Summary Background Reports of serious joint adverse events (AEs) due to osteonecrosis were noted during randomized placebo-controlled clinical trials of monoclonal antibodies to nerve growth factor ...(NGF), including tanezumab and fulranumab. Methods All available medical records from subjects with reported cases of osteonecrosis, as well as records of subjects who underwent joint replacement during these studies, were reviewed by an independent adjudication committee that was established by each company; the committees were different for each company and included distinct individual experts. Cases were categorized as having definite osteonecrosis, normal or rapid progression of osteoarthritis (OA), another diagnosis or unable to determine the underlying diagnosis. Results The vast majority of investigator reported cases of osteonecrosis were adjudicated as either normal or rapid progression of OA. Indeed, the syndrome of rapid progression of OA associated with chondrolysis and bone destruction appears to be a safety signal that is associated with not only increasing doses of anti-NGF antibodies but also concomitant therapy with nonsteroidal anti-inflammatory drugs. Conclusions These results have implications for future clinical trials of anti-NGF agents in OA and other painful conditions.
Objective
Use of several immunomodulatory agents has been associated with reduced numbers of cardiovascular (CV) events in epidemiologic studies of rheumatoid arthritis (RA). However, it is unknown ...whether time‐averaged disease activity in RA correlates with CV events.
Methods
We studied patients with RA whose cases were followed in a longitudinal US‐based registry. Time‐averaged disease activity was assessed during followup using the area under the curve of the Clinical Disease Activity Index (CDAI), a validated measure of RA disease activity. Age, sex, presence of diabetes mellitus, hypertension, or hyperlipidemia, body mass index, family history of myocardial infarction (MI), use of aspirin or nonsteroidal antiinflammatory drugs (NSAIDs), presence of CV disease, and baseline use of an immunomodulator were assessed at baseline. Cox proportional hazards regression models were examined to determine the risk of a composite CV end point that included MI, stroke, and death from CV causes.
Results
A total of 24,989 patients who had been followed up for a median of 2.7 years were included in these analyses. During followup, we observed 534 confirmed CV end points, for an incidence rate of 7.8 per 1,000 person‐years (95% confidence interval 95% CI 6.7–8.9). In models adjusted for variables noted above, a 10‐point reduction in the time‐averaged CDAI was associated with a 21% reduction in CV risk (95% CI 13–29). These results were robust in subgroup analyses stratified by the presence of CV disease, use of corticosteroids, use of NSAIDs or selective cyclooxygenase 2 inhibitors, and change in RA treatment, as well as when restricted to events adjudicated as definite or probable.
Conclusion
Our findings showed that reduced time‐averaged disease activity in RA is associated with fewer CV events.
Abstract Objectives Existing practice guidelines for osteoarthritis (OA) analyze the evidence behind each proposed treatment but do not prioritize the interventions in a given sequence. The objective ...was to develop a treatment algorithm recommendation that is easier to interpret for the prescribing physician based on the available evidence and that is applicable in Europe and internationally. The knee was used as the model OA joint. Methods ESCEO assembled a task force of 13 international experts (rheumatologists, clinical epidemiologists, and clinical scientists). Existing guidelines were reviewed; all interventions listed and recent evidence were retrieved using established databases. A first schematic flow chart with treatment prioritization was discussed in a 1-day meeting and shaped to the treatment algorithm. Fine-tuning occurred by electronic communication and three consultation rounds until consensus. Results Basic principles consist of the need for a combined pharmacological and non-pharmacological treatment with a core set of initial measures, including information access/education, weight loss if overweight, and an appropriate exercise program. Four multimodal steps are then established. Step 1 consists of background therapy, either non-pharmacological (referral to a physical therapist for re-alignment treatment if needed and sequential introduction of further physical interventions initially and at any time thereafter) or pharmacological. The latter consists of chronic Symptomatic Slow-Acting Drugs for OA (e.g., prescription glucosamine sulfate and/or chondroitin sulfate) with paracetamol at-need; topical NSAIDs are added in the still symptomatic patient. Step 2 consists of the advanced pharmacological management in the persistent symptomatic patient and is centered on the use of oral COX-2 selective or non-selective NSAIDs, chosen based on concomitant risk factors, with intra-articular corticosteroids or hyaluronate for further symptom relief if insufficient. In Step 3, the last pharmacological attempts before surgery are represented by weak opioids and other central analgesics. Finally, Step 4 consists of end-stage disease management and surgery, with classical opioids as a difficult-to-manage alternative when surgery is contraindicated. Conclusions The proposed treatment algorithm may represent a new framework for the development of future guidelines for the management of OA, more easily accessible to physicians.
