The effect of risankizumab on achieving minimal clinically important differences in patient-reported outcomes in patients with psoriatic arthritis: results from KEEPsAKE 1 and 2.

BACKGROUND: Psoriatic arthritis (PsA) is a chronic inflammatory disease that reduces the quality of life. This study assessed the effects of risankizumab (RZB) on the achievement of minimal clinically important differences (MCID) in patient-reported outcomes (PROs). METHODS: KEEPsAKE-1 and -2 are randomized, placebo-controlled Phase 3 clinical studies assessing RZB (150 mg) vs. placebo (PBO) in adult patients with PsA with inadequate response or intolerance to disease-modifying antirheumatic drugs and/or biologics. Patients were randomized 1:1 to receive RZB or PBO for 24 weeks; starting at Week 24, all patients received RZB 150 mg through Week 52. PROs assessed were Patient's Global Assessment of Disease Activity (PtGA), Patient's Assessment of Pain, Health Assessment Questionnaire-Disability Index (HAQ-DI), Short-Form 36 Physical and Mental Component Summary scores (PCS and MCS, respectively), 5-Level EQ-5D (EQ-5D-5L), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), and Work Productivity and Activity Impairment (WPAI). The proportion of patients achieving MCID at Weeks 24 and 52 are reported. Odds ratios of achieving MCID with RZB treatment at Week 24, relative to PBO, were estimated by logistic regression controlling for baseline and stratification factors. RESULTS: In KEEPsAKE-1, RZB- vs. PBO-treated patients were more likely to report MCID in all PROs at Week 24; similar results were obtained in KEEPsAKE-2, except for SF-36 MCS and WPAI presenteeism domain. In KEEPsAKE-1 and KEEPsAKE-2, 65% and 62% of RZB-treated patients, respectively, reported MCID in PtGA at Week 24, which increased to 74% and 68%, respectively, at Week 52. Approximately 48% of all PBO-treated patients reported MCID in PtGA at Week 24 and, after initiating RZB, >65% reported MCID at Week 52. Results were similar in the remaining PROs. CONCLUSIONS: These data demonstrate that patients with PsA receiving RZB treatment are more likely to report clinically important improvements in PROs compared with patients receiving PBO.

Rituximab versus an alternative TNF inhibitor in patients with rheumatoid arthritis who failed to respond to a single previous TNF inhibitor: SWITCH-RA, a global, observational, comparative effectiveness study.

OBJECTIVES: To compare the effectiveness of rituximab versus an alternative tumour necrosis factor (TNF) inhibitor (TNFi) in patients with rheumatoid arthritis (RA) with an inadequate response to one previous TNFi. METHODS: SWITCH-RA was a prospective, global, observational, real-life study. Patients non-responsive or intolerant to a single TNFi were enrolled ≤4 weeks after starting rituximab or a second TNFi. Primary end point: change in Disease Activity Score in 28 joints excluding patient's global health component (DAS28-3)-erythrocyte sedimentation rate (ESR) over 6 months. RESULTS: 604 patients received rituximab, and 507 an alternative TNFi as second biological therapy. Reasons for discontinuing the first TNFi were inefficacy (n=827), intolerance (n=263) and other (n=21). A total of 728 patients were available for primary end point analysis (rituximab n=405; TNFi n=323). Baseline mean (SD) DAS28-3-ESR was higher in the rituximab than the TNFi group: 5.2 (1.2) vs 4.8 (1.3); p<0.0001. Least squares mean (SE) change in DAS28-3-ESR at 6 months was significantly greater in rituximab than TNFi patients: -1.5 (0.2) vs -1.1 (0.2); p=0.007. The difference remained significant among patients discontinuing the initial TNFi because of inefficacy (-1.7 vs -1.3; p=0.017) but not intolerance (-0.7 vs -0.7; p=0.894). Seropositive patients showed significantly greater improvements in DAS28-3-ESR with rituximab than with TNFi (-1.6 (0.3) vs -1.2 (0.3); p=0.011), particularly those switching because of inefficacy (-1.9 (0.3) vs -1.5 (0.4); p=0.021). The overall incidence of adverse events was similar between the rituximab and TNFi groups. CONCLUSIONS: These real-life data indicate that, after discontinuation of an initial TNFi, switching to rituximab is associated with significantly improved clinical effectiveness compared with switching to a second TNFi. This difference was particularly evident in seropositive patients and in those switched because of inefficacy.

The long road of biopharmaceutical drug development: from inception to marketing.

