study and one additional patient who was assessed in the treatment period weeks 212-260, but did not complete the study. 134 (61%) of 219 patients were anti-TNF-naive and 85 (39%) were anti-TNF inadequate responders. ASAS responses at 5 years with secukinumab 150 mg were 36 (67%) of 54 patients (ASA20) and 27 (50%) patients (ASAS40). Sustained improvement was observed across other efficacy endpoints with secukinumab 150 mg at 5 years. At 5 years, the proportion of patients achieving efficacy endpoints of BASDAI 50 response was 53% (44/83); ASAS 5/6 response was 51% (42/83); ASDAS-CRP inactive disease was 21% (17/81); and ASAS partial remission was 25% (21/83). Exposure-adjusted incidence rates with any secukinumab dose for selected adverse events were 1·0 per 100 patient-years (95% CI 0·4-1·9) for Candida infections, 0·5 (0·1-1·2) for Crohn's disease, 0·4 (0·1-1·1) for ulcerative colitis, 0·6 (0·2-1·4) for major adverse cardiovascular events, 0·5 (0·1-1·2) for uveitis, and 0·6 (0·2-1·4) for malignant or unspecified tumours. INTERPRETATION: Secukinumab 150 mg provided sustained improvement in the signs, symptoms, and physical function in patients with ankylosing spondylitis after 5 years of treatment. The safety profile of secukinumab remained consistent with previous reports. FUNDING: Novartis Pharma.

Secukinumab shows sustained efficacy and low structural progression in ankylosing spondylitis: 4-year results from the MEASURE 1 study.

OBJECTIVE: To evaluate the effect of secukinumab, a fully human anti-interleukin-17A monoclonal antibody, on efficacy, imaging outcomes, and safety through 4 years (208 weeks) in patients with ankylosing spondylitis. METHODS: Patients opting to enrol had completed 2 years' treatment in the MEASURE 1 core study with subcutaneous secukinumab 150 or 75 mg every 4 weeks (q4Wk), following intravenous loading to Week (Wk) 4, or placebo treatment to Wk16/24. Up-titration from secukinumab 75-150 mg q4Wk was permitted following a protocol amendment. Efficacy is reported for patients originally randomized to secukinumab. Radiographic changes were assessed using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) and changes in MRI measures of inflammation using the Berlin scoring method. Safety and tolerability were evaluated. RESULTS: Among 274 extension study participants, 89.7% (78/87) and 93.0% (93/100) originally randomized to secukinumab 150 and 75 mg, respectively, completed 208Wk. Through Wk208, Assessment of Spondyloarthritis International Society 20/40 (observed) were 79.7%/60.8% (150 mg), 71.0%/43.5% (75 mg) and 80.0%/76% (up-titrators; n = 25). Mean (s.d.) changes in mSASSS were 1.2 (3.91) (150 mg), 1.8 (4.32) (75 mg) and 1.6 (5.67) (up-titrators). No radiographic progression (mSASSS change from Baseline < 2) was observed in 79% of patients receiving either secukinumab dose. Exposure-adjusted incidence rates per 100 patient-years were: serious infections (1.0), Candida infections (0.4), Crohn's disease (0.6), ulcerative colitis (0.2), and malignant/unspecified tumours (0.5), with no new safety signals. CONCLUSION: Through 4 years, secukinumab provided sustained efficacy on signs and symptoms, and MRI outcomes, a low rate of radiographic progression and a consistent safety profile. TRIAL REGISTRATION: NCT01863732.

LFA-1 expression in a series of colorectal adenocarcinomas.

INTRODUCTION: LFA-1 is an adhesion molecule which belongs to the ß2-integrin family. Overexpression of LFA-1 in hepatic natural killer cells has been associated with increased apoptosis of neoplastic cells in colorectal cancer (CRC); moreover, studies in CRC have linked LFA-1 overexpression in neoplastic cells with vascular intrusion through adhesion to endothelial cells, thus implying a possible role in creation of metastases. AIMS AND METHODS: We studied the expression of LFA-1 in a series of 82 patients with CRC. A standard three-step immunohistochemical analysis was performed on formalin-fixed, paraffin-embedded tissue sections. An IgG2a anti-CD11a monoclonal antibody was used. Cases were characterized according to clinicopathological variables including sex, age, tumor localization, size, grade, Dukes stage, wall invasion, and presence of metastatic lymph nodes (mLNs) or distal metastases. RESULTS: LFA-1 was expressed at the primary tumor site in 51 cases and 6/33 cases with metastatic lymphnodes. In Dukes D cases (n = 4), only one case was LFA-1(+). LFA-1 expression at the primary tumor site was associated with the absence of metastatic disease and with Dukes B stage. However, in those cases with LFA-1 expression in cancer cells in mLNs, this was associated with its expression at the primary tumor site. CONCLUSION: The positive association of LFA-1 expression in mLNs when the primary tumor site is also LFA-1(+) could imply an adaptation advantage of this specific cellular clone to its micro-environment, predisposing it to creation of mLNs, pointing to a role for LFA-1 in creation of mLNs in CRC.