To compare the efficacy and safety of chondroitin sulfate plus glucosamine hydrochloride (CS+GH) versus celecoxib in patients with knee osteoarthritis and severe pain.
Double-blind Multicentre ...Osteoarthritis interVEntion trial with SYSADOA (MOVES) conducted in France, Germany, Poland and Spain evaluating treatment with CS+GH versus celecoxib in 606 patients with Kellgren and Lawrence grades 2-3 knee osteoarthritis and moderate-to-severe pain (Western Ontario and McMaster osteoarthritis index (WOMAC) score ≥301; 0-500 scale). Patients were randomised to receive 400 mg CS plus 500 mg GH three times a day or 200 mg celecoxib every day for 6 months. The primary outcome was the mean decrease in WOMAC pain from baseline to 6 months. Secondary outcomes included WOMAC function and stiffness, visual analogue scale for pain, presence of joint swelling/effusion, rescue medication consumption, Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society International (OMERACT-OARSI) criteria and EuroQoL-5D.
The adjusted mean change (95% CI) in WOMAC pain was -185.7 (-200.3 to -171.1) (50.1% decrease) with CS+GH and -186.8 (-201.7 to -171.9) (50.2% decrease) with celecoxib, meeting the non-inferiority margin of -40: -1.11 (-22.0 to 19.8; p=0.92). All sensitivity analyses were consistent with that result. At 6 months, 79.7% of patients in the combination group and 79.2% in the celecoxib group fulfilled OMERACT-OARSI criteria. Both groups elicited a reduction >50% in the presence of joint swelling; a similar reduction was seen for effusion. No differences were observed for the other secondary outcomes. Adverse events were low and similarly distributed between groups.
CS+GH has comparable efficacy to celecoxib in reducing pain, stiffness, functional limitation and joint swelling/effusion after 6 months in patients with painful knee osteoarthritis, with a good safety profile.
NCT01425853.
Summary Objective To update a published meta-analysis of double-blind placebo-controlled randomized clinical trials (RCTs) to assess the efficacy of chondroitin sulfate as a structure-modifying drug ...for knee osteoarthritis (OA). Design A published meta-analysis of randomized controlled trials was updated to include data from one new trial and final data from a second trial both published recently in peer-reviewed literature. This meta-analysis was limited to three RCTs of 2-year duration. Data were pooled using a fixed effects model as there was no evidence of important heterogeneity. Results Pooled results demonstrated a small significant effect of chondroitin sulfate on the reduction in rate of decline in minimum joint space width of 0.13 mm 95% confidence interval (CI) 0.06, 0.19 ( P = 0.0002) that corresponded to an effect size of 0.23 (95% CI 0.11, 0.35) ( P = 0.0001). Conclusion These results demonstrate that chondroitin sulfate is effective for reducing the rate of decline in minimum joint space width in patients with knee OA.
