Real-World Efficacy and Tolerability of Brigatinib in Patients with Non-Small Cell Lung Cancer with Prior ALK-TKIs in the United States.

BACKGROUND: Real-world evidence for brigatinib, a next-generation anaplastic lymphoma kinase-tyrosine kinase inhibitor (ALK-TKI) used in ALK-rearranged non-small cell lung cancer, is scarce. This retrospective study evaluated real-world brigatinib utilization in the US post other ALK-TKIs. MATERIALS AND METHODS: Adults with ≥1 brigatinib claim (index date) between 1 April 2017 and 30 September 2020 in the IQVIA longitudinal pharmacy claims database were followed until dose reduction, discontinuation, or end of follow-up. Patients had ≥12 months pre- and ≥1-month post-index observations. RESULTS: A total of 413 patients treated with brigatinib were analyzed. Over 80% received ≥1 prior ALK-TKI; alectinib and crizotinib were the most common (58.8% and 51.3% patients, respectively). The median follow-up was 8.4 months. The median time to treatment discontinuation (TTD) for brigatinib was 10.3 months (95% CI, 8.2-15.0), with 45% remaining on therapy at 12 months. The TTD was shortest (~8 months) in patients receiving both crizotinib and alectinib and longest in patients who received alectinib only prior to brigatinib (11.8 months). Adherence was high, with 92.7% of patients having a medication possession ratio of >80%. The mean dose compliance score was 1.0. Most patients reached the brigatinib dose of 180 mg/day (77%); 13.2% of patients had a dose reduction, with 89.3% and 84.6% continuing 180 mg/day therapy at 3 and 6 months, respectively. CONCLUSIONS: Brigatinib appears to be effective and well-tolerated in the real-world ALK+ NSCLC population in the US, showing benefit in patients after a next-generation ALK-TKI. Notably, dose reduction rates appeared markedly less than those seen in trials when most trial-related dose reductions were for asymptomatic laboratory abnormalities.

Comparison of change in end tidal carbon dioxide after three minutes of step exercise between systemic sclerosis patients with and without pulmonary hypertension.

OBJECTIVES: Pulmonary hypertension (PH) is an important cause of morbidity and mortality in patients with SSc. The submaximal heart and pulmonary evaluation (step test) is a non-invasive, submaximal stress test that could be used to identify SSc patients with PH. Our aims were to determine whether change in end tidal carbon dioxide ([Formula: see text]) from rest to end-exercise, and the minute ventilation to carbon dioxide production ratio ([Formula: see text]), both as measured by the step test, differ between SSc patients with and without PH. We also examined differences in validated self-report questionnaires and potential PH biomarkers between SSc patients with and without PH. METHODS: We performed a cross-sectional study of 27 patients with limited or dcSSc who underwent a right heart catheterization within 24 months prior to study entry. The study visit consisted of questionnaire completion; history; physical examination; step test performance; and phlebotomy. [Formula: see text], [Formula: see text], self-report data and biomarkers were compared between patients with and without PH. RESULTS: SSc patients with PH had a statistically significantly lower median (interquartile range) [Formula: see text] than SSc patients without PH [-2.1 (-5.1 to 0.7) vs 1.2 (-0.7 to 5.4) mmHg, P = 0.035], and a statistically significantly higher median (interquartile range) [Formula: see text] [53.4 (39-64.1) vs 36.4 (31.9-41.1), P = 0.035]. There were no statistically significant differences in self-report data or biomarkers between groups. CONCLUSION: [Formula: see text] and [Formula: see text] as measured by the step test are statistically significantly different between SSc patients with and without PH. [Formula: see text] and [Formula: see text] may be useful screening tools for PH in the SSc population.

Increased rho kinase activity in temporal artery biopsies from patients with giant cell arteritis.