The development of therapeutics is costly, time-consuming and has high attrition rates. Biopharmaceutical medications differ from traditional agents in their discovery, design, structure and formulation. Prior to marketing a drug must show efficacy and acceptable toxicity in both preclinical and clinical trials. Regulatory bodies have a pivotal role in the licensing, naming and marketing of an agent.

Assessment of anti-TNF-alpha efficacy in rheumatoid arthritis: is 3 months sufficient?

OBJECTIVES: The optimal therapeutic trial duration of anti-TNF-alpha therapy is currently unknown. The British Society for Rheumatology (BSR) guidance states that non-response at 3 months warrants re-evaluation of treatment and recommends not to persist beyond 6 months. The National Institute for Health and Clinical Excellence (NICE) specifies treatment continuation if response is achieved by 6 months, yet the European League against Rheumatism (EULAR) and the American College of Rheumatology (ACR) maintain a 3 month cut-off. No evidence exists to support a 6 month therapeutic trial over 3 months. Thus, we undertook a study to evaluate the proportion of patients who failed to meet NICE response criteria at 3 months but obtained this by 6 months, and to identify predictive factors for this. METHODS: Patients who commenced anti-TNF-alpha therapy for RA were studied, counting those who switched to a second or third agent separately for each instigation of therapy (n = 244). Response at 3 and 6 months was defined according to NICE criteria as a >or=1.2 reduction in Disease Activity Score (DAS28). RESULTS: Of the 189 patients with available 3 month DAS28 responses, 149 fulfilled response criteria. Of the 40 who failed, 27 continued treatment, of whom 21 were available for follow-up at 6 months. Out of the 21 patients, 12 (57%; 95% CI 36, 78) achieved a response at this time. This data set was too small to investigate predictors of response at 6 months. CONCLUSIONS: A substantial proportion of patients who fail NICE response criteria at 3 months and continue on treatment to 6 months achieve a response. These results support a 6 month therapeutic trial over 3 months.

Hypovitaminosis D among rheumatology outpatients in clinical practice.

OBJECTIVES: A role for vitamin D in the pathogenesis of autoimmune and inflammatory diseases is emerging. We undertook an audit of 25-hydroxyvitamin D (25OHD) investigation and treatment in rheumatology outpatients. METHODS: Serum 25OHD requests were matched to electronic medical records from rheumatology and metabolic bone clinics (April 2006-March 2007). Data were analysed separately for two groups, 'Documented osteoporosis/osteopaenia' (Group 1) and 'General rheumatology outpatients' (Group 2, sub-divided by diagnosis). Hypovitaminosis D was defined by 25OHD levels <50 nmol/l. Values were compared with healthy adults to calculate geometric z-scores. RESULTS: A total of 263 patients were included (Group 1, n = 122; Group 2, n = 141) with an overall median 25OHD of 44 nmol/l. The 25OHD level among general rheumatology patients (median 39 nmol/l, mean z score -1.2, was statistically significantly lower than among osteoporotic/osteopaenic patients (median 49 nmol/l, mean z score of -0.9, p < 0.05 for the difference). 25OHD was lower in inflammatory arthritis and chronic pain/fibromyalgia than in other groups. Prescribing was recorded in 100 in Group 1 (of whom 95% were prescribed calcium/800 IU cholecalciferol) and 83 in Group 2 (91% calcium/800 IU). Only 31% of the patients with 25OHD <50 nmol/l would have been identified using general guidelines for screening patients at 'high risk' of hypovitaminosis D. CONCLUSIONS: Improved guidelines for managing hypovitaminosis D in rheumatology patients are needed. We found a high prevalence of hypovitaminosis D among secondary care patients in rheumatology and widespread supplementation with 800 IU cholecalciferol. Substantially reduced levels of serum 25OHD were identified among patients with inflammatory arthritis and chronic pain.

Pulsed low-intensity ultrasound therapy for chronic lateral epicondylitis: a randomized controlled trial.

OBJECTIVES: Pulsed low-intensity ultrasound therapy (LIUS) has been found to be beneficial in accelerating fracture healing and has produced positive results in animal tendon repair. In the light of this we undertook a randomized, double-blind, placebo controlled trial to assess the effectiveness of LIUS vs placebo therapy daily for 12 weeks in patients with chronic lateral epicondylitis (LE). METHODS: Patients with LE of at least 6 weeks' duration were recruited from general practice, physiotherapy and rheumatology clinics, and had to have failed at least one first-line treatment including non steroidal anti-inflammatory drugs (NSAIDs) and corticosteroid injection. Participants were assigned either active LIUS or placebo. Treatment was self-administered daily for 20 min over a 12-week period. The primary end-point was a 50% improvement from baseline in elbow pain measured at 12 weeks using a patient-completed visual analogue scale. RESULTS: Fifty-five subjects aged 18-80 were recruited over a 9-month period. In the active group 64% (16/25) achieved at least 50% improvement from baseline in elbow pain at 12 weeks compared with 57% (13/23) in the placebo group (difference of 7%; 95% confidence interval -20 to 35%). However, this was not statistically significant (chi(2) = 0.28, P = 0.60). CONCLUSION: In this study LIUS was no more effective for a large treatment effect than placebo for recalcitrant LE. This is in keeping with other interventional studies for the condition.

