The safety, tolerability, and efficacy of fasinumab (REGN475), a fully human monoclonal antibody against nerve growth factor, was evaluated for the treatment of pain in patients with osteoarthritis ...(OA) of the knee. This was a 24-week, double-blind, placebo-controlled, parallel-group, repeat-dose, exploratory study. Eligible patients 40 to 75 years of age with a diagnosis of OA of the knee and moderate to severe pain were randomized 1:1:1:1 to intravenous fasinumab 0.03, 0.1, or 0.3 mg/kg or placebo and received study drug on day 1 and day 57. Pain intensity was recorded daily using the numeric rating scale. Safety and tolerability, assessed by the incidence of treatment-emergent adverse events (TEAEs), was the primary study endpoint. Secondary study endpoints included the change from baseline in daily walking knee pain and the assessment of pain, function, and stiffness using the Western Ontario and McMaster Osteoarthritis (WOMAC) index. Baseline characteristics were similar among treatment groups (N=217). After 24 weeks, the incidence of TEAEs ranged from 66.1% to 75.0% in the fasinumab groups vs. 63.6% for placebo. The most common TEAEs included arthralgia, hyperesthesia, myalgia, peripheral edema, and joint swelling. Discontinuation for TEAEs occurred in 5.6% of fasinumab patients and 3.7% of placebo patients. All 3 doses of fasinumab were associated with significant (P<.05) improvements compared with placebo in walking knee pain and WOMAC total and subscale scores. Fasinumab was generally well tolerated, and was associated with a significant reduction in walking knee pain and an improvement in function for up to 8 weeks.
We integrated whole-exome sequencing (WES) and chromosomal microarray analysis (CMA) into a clinical workflow to serve an endogamous, uninsured, agrarian community.
Seventy-nine probands (newborn to ...49.8 years) who presented between 1998 and 2015 remained undiagnosed after biochemical and molecular investigations. We generated WES data for probands and family members and vetted variants through rephenotyping, segregation analyses, and population studies.
The most common presentation was neurological disease (64%). Seven (9%) probands were diagnosed by CMA. Family WES data were informative for 37 (51%) of the 72 remaining individuals, yielding a specific genetic diagnosis (n=32) or revealing a novel molecular etiology (n=5). For five (7%) additional subjects, negative WES decreased the likelihood of genetic disease. Compared to trio analysis, “family” WES (average seven exomes per proband) reduced filtered candidate variants from 22±6 to 5±3 per proband. Nineteen (51%) alleles were de novo and 17 (46%) inherited; the latter added to a population-based diagnostic panel. We found actionable secondary variants in 21 (4.2%) of 502 subjects, all of whom opted to be informed.
CMA and family-based WES streamline and economize diagnosis of rare genetic disorders, accelerate novel gene discovery, and create new opportunities for community-based screening and prevention in underserved populations.
Purpose: Effective pain management remains a serious problem in the nursing home setting. Barriers to achieving optimal pain practices include staff knowledge deficits, biases, and attitudes that ...influence assessment and management of the residents' pain. Design and Methods: Twelve nursing homes participated in this intervention study: six treatment homes and six control homes, divided evenly between urban and rural locations. Three hundred licensed and unlicensed nursing home staff members completed written knowledge and attitude surveys at baseline, and 378 staff members completed the surveys after intervention implementation. Results: Baseline results revealed notable knowledge deficits in the areas of pharmacology, drug addiction and dependence, side effect management, and nonpharmacologic management-strategy effectiveness. Significant differences were noted by job title (registered nurse/licensed practical nurse/certified nursing assistant). Case studies displayed a knowledge application problem, with nurses often filtering resident pain reports through observed resident behaviors. The intervention led to significant improvement in knowledge scores in some, but not all, the treatment homes. Perceived barriers to effective pain management showed a significant decline across all study nursing homes. Implications: Knowledge deficits related to pain management persist in nursing homes. An interactive multifaceted educational program was only partially successful in improving knowledge across settings and job categories. Attitudes and beliefs appear more difficult to change, whereas environmental and contextual factors appeared to be reducing perceived barriers to effective pain management across all participating nursing homes.
ABSTRACT
Objective: Development of an instrument for characterization of symptom patterns and severity in patients with cryopyrin-associated periodic syndromes (CAPS).