OBJECTIVE: Aberrant rho kinase (ROCK) activity is implicated in the pathogenesis of several vascular diseases and is associated with Th17 differentiation. Th17 immune response is recognized in the pathogenesis of GCA. The aim of this study was to assess ROCK activity in GCA. METHODS: All patients who underwent temporal artery biopsy (TAB) at a tertiary care centre over 5 years were identified and charts reviewed. Subjects were categorized into three groups: TAB-positive GCA, TAB-negative GCA and age- and sex-matched controls. TABs were stained for phosphorylated ezrin/radixin/moesin (pERM), a surrogate of ROCK activity, and reviewed by a pathologist blinded to clinical status. Three areas were scored for staining intensity on a scale of 0-2, with a maximum possible score of 6. RESULTS: Nineteen subjects with TAB-positive GCA, 17 with TAB-negative GCA and 18 controls were analysed. Compared with controls, GCA subjects with either positive or negative TABs had significantly higher pERM intensity scores (P = 0.0109). Adjusting for diabetes, hypertension, prednisone and statin use, GCA subjects still had higher pERM scores [odds ratio 7.3 (95% CI 1.9, 25.9), P = 0.0046]. The high pERM score had a sensitivity of 90% and a negative predictive value of 91% for the diagnosis of GCA in those with a negative TAB, compared with 51% sensitivity for histopathology alone. CONCLUSION: Subjects with GCA had more intense pERM staining in TAB specimens compared with age- and sex-matched controls, regardless of whether TAB was positive or negative by routine histopathology, suggesting increased ROCK activity in GCA. The ROCK pathway warrants further investigation in GCA, as it may have diagnostic significance in enhancing the sensitivity of TAB.

Short-term total hip replacement outcomes in ankylosing spondylitis.

BACKGROUND: While rates of total hip replacement (THR) in spondyloarthritis are increasing, contemporary outcomes are not well described. OBJECTIVES: This study analyzes 2-year outcomes in a contemporary cohort of ankylosing spondylitis (AS) patients undergoing THR. METHODS: A case-control study was performed using data from an institutional arthroplasty registry. Validated AS cases were matched 4:1 by age and procedure to patients with osteoarthritis (OA). Data were obtained prior to surgery and at 2 years. Multiple imputation techniques were performed to avoid systematic bias due to missing data. RESULTS: Thirty eligible AS cases were identified between May 2007 and February 2010. Ankylosing spondylitis cases had worse American Society of Anesthesia class (P < 0.001) and more comorbidities (P = 0.02) compared with OA. Ankylosing spondylitis had worse preoperative lower-extremity Western Ontario and McMaster Universities Arthritis Index pain (46.8 vs 55.4; P = 0.03), function (43.0 vs 55.1; P = 0.04), and general health status measured as SF-12 (Short-Form Health Survey) physical component scale (PCS) score (29.6 vs 36.0; P < 0.001), however, there was no difference at two years in pain (89.4 vs 92.5; P = 0.23) or function (83.9 vs 90.1; P = 0.04). Physical component scale score remained significantly worse (41.2 vs 50.1; P < 0.001). Better preoperative SF-12 PCS score significantly decreased the risk of a poor pain outcome (odds ratio, 0.06; 95% confidence interval, 0.01-0.40). Overall satisfaction was high. CONCLUSIONS: Although patients with AS in a contemporary cohort have more comorbidities and worse physical function prior to THR, they achieve similar gains as OA. In a multivariate regression controlling for multiple potential confounders including back pain, only preoperative health status measured as SF-12 PCS score was a significant risk factor for a poor 2-year pain. Among contemporary patients, AS is not an independent risk factor for poor THR outcomes.Take-Home Message Patients with AS have significant improvement in pain and function after THR.Poor preoperative function and low-back pain are not risk factors for poor THR outcomes for patients with AS.Despite improvements, low SF-12 PCS scores indicate persistent limitations due to health.

Short-Term Total Hip Arthroplasty Outcomes in Patients With Psoriatic Arthritis or Psoriatic Skin Disease Compared to Patients With Osteoarthritis.

OBJECTIVE: Outcomes of total hip arthroplasty (THA) in patients with psoriasis have been poorly studied. This study was undertaken to assess whether patients with psoriatic arthritis (PsA) or those with cutaneous psoriasis (PsC) without evidence of inflammatory joint disease are at an increased risk for worse outcomes after THA as compared to patients with osteoarthritis (OA). METHODS: Among subjects in a prospective THA registry, PsA and PsC cases were identified by International Classification of Diseases, Ninth Revision codes, and all cases were matched with patients with OA as controls. Analyses were performed to identify predictors of poor postoperative pain or function. RESULTS: Of the 289 potential cases of PsA or PsC, 63 with PsA and 153 with PsC were validated. Self-report data were available postoperatively from 75% of PsA patients, 69% of PsC patients, and 94% of OA controls. In total, 51% of PsA patients and 56% of PsC patients were male, compared to 45% of OA controls (P = 0.04). Body mass index was higher in those with PsA or PsC (P = 0.002 versus controls). There were no differences in race or education between the 3 groups. PsA patients and PsC patients had more comorbidities than OA controls. PsA patients were more likely than PsC patients and OA controls to be current or previous smokers. Moreover, 54% of PsA patients were being treated with biologics or nonbiologic disease-modifying antirheumatic drugs, compared to 8% of PsC patients. There were no significant differences in pre- or postoperative Western Ontario and McMaster Universities OA Index scores for pain or function between the 3 groups. Short-Form 36 mental component summary scores were significantly better in the OA controls, both pre- and postoperatively (P = 0.006 and P < 0.001, respectively, versus PsA or PsC). EuroQol 5-domain health-related quality of life scores were significantly worse postoperatively for those with PsA or PsC (P < 0.0001 versus OA controls). In regression analyses, neither PsA nor PsC were risk factors for worse THA outcomes. Satisfaction with the outcomes of THA was similarly high among all 3 groups (P = 0.54). CONCLUSION: Neither PsA nor PsC are risk factors for poor outcomes after THA. This is important information to convey to patients with either PsA or PsC who are contemplating surgical intervention with THA.