Abstract The European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) published a treatment algorithm for the management of knee osteoarthritis (OA) in 2014, ...which provides practical guidance for the prioritization of interventions. Further analysis of real-world data for OA provides additional evidence in support of pharmacological interventions, in terms of management of OA pain and function, avoidance of adverse events, disease-modifying effects and long-term outcomes, e.g., delay of total joint replacement surgery, and pharmacoeconomic factors such as reduction in healthcare resource utilization. This article provides an updated assessment of the literature for selected interventions in OA, focusing on real-life data, with the aim of providing easy-to-follow advice on how to establish a treatment flow in patients with knee OA in primary care clinical practice, in support of the clinicians’ individualized assessment of the patient. In step 1, background maintenance therapy with symptomatic slow-acting drugs for osteoarthritis (SYSADOAs) is recommended, for which high-quality evidence is provided only for the prescription formulations of patented crystalline glucosamine sulfate and chondroitin sulfate. Paracetamol may be added for rescue analgesia only, due to limited efficacy and increasing safety signals. Topical non-steroidal anti-inflammatory drugs (NSAIDs) may provide additional symptomatic treatment with the same degree of efficacy as oral NSAIDs without the systemic safety concerns. Oral NSAIDs maintain a central role in step 2 advanced management of persistent symptoms. However, oral NSAIDs are highly heterogeneous in terms of gastrointestinal and cardiovascular safety profile, and patient stratification with careful treatment selection is advocated to maximize the risk:benefit ratio. Intra-articular hyaluronic acid as a next step provides sustained clinical benefit with effects lasting up to 6 months after a short-course of weekly injections. As a last step before surgery, the slow titration of sustained-release tramadol, a weak opioid, affords sustained analgesia with improved tolerability.
Abstract Objectives There is an important need to evaluate therapeutic approaches for osteoarthritis (OA) in terms of cost-effectiveness as well as efficacy. Methods The ESCEO expert working group ...met to discuss the epidemiological and economic evidence that justifies the increasing concern of the impact of this disease and reviewed the current state-of-the-art in health economic studies in this field. Results OA is a debilitating disease; it is increasing in frequency and is associated with a substantial and growing burden on society, in terms of both burden of illness and cost of illness. Economic evaluations in this field are relatively rare, and those that do exist, show considerable heterogeneity of methodological approach (such as indicated population, comparator, decision context and perspective, time horizon, modeling and outcome measures used). This heterogeneity makes comparisons between studies problematic. Conclusions Better adherence to guidelines for economic evaluations is needed. There was strong support for the definition of a reference case and for what might constitute “standard optimal care” in terms of best clinical practice, for the control arms of interventional studies.
Acetaminophen for osteoarthritis Towheed, Tanveer; Maxwell, Lara; Judd, Maria ...
Cochrane database of systematic reviews,
01/2006, Letnik:
2010, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Background
Osteoarthritis (OA) is the most common form of arthritis. Published guidelines and expert opinion are divided over the relative role of acetaminophen (also called paracetamol or Tylenol) ...and non‐steroidal anti‐inflammatory drugs (NSAIDs) as first‐line pharmacologic therapy. The comparative safety of acetaminophen and NSAIDs is also important to consider. This update to the original 2003 review includes nine additional RCTs.
Objectives
To assess the efficacy and safety of acetaminophen versus placebo and versus NSAIDs (ibuprofen, diclofenac, arthrotec, celecoxib, naproxen, rofecoxib) for treating OA.
Search methods
We searched MEDLINE (up to July 2005), EMBASE (2002‐July 2005), Cochrane Central Register of Controlled Trials (CENTRAL), ACP Journal Club, DARE, Cochrane Database of Systematic Reviews (all from 1994 to July 2005). Reference lists of identified RCTs and pertinent review articles were also hand searched.
Selection criteria
Published randomized controlled trials (RCTs) evaluating the efficacy and safety of acetaminophen alone in OA were considered for inclusion.
Data collection and analysis
Pain, physical function and global assessment outcomes were reported. Results for continuous outcome measures were expressed as standardized mean differences (SMD). Dichotomous outcome measures were pooled using relative risk (RR) and the number needed to treat (NNT) was calculated.