Methods: Two generations of ...daily health assessment forms (DHAFs) were evaluated in this study. The first-generation DHAF queried 11 symptoms. Analyses of results obtained with that instrument identified five symptoms included in a revised second-generation DHAF that was tested for internal consistency and test-retest reliability. This DHAF was also assessed during the initial portion of a phase 3 clinical study of CAPS treatment.
Results: Forty-eight CAPS patients provided data for the first-generation DHAFs. Five symptoms (rash, fever, joint pain, eye redness/pain, and fatigue) were included in the revised second-generation DHAF. Symptom severity was highly variable during all study phases with as many as 89% of patients reporting at least one symptom flare, and percentages of days with flares reaching 58% during evaluation of the second-generation instrument. Mean composite key symptom scores (KSSs) computed during evaluation of the second-generation DHAF correlated well with Physician's Global Assessment of Disease Activity (r = 0.91, p < 0.0001) and patient reports of limitations of daily activities (r = 0.68, p < 0.0001). Test-retest reliability and Cronbach's α's were high (0.93 and 0.94, respectively) for the second-generation DHAF. Further evaluation of this DHAF during a baseline period and placebo treatment in a phase 3 clinical study of CAPS patients indicated strong correlations between baseline KSS and Physician's Global Assessment of Disease Activity. Cronbach's α's at baseline and test-retest reliability were also high. Potentially important study limitations include small sample size, the lack of a standard tool for CAPS symptom assessment against which to validate the DHAF, and no assessment of the instrument's responsivity to CAPS therapy.
Conclusions: The DHAF is a new instrument that may be useful for capturing symptom patterns and severity in CAPS patients and monitoring responses to therapies for these conditions.
Assessing pain intensity in nursing home residents remains a challenge. As part of a multifaceted intervention study to improve pain practices in nursing homes, quarterly pain assessments were ...conducted in 12 Colorado nursing homes. Residents who reported pain or discomfort of any kind in the past 24 hours were asked to choose one of three pain intensity scales to quantify their current and highest level of pain intensity. They were also observed for pain behaviors using Feldt's Checklist of Nonverbal Pain Indicators. Residents preferred the Verbal Descriptor Scale almost 2:1 over the 11-point Verbal Numeric Rating Scale and the Faces Pain Scale. Sex and ethnicity were associated with differences in scale preference. More than one-half of residents reporting pain had an observable pain indicator. There was a monotonic relationship between reported pain intensity and number of observed pain indicators. To improve pain assessment and management in nursing homes, residents should be given a choice of pain intensity scales and observed for possible pain behaviors.
Objective
To assess the efficacy and safety of rilonacept (Interleukin‐1 IL‐1 Trap), a long‐acting and potent inhibitor of IL‐1, in patients with cryopyrin‐associated periodic syndromes (CAPS), ...including familial cold autoinflammatory syndrome (FCAS) and Muckle‐Wells syndrome (MWS).
Methods
Forty‐seven adult patients with CAPS, as defined by mutations in the causative NLRP3 (CIAS1) gene and pathognomonic symptoms, were enrolled in 2 consecutive phase III studies. Study 1 involved a 6‐week randomized double‐blind comparison of weekly subcutaneous injections of rilonacept (160 mg) versus placebo. Study 2 consisted of 9 weeks of single‐blind treatment with rilonacept (part A), followed by a 9‐week, randomized, double‐blind, placebo‐controlled withdrawal procedure (part B). Primary efficacy was evaluated using a validated composite key symptom score.
Results
Forty‐four patients completed both studies. In study 1, rilonacept therapy reduced the group mean composite symptom score by 84%, compared with 13% with placebo therapy (primary end point; P < 0.0001 versus placebo). Rilonacept also significantly improved all other efficacy end points in study 1 (numbers of multisymptom and single‐symptom disease flare days, single‐symptom scores, physician's and patient's global assessments of disease activity, limitations in daily activities, and C‐reactive protein and serum amyloid A SAA levels). In study 2 part B, rilonacept was superior to placebo for maintaining the improvements seen with rilonacept therapy, as shown by all efficacy parameters (primary end point; P < 0.0001 versus placebo). Rilonacept was generally well tolerated; the most common adverse events were injection site reactions.