Patients with Rheumatoid Arthritis have Similar Excellent Outcomes after Total Knee Replacement Compared with Patients with Osteoarthritis.

OBJECTIVE: Although new treatments for rheumatoid arthritis (RA) are extremely effective in preventing disease progression, rates of total knee replacement (TKR) continue to rise. The ongoing need for TKR is problematic, especially as functional outcomes in patients with RA have been reported to be worse than in patients with osteoarthritis (OA). The purpose of this study is to assess pain, function, and quality of life 2 years after TKR in contemporary patients with RA compared with patients with OA. METHODS: Primary TKR cases enrolled between May 1, 2007 and July 1, 2010 in a single institution TKR registry were eligible for this study. Validated RA cases were compared with OA at baseline and at 2 years. RESULTS: We identified 4456 eligible TKR, including 136 RA. Compared with OA, RA TKR had significantly worse preoperative Western Ontario and McMaster Universities Osteoarthritis Index pain (55.9 vs 46.6, p < 0.0001) and function (58.7 vs 47.3, p < 0.0001); however, there were no differences at 2 years. Within RA, there was no difference for patients who were treated with biologic disease-modifying antirheumatic drugs versus those who did not in pain (p = 0.41) or function (p = 0.39) at 2 years. In a multivariate regression, controlling for multiple potential confounders, there was no independent association of RA with 2-year pain (p = 0.18) or function (p = 0.71). Satisfaction was high for both RA and OA. CONCLUSION: Patients with RA undergoing primary TKR have excellent 2-year outcomes, comparable with OA, in spite of worse preoperative pain and function. In this contemporary cohort, RA is not an independent risk factor for poor outcomes.

Fellow use of medical jargon correlates inversely with patient and observer perceptions of professionalism: results of a rheumatology OSCE (ROSCE) using challenging patient scenarios.

The NYC Rheumatology Objective Structured Clinical Examination (NYC-ROSCE) is held annually to assess fellow competencies. We recently redesigned our OSCE to better assess subspecialty trainee communication skills and professionalism by developing scenarios in which the patients encountered were psychosocially or medically complex. The objective of this study is to identify which types of verbal and non-verbal skills are most important in the perception of professionalism in the patient-physician interaction. The 2012-2013 NYC-ROSCEs included a total of 53 fellows: 55 MD evaluators from 7 NYC rheumatology training programs (Hospital for Special Surgery-Weill Cornell (HSS), SUNY/Downstate, NYU, Einstein, Columbia, Mount Sinai, and North Shore/Long Island Jewish (NSLIJ)), and 55 professional actors/standardized patients participated in 5 stations. Quantitative fellow performance assessments were made on the following: maintaining composure; partnering with the patient; honesty; professionalism; empathy; and accountability. Free-text comments were solicited regarding specific strengths and weaknesses. A total of 53/53 eligible (100 %) fellows were evaluated. MD evaluators rated fellows lower for professionalism than did the standardized patients (6.8 ± 0.6 vs. 7.4 ± 0.8, p = 0.05), suggesting that physicians and patients view professionalism somewhat differently. Fellow self-evaluations for professionalism (6.6 ± 1.2) were concordant with those of the MD evaluators. Ratings of empathy by fellows themselves (6.6 ± 1.0), MD evaluators (6.6 ± 0.7), and standardized patients (6.6 ± 1.1) agreed closely. Jargon use, frequently cited by evaluators, showed a moderate association with lower professionalism ratings by both MD evaluators and patients. Psychosocially challenging patient encounters in the NYC-ROSCE permitted critical assessment of the patient-centered traits contributing to impressions of professionalism and indicate that limiting medical jargon is an important component of the competency of professionalism.