Main results
Fifteen RCTs involving 5986 participants were included in this review. Seven RCTs compared acetaminophen to placebo and ten RCTs compared acetaminophen to NSAIDs. In the placebo‐controlled RCTs, acetaminophen was superior to placebo in five of the seven RCTs and had a similar safety profile. Compared to placebo, a pooled analysis of five trials of overall pain using multiple methods demonstrated a statistically significant reduction in pain (SMD ‐0.13, 95% CI ‐0.22 to ‐0.04), which is of questionable clinical significance. The relative percent improvement from baseline was 5% with an absolute change of 4 points on a 0 to 100 scale. The NNT to achieve an improvement in pain ranged from 4 to 16. In the comparator‐controlled RCTs, acetaminophen was less effective overall than NSAIDs in terms of pain reduction, global assessments and in terms of improvements in functional status. No significant difference was found overall between the safety of acetaminophen and NSAIDs, although patients taking traditional NSAIDS were more likely to experience an adverse GI event (RR 1.47, (95% CI 1.08 to 2.00). 19% of patients in the traditional NSAID group versus 13% in the acetaminophen group experienced an adverse GI event. However, the median trial duration was only 6 weeks and it is difficult to assess adverse outcomes in a relatively short time period.
Authors' conclusions
The evidence to date suggests that NSAIDs are superior to acetaminophen for improving knee and hip pain in people with OA. The size of the treatment effect was modest, and the median trial duration was only six weeks, therefore, additional considerations need to be factored in when making the decision between using acetaminophen or NSAIDs. In OA subjects with moderate‐to‐severe levels of pain, NSAIDs appear to be more effective than acetaminophen.
Summary Objective To respond to a pre-specified set of questions posed by the United States Food and Drug Administration (FDA) on defining the disease state to inform the clinical development of ...drugs, biological products, and medical devices for the prevention and treatment of osteoarthritis (OA). Methods An Osteoarthritis Research Society International (OARSI) Disease State working group was established, comprised of representatives from academia and industry. The Working Group met in person and by teleconference on several occasions from the Spring of 2008 through the Autumn of 2009 to develop consensus-based, evidence-informed responses to these questions. A report was presented at a public forum in December 2009 and accepted by the OARSI Board of Directors in the Summer of 2010. Results An operational definition of OA was developed incorporating current understanding of the condition. The structural changes that characterize OA at the joint level were distinguished from the patients’ experience of OA as the ‘disease’ and ‘illness’, respectively. Recommendations were made regarding the evaluation of both in future OA clinical trials. The current poor understanding of the phenotypes that characterize OA was identified as an important area for future research. Conclusions The design and conduct of clinical trials for new OA treatments should address the heterogeneity of the disease, treatment-associated structural changes in target joints and patient-reported outcomes.
To assess the safety, pharmacokinetics, and exploratory efficacy of SM04690, a novel Wnt pathway inhibitor, as a potential disease modifying treatment for knee osteoarthritis (OA).
Subjects with ...Kellgren-Lawrence grade 2–3 knee OA were randomized in successive dose-escalation cohorts to receive a knee intra-articular (IA) injection with 0.03, 0.07, or 0.23 mg SM04690, or placebo (PBO) (4:1 ratio). Safety, pharmacokinetics, efficacy (WOMAC Total/Function/Pain, Pain VAS, Physician Global Assessment MDGA, and OMERACT-OARSI Response), OA-related biomarker (P1NP, ß-CTX, and cartilage oligomeric matrix protein COMP), and radiographic/imaging data were collected at baseline and during 24-week follow-up.
61 subjects (SM04690 n = 50; PBO n = 11) enrolled. Two dose limiting toxicities (DLTs), increased pain following injection and paroxysmal tachycardia (also the single serious AE), were reported in the 0.07 mg cohort. A total of 72 AEs were reported; Sixteen (occurring in eight subjects) were considered related to study medication. There were three discontinuations; one due to an AE (0.03 mg cohort). Bone marrow edema (BME) remained constant for most subjects. No doses were excluded from further study due to DLT criteria. Plasma levels of SM04690 were below the limit of detection at all time points. At Week 24, improvements from baseline were seen in all cohorts for the exploratory measures WOMAC Total, WOMAC Function, WOMAC Pain, MDGA, Pain VAS, and OMERACT-OARSI response. Joint space width (JSW) improvement was observed in the 0.07 mg cohort (P = 0.02 vs PBO).
SM04690 appeared safe and well tolerated, with no evidence of systemic exposure. Exploratory efficacy analyses suggested positive trends for measurements of OA pain, function and disease-modifying osteoarthritis drug (DMOAD) properties.
NCT02095548.
PDF