Conclusion
Treatment with weekly rilonacept provided marked and lasting improvement in the clinical signs and symptoms of CAPS, and normalized the levels of SAA from those associated with risk of developing amyloidosis. Rilonacept exhibited a generally favorable safety and tolerability profile.
Functional, biochemical and genetic studies have over the past decade identified many causative genes in the osteoclast diseases osteopetrosis and Paget's disease of bone. Here, we outline all ...osteoclast diseases and their genetic associations and then focus specifically on those diseases caused by mutations in the critical osteoclast molecule Receptor Activator of Nuclear factor Kappa B (RANK). Both loss and gain-of-function mutations have been found in humans leading to osteopetrosis and high bone turnover phenotypes, respectively. Osteopetrosis-associated RANK mutations are widely distributed over the RANK molecule. It is likely that some negatively affect ligand binding, whereas others preclude appropriate association of RANK with downstream signalling molecules. In the Paget-like disorders, familial expansile osteolysis, early onset Paget's disease and expansile skeletal hyperphosphatasia, heterozygous insertion mutations are found in the RANK signal peptide. These prevent signal peptide cleavage, trapping the protein translated from the mutated allele in the endoplasmic reticulum. Whole animal studies replicate the hyperactive osteoclast phenotype associated with these disorders and present only with heterozygous expression of the mutation, suggesting an as yet unexplained effect of the mutant allele on normal RANK function. We discuss the cell biological studies and animal models that help us to understand the nature of these different RANK defects and describe how careful dissection of these conditions can help understand critical pathways in osteoclast development and function. We highlight areas that require further study, particularly in light of the pharmacological interest in targeting the RANK signalling pathway to treat diseases caused by excessive bone resorption.
Objective
To evaluate the interleukin‐1 inhibitor rilonacept (Interleukin‐1 Trap) for prevention of gout flares occurring in the first few months following initiation of urate‐lowering therapy.
...Methods
In this double‐blind study, adult patients with hyperuricemia and gout were randomized to receive rilonacept administered subcutaneously once per week (loading dose 320 mg followed by 160 mg weekly) or placebo, and started on allopurinol (300 mg/day, titrated to serum urate <6 mg/dl). At study visits, physical and laboratory assessments were performed and information on any adverse events was ascertained.
Results
Baseline characteristics were similar between the rilonacept and placebo groups (n = 41 and n = 42, respectively). The mean number of gout flares per patient through week 12 (primary efficacy end point) was markedly lower in the rilonacept group than in the placebo group (0.15 6 flares versus 0.79 33 flares; P = 0.0011). Fewer flares were observed with rilonacept as early as 4 weeks after initiation of treatment (P = 0.007). The proportion of patients experiencing a flare during the 12 weeks was lower in the rilonacept group than in the placebo group (14.6% versus 45.2%; P = 0.0037). No rebound in the flare rate was observed for 6 weeks after discontinuation of rilonacept or placebo at week 16. Adverse events were similar between groups, and no deaths or serious infectious adverse events were reported; the most common adverse events were infections (14.6% and 26.2% of rilonacept‐ and placebo‐treated patients, respectively) and musculoskeletal disorders (14.6% and 21.4%, respectively). A higher percentage of rilonacept‐treated patients (98%) compared with placebo‐treated patients (79%) completed the primary 12‐week evaluation period (P = 0.015).
Conclusion
The current findings indicate that rilonacept significantly reduces the frequency of gout flares during the initial period of treatment with urate‐lowering therapy, with a favorable safety profile.
The DiscovEHR collaboration between the Regeneron Genetics Center and Geisinger Health System couples high-throughput sequencing to an integrated health care system using longitudinal electronic ...health records (EHRs). We sequenced the exomes of 50,726 adult participants in the DiscovEHR study to identify ~4.2 million rare single-nucleotide variants and insertion/deletion events, of which ~176,000 are predicted to result in a loss of gene function. Linking these data to EHR-derived clinical phenotypes, we find clinical associations supporting therapeutic targets, including genes encoding drug targets for lipid lowering, and identify previously unidentified rare alleles associated with lipid levels and other blood level traits. About 3.5% of individuals harbor deleterious variants in 76 clinically actionable genes. The DiscovEHR data set provides a blueprint for large-scale precision medicine initiatives and genomics-guided therapeutic discovery.
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