Nilotinib (Tasigna™) in the treatment of early diffuse systemic sclerosis: an open-label, pilot clinical trial.

INTRODUCTION: Tyrosine kinase inhibitors (TKI) are medications of interest in the treatment of Systemic Sclerosis (SSc) because of their ability to inhibit pathways involved in fibrosis. In this open-label pilot trial, our objectives were to assess the safety, efficacy, and molecular change associated with treatment of patients with diffuse cutaneous (dc)SSc with the TKI nilotinib (Tasigna™). METHODS: Ten adult patients with early dcSSc were treated with nilotinib. Primary endpoints were safety and change in modified Rodnan Skin Score (MRSS) after 6 months. Lesional skin biopsies at baseline, 6 and 12 months of treatment were assessed by histopathology, immunohistochemistry, and DNA microarray. RESULTS: Patients had early and active dcSSc with median disease duration of 0.7 years (range 0.5, 1.7) and increasing MRSS in the month prior to baseline (mean +2.9, p=0.02). Seven out of ten patients completed 6 and 12 months of treatment. Seventy-one adverse events (AEs) including 2 serious AEs were observed, and 92 % of AEs were grade 1-2. Two patients discontinued the medication due to mild QTc prolongation. MRSS improved by a mean of 4.2 points (16 %) at 6 months and by 6.3 points (23 %) at 12 months in the 7 completers, p=0.02 and 0.01, respectively. Patients with a decrease in MRSS >20 % from baseline at 12 months (classified as improvers) had significantly higher expression of transforming growth factor beta receptor (TGFBR) and platelet-derived growth factor receptor beta (PDGFRB) signaling genes at baseline than non-improvers, and the expression of these genes significantly decreased in improvers post-treatment. CONCLUSION: Nilotinib was well tolerated by the majority of patients in this study, with tolerability limited primarily by mild QTc-prolongation. Significant MRSS improvement was observed in these early, active patients, but is not conclusive of treatment effect given the open-label study-design and small number of patients in this pilot study. Improvers had higher levels of expression of genes associated with TGFBR and PDGFRB signaling at baseline, and a significant decrease in the expression of these genes occurred only in patients with higher MRSS improvement. The findings of this pilot study warrant more conclusive evaluation. TRIAL REGISTRATION: Clinicaltrials.gov NCT01166139 , July 1, 2010.

A prospective study comparing infection risk and disease activity in children with juvenile idiopathic arthritis treated with and without tumor necrosis factor-alpha inhibitors.

Tumor necrosis factor-alpha (TNF-α) inhibitors are effective treatment for juvenile idiopathic arthritis (JIA) but may increase infection rates. However, active JIA may also render patients vulnerable to infection. In this study, we prospectively assessed infection rates in JIA patients treated with and without TNF-α inhibitors and correlated disease activity with infection risk. TNF-α inhibitor-naïve JIA subjects were followed up for 12 months. Subjects initiated on TNF-α inhibitors after enrollment were analyzed in the TNF group. Subjects treated without TNF-α inhibitors were analyzed in the non-TNF group. Questionnaires captured mild or severe infections. JIA disease activity by Childhood Health Assessment Questionnaire (CHAQ) disability index/pain score and physician joint count/global assessment was recorded. Twenty TNF and 36 non-TNF subjects were analyzed. The total infection rate ratio for TNF versus non-TNF group subjects was 1.14 (95% CI, 0.78-1.66; p = 0.51). The average rate of infections per month was 0.29 for TNF and 0.24 for non-TNF subjects. No severe infections or hospitalizations occurred in either group. Secondary infectious outcomes were also similar between groups. Controlling for study group, an increase in CHAQ pain score correlated with an increase in several infectious outcome measures. Our results suggest no difference in infection rates between JIA subjects treated with and without TNF-α inhibitors. Additionally, JIA disease activity may have contributed to infection risk in our cohort, irrespective of immunosuppressive therapy. Future analysis of the relationship between treatment regimens, disease activity, and infection rates may help to further delineate predictors of infection risk in JIA patients.

Effect of age at menopause on disease presentation in early rheumatoid arthritis: results from the Canadian Early Arthritis Cohort.