Diagnosis and relation to general health of shoulder disorders presenting to primary care.

OBJECTIVES: To prospectively evaluate the incidence, spectrum of disease and relation to general health of shoulder disorders in primary care. METHODS: Patients presenting with shoulder pain to two large general practices in the Cambridge area over a 1-month period were invited to participate. After consulting their general practitioner, patients were administered a demographic information questionnaire, a shoulder pain and disability index (SPADI) and a short form 36 (SF-36) health survey. Subsequent review in a clinic held by a rheumatology registrar every 2 weeks was undertaken. RESULTS: The sex- and age-standardized incidence of shoulder pain was 9.5 per 1000 (95% confidence interval 7.9 to 11.2 per 1000). Rotator cuff tendinopathy was found in 85%, signs of impingement in 74%, acromioclavicular joint disease in 24%, adhesive capsulitis in 15% and referred pain in 7%. On the SPADI the mean disability subscale score was 45 (95% confidence interval 41 to 50) and the mean pain score was 58 (95% confidence interval 53 to 62) (range 0 to 100). Evaluation of general health status using the SF-36 showed the difference between population norms and those with shoulder pain was significant in six of the eight domains, being especially marked (greater than 20 point reduction) for emotional role, physical function and physical role. CONCLUSION: Shoulder pain, most commonly due to rotator cuff tendinopathy, is associated with significantly reduced health when measured by both specific and generic means. Effort towards prevention and early intervention in these complaints is warranted.

Interrater reproducibility of clinical tests for rotator cuff lesions.

BACKGROUND: Rotator cuff lesions are common in the community but reproducibility of tests for shoulder assessment has not been adequately appraised and there is no uniform approach to their use. OBJECTIVE: To study interrater reproducibility of standard tests for shoulder evaluation among a rheumatology specialist, rheumatology trainee, and research nurse. METHODS: 136 patients were reviewed over 12 months at a major teaching hospital. The three assessors examined each patient in random order and were unaware of each other's evaluation. Each shoulder was examined in a standard manner by recognised tests for specific lesions and a diagnostic algorithm was used. Between-observer agreement was determined by calculating Cohen's kappa coefficients (measuring agreement beyond that expected by chance). RESULTS: Fair to substantial agreement was obtained for the observations of tenderness, painful arc, and external rotation. Tests for supraspinatus and subscapularis also showed at least fair agreement between observers. 40/55 (73%) kappa coefficient assessments were rated at >0.2, indicating at least fair concordance between observers; 21/55 (38%) were rated at >0.4, indicating at least moderate concordance between observers. CONCLUSION: The reproducibility of certain tests, employed by observers of varying experience, in the assessment of the rotator cuff and general shoulder disease was determined. This has implications for delegation of shoulder assessment to nurse specialists, the development of a simplified evaluation schedule for general practitioners, and uniformity in epidemiological research studies.

Decreased tissue inhibitor of metalloproteinase in the endometrium of women using depot medroxyprogesterone acetate: a role for altered endometrial matrix metalloproteinase/tissue inhibitor of metalloproteinase balance in the pathogenesis of abnormal uterine bleeding?