A pilot quality improvement intervention in patients with diabetes and hypertension in primary care settings of Cyprus.

BACKGROUND: The achievement of quality of care constitutes a priority for modern health care systems. The objective of our study was to evaluate a quality improvement intervention in primary care of Cyprus. METHODS: In a two-arm non-randomized controlled study in primary care centres in Cyprus, all patients with hypertension (HTN) and diabetes (n = 539) were invited. In one urban and one rural centre, a quality improvement programme was implemented; two other centres (one urban and one rural) served as control practices. The intervention mainly consisted of the introduction of clinical disease management guidelines and an electronic medical record system. The primary outcome measurement was improvement of specific clinical indicators for HTN and diabetes. Patients' satisfaction was evaluated using the European Task Force on Patient Evaluations of General Practice (EUROPEP) questionnaire over an 18-month follow-up period. RESULTS: Five hundred and four patients completed the study, 278 patients in the intervention practices and 226 patients in the control practices. Mean results for blood pressure, total cholesterol and low density lipoprotein-cholesterol and three annual performance measures (urine protein testing, dilated eye and foot examination) had improved at 18-month follow-up in the intervention as compared to the control group. There was no improvement of HbA1c levels. Patients' satisfaction improved in the intervention practices (improvement of 10/23 EUROPEP items) but decreased in the control group (decline of 20/23 items). CONCLUSIONS: A pilot multifaceted quality improvement intervention programme for patients with diabetes and HTN implemented in primary care settings in Cyprus showed promising results. Future studies need to involve a broader number of practices and patient populations.

EUS-guided FNA of solid pancreatic masses: high yield of 2 passes with combined histologic-cytologic analysis.

BACKGROUND: EUS-guided FNA (EUS-FNA) is an established tissue-acquisition technique, with most studies concentrating on cytologic analyses of specimens, with only few data existing on histologic assessment. OBJECTIVE: To assess the sensitivity of a combined analysis of histologic followed by cytologic tissue diagnosis. DESIGN: A retrospective 3-center study. METHODS: In consecutive patients undergoing FNA of solid pancreatic masses, core specimens were harvested for histology; residual tissue was examined cytologically. Only unequivocally positive results were regarded as malignant. Criterion standards were positive results from EUS-FNA or other histologic findings, or, if negative, clinical follow-up data (minimum 12 months). RESULTS: Among 192 patients (110 men; mean age 63 years) with mostly pancreatic-head masses (72.4%), overall, adequate tissue was obtained in 98.9% of all cases, with a mean of 1.88 needle passes and an overall sensitivity of 82.9% (95% CI, 76.0%-88.5%). Histology and subsequent cytology provided adequate tissue and sensitivities of 86.5% and 60%, and 92.7% and 68.1%, respectively. Excluding cases with inadequate specimens, sensitivities rose by 4% to 10%. Histology showed a trend for superiority over cytology only in characterizing nonadenocarcinoma tumor types. No differences in sensitivity were found between the centers involved. LIMITATIONS: Retrospective design, different processing of cytologic specimens. CONCLUSIONS: At EUS-FNA in pancreatic masses, combined histologic-cytologic analysis achieved a sensitivity of more than 80%, despite a low number of needle passes and may thus save time. Histology alone did not reach higher sensitivity than cytology. In particular situations, eg, rare tumors, histology may still be required.

Prospective, randomized comparison of mechanical and electronic radial endoscopic ultrasound systems: assessment of performance parameters and image quality.

OBJECTIVE: Implementation of electronic image technology in endoscopic ultrasonography (EUS) should improve image quality, but systematic data are scarce. The purpose of this study was to compare the image quality and performance of an electronic and a mechanical radial echoendoscope. MATERIAL AND METHODS: Eighty consecutive patients (42 M, mean age 56 years) in a tertiary referral center, without gross pathology (advanced tumors excluded), were prospectively randomized to EUS with the mechanical or electronic echoendoscope. Images from five standardized positions (pancreatobiliary and upper gastrointestinal (GI) tract) were taken by two examiners of differing experience. Time to acquire images was noted. Penetration depth was also measured. Image quality variables (overall quality, contrast, and structure discrimination) were assessed blindly on the basis of randomly shuffled images during three independent evaluations by the same experienced examiner (mean values were taken), using a visual analogue scale (VAS) from 1 (excellent) to 10 (inadequate). RESULTS: Time needed to achieve visualization of the distal common bile duct (CBD) was significantly shorter with the electronic scope (49.7+/-8.6 versus 97.4+/-8.5 s; p<0.001). Image quality with the electronic scope was rated significantly better for all variables assessed, whereas EUS penetration depth was similar in both groups. There were no differences in examiner experience. CONCLUSIONS: Electronic EUS provided better quality images according to the examiner's subjective assessment. An objective advantage was faster identification of the distal CBD.