OBJECTIVE: Studies suggest that hormonal states affect disease characteristics in women with rheumatoid arthritis (RA). This study investigated how age at menopause affects disease in women presenting with early RA. METHODS: This was a cross-sectional study of postmenopausal women with early RA under age 65 years at time of enrollment in the Canadian Early Arthritis Cohort. RA-related disease characteristics in women who had early age at menopause (EM; age at menopause <45 years) were compared to those who had usual age at menopause (age at menopause ≥45 years). The t-test was applied to continuous variables and the chi-square test to categorical variables. Multivariate logistic regression analysis was used to adjust for age at menopause, smoking, and use of exogenous hormones. RESULTS: A total of 534 women were included; 93 were in the EM group. The age at RA onset was similar between groups. The EM group had higher mean patient global and pain scores and was more likely to be rheumatoid factor (RF) positive and meet the 1987 American College of Rheumatology criteria for RA. Using multivariate logistic regression, the EM group was more likely to be RF positive (odds ratio 2.2 [95% confidence interval 1.3-3.8], P = 0.005). Symptom duration, joint counts, Disease Activity Score in 28 joints, Health Assessment Questionnaire scores, and inflammatory markers did not differ between groups. CONCLUSION: These data suggest that early age at menopause, compared to usual age at menopause, is associated with seropositivity in women with early RA.

Effectiveness of rituximab for the otolaryngologic manifestations of granulomatosis with polyangiitis (Wegener's).

OBJECTIVE: Ear, nose, and throat (ENT) involvement is the most prevalent manifestation of granulomatosis with polyangiitis (Wegener's) (GPA) and correlates with permanent damage and decreased quality of life. Although prior studies have evaluated the efficacy of rituximab (RTX) for granulomatous features of GPA, none have evaluated its efficacy solely for ENT manifestations. We compared the effectiveness of RTX to other therapies for the ENT manifestations of GPA in a large, well-characterized cohort. METHODS: We performed a retrospective analysis of 975 visits from 99 GPA patients seen at a tertiary care ENT practice between 2003 and 2013. At each visit, subjects had a complete ENT examination, with ENT activity assessed by a single expert otolaryngologist. ENT disease activity during the observational period in subjects receiving RTX was compared to subjects receiving all other therapy. RESULTS: In total, 48 subjects had never received RTX and 51 received RTX at least once. There was no active ENT disease during 92.4% of the observational period (days) for subjects receiving RTX, compared with 53.7% of the observational period for subjects not receiving RTX (odds ratio 11.0 [95% confidence interval 5.5­22.0], P < 0.0001). Subjects receiving RTX, compared with those receiving methotrexate, azathioprine, cyclophosphamide, or trimethoprim-sulfamethoxazole, were significantly more likely to have no active ENT disease (P < 0.0001 for each comparison). CONCLUSION: RTX is an effective treatment for ENT manifestations of GPA. Subjects treated with RTX were significantly less likely to have active ENT disease compared with those not receiving RTX. Patients being treated with RTX were 11 times less likely to have active ENT disease than patients being treated with other therapies.

Patients with rheumatoid arthritis are more likely to have pain and poor function after total hip replacements than patients with osteoarthritis.

OBJECTIVE: Total hip replacement (THR) outcomes have been worse for patients with rheumatoid arthritis (RA) compared with those who have osteoarthritis (OA). Whether this remains true in contemporary patients with RA with a high use of disease-modifying and biologic therapy is unknown. The purpose of our study is to assess pain, function, and quality of life 2 years after primary THR, comparing patients with RA and patients with OA. METHODS: Baseline and 2-year data were compared between validated patients with RA and patients with OA who were enrolled in a single-center THR registry between May 1, 2007, and February 25, 2011. RESULTS: There were 5666 eligible primary THR identified, of which 193 were for RA. RA THR had worse baseline Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain (44.8 vs 53.2, p < 0.001) and function (38.7 vs 49.9, p < 0.001) compared with OA. These differences remained after surgery: pain (88.4 vs 94.0, p < 0.001) and function (82.9 vs 91.8, p < 0.001). Patients with RA were as likely to have a significant improvement as patients with OA (Δ WOMAC > 10) in pain (94% vs 96%, p = 0.35) and function (95% vs 94%, p = 0.69), but were 4 times as likely to have worse function (WOMAC ≤ 60; 19% vs 4%, p < 0.001) and pain (12% vs 3%, p < 0.001). In multivariate logistic regression controlling for multiple potential confounders, RA increased the odds of poor postoperative function (OR 4.32, 95% CI 1.57-11.9), and in patients without a previous primary THR, worse postoperative pain (OR 3.17, 95% CI 1.06-9.53). CONCLUSION: Contemporary patients with RA have significant improvements in pain and function after THR, but higher proportions have worse 2-year pain and function. In addition, RA is an independent predictor of 2-year pain and poor function after THR, despite high use of disease-modifying therapy.