BACKGROUND: Abnormal uterine bleeding is commonly associated with progestin-only contraceptives, including depot medroxyprogesterone acetate (DMPA), and remains the main reason why these agents are discontinued. Matrix metalloproteinases (MMP), enzymes which degrade specific extracellular matrix components, and leukocytes are implicated in menstruation. Alteration in endometrial MMP-9 and leukocytes has been described in users of other progestin-only contraceptives, suggesting a potential role in the pathogenesis of abnormal uterine bleeding. METHODS: This study describes the immunohistochemical localization of MMP-9, the tissue inhibitors of metalloproteinases (TIMP)-1, TIMP-2 and TIMP-3, and leukocytes [CD3+ T lymphocytes, CD68+ macrophages and CD56+ uterine natural killer cells (uNK cells)] in the endometrium of women using DMPA. Comparison is made with perimenstrual endometria from normal cycling women. RESULTS: Similar to the perimenstrual period, an influx of MMP-9 positive cells (identified as neutrophils and CD3+ T cells on the basis of dual immunofluorescence), macrophages and uNK cells was observed in the endometrium of DMPA users. However, significantly more endometrial T lymphocytes were observed in DMPA users. Immunoreactive TIMP, present in all endometrial compartments, demonstrated a significantly decreased immunostaining intensity score in endometrial epithelium (TIMP-1 and TIMP-2), stroma (TIMP-1, TIMP-2 and TIMP-3), endothelium (TIMP-1 and TIMP-2) and vascular smooth muscle (TIMP-1) of DMPA users compared with controls. No correlation was observed between the parameters studied and bleeding patterns reported by subjects. CONCLUSIONS: These findings provide additional evidence for the importance of the MMP/TIMP balance in the loss/maintenance of endometrial integrity and in the complex pathological mechanisms involved in the troubling side-effect of menstrual bleeding disturbance.

The accuracy and interobserver reproducibility of endometrial dating.

Although controversial, diagnosis of luteal phase defect (LPD) includes the morphological assessment of endometrial development. This study was conducted to determine if refresher training in the histological criteria could improve the accuracy and interobserver reproducibility of endometrial dating. Seventy-eight endometrial biopsies were dated by a reference panel of two pathologists and then reviewed twice by a study panel of four pathologists. In the first review, usual practice was applied. Prior to the second review, they studied a standard document of histological criteria. Samples were dated as proliferative, secretory (post-ovulatory day, POD), menstrual, and undatable. Accuracy levels based on the reference dating and agreement levels using kappa values were calculated per review and compared. The kappa for overall dating was 0.683 in the first review and 0.696 in the second. The respective first and second review kappa values were 0.736 and 0.771 for proliferative, and 0.794 and 0.764 for secretory. Amongst those dated as secretory in the first and second reviews, respectively, 31 and 28% were assigned the same POD by any two panellists, 68 and 63% were dated to within 1 day, and 77 and 71% were dated to within 2 days. Accuracy levels per panellist for overall dating were very high in both reviews but were low for individual PODs. Accuracy and interobserver reproducibility were unaffected by refresher training, suggesting the limits of histological dating have been reached.

What's new in rheumatoid arthritis? An evidenced based review.

BACKGROUND: Rheumatoid arthritis (RA) is the most common inflammatory arthritis and has been associated with significant functional impairment and a shortened life expectancy. Fortunately, over the past 10 years, there has been a significant change in its management, which has resulted in improved outcomes for RA patients. OBJECTIVE: To critically appraise the recent evidence which affects the contemporary management of RA. DISCUSSION: The bulk of recent evidence suggests that disease modifying anti-rheumatic drugs (DMARDs) should be commenced early and continued indefinitely in RA patients. Single DMARD therapy may be sufficient in some patients but combinations, particularly those which include methotrexate, improve symptomatic and radiological outcomes. The use of newer therapies, including leflunomide and tumour necrosis factor-alpha blocking drugs, promise to further improve these outcomes.

Adenocarcinoma in situ of the uterine cervix: an experience with 100 cases.

OBJECTIVE: The aim of this study was to ascertain whether cold knife conization alone for cervical adenocarcinoma in situ is safe. METHODS: One hundred consecutive patients with a histologically proven adenocarcinoma in situ (AIS) of the cervix were studied from 1970 to 1992. RESULTS: Ninety-two women presented with abnormal smears, and of these 56% contained abnormal glandular cells. Sixty-seven (74%) of 90 women who underwent colposcopy had an abnormal examination, but a glandular abnormality was suspected in only 19 (28%). In all, 80 cold knife conizations were performed. In 7, no abnormality was found following punch biopsy. The margins were free of disease in 55 (75%). The most commonly involved margin in the remainder was the apical. Conization was followed by hysterectomy in 20 women: in 8 of these the cone margins were free and residual disease was found in 2 of the extirpated uteri: as these were extramural cases, inadequate sampling could not be excluded. Of the 12 women where hysterectomy followed conization with diseased margins, 9 had residual disease in the hysterectomy specimen. The definitive therapy was cold knife conization in 56 patients, hysterectomy in 38, and electrocoagulation diathermy in 6. Follow-up of the 53 patients treated by conization alone ranging from 1 to 16 years, with a mean of 8 years (3 have been lost to follow-up) revealed no recurrence of AIS or adenocarcinoma to date. CONCLUSION: It is concluded that cold knife conization is a safe therapeutic modality, provided that the cone biopsy has been adequately sampled and the margins are free.