Critical appraisal of intra-articular glucocorticoid injections for symptomatic osteoarthritis of the knee.

OBJECTIVE: Intra-articular (IA) injections of glucocorticoids (GCs) have been shown to decrease pain, increase mobility, and improve quality of life in patients with osteoarthritis (OA) of the knee. Concerns about cartilage loss with IA GCs have prompted reconsideration of their use in knee OA. This review has three objectives: 1) critically review the clinical, molecular, and structural effects of IA GCs in knee OA; 2) provide a design for a clinical trial aimed at improving our understanding of the long-term consequences of IA GCs; and 3) provide practical guidance on the use of IA GCs in patients with knee OA based on current information. DESIGN: A narrative review of current literature on the use of IA GCs for OA of the knee. RESULTS: Important questions remain to be fully answered with respect to IA GCs, including long-term effects on all aspects of the structural and molecular environment of the knee, and identification of factors that can reliably predict a positive or negative response to IA GCs. CONCLUSIONS: While awaiting results from an appropriately designed study, several provisional statements regarding IA GCs can be put forward: 1) IA GCs appear to be a relatively safe option that is effective in specific patients with symptomatic knee OA; 2) there is no definitive evidence that IA GCs accelerate joint deterioration to an important extent or hastens the requirement for knee replacement; and 3) there are few contraindications to IA GCs and injection-associated complications are rare when IA GCs are delivered with proper technique.

Proposed study designs for approval based on a surrogate endpoint and a post-marketing confirmatory study under FDA's accelerated approval regulations for disease modifying osteoarthritis drugs.

In 1992, the Food and Drug Administration (FDA) instituted the accelerated approval regulations that allow drugs or biologics for serious conditions that fill an unmet medical need to be approved on the basis of a surrogate endpoint or an intermediate clinical endpoint. The current definition of a serious condition includes chronic disabling conditions, such as osteoarthritis (OA), and thereby provides expanded opportunities for the use of biomarkers for regulatory approval of drugs for OA. The use of surrogates or intermediate clinical endpoints for initial regulatory approval of a drug or biologic requires confirmation in a post-marketing study of a drug effect on a clinically relevant outcome, such as on how a patient feels, functions or survives. Current FDA guidance requires that the post-marketing approval (PMA) study be ongoing during the time of initial drug approval. This white paper arose out of the need to brainstorm trial designs that might be suitable for PMA of drugs initially approved, on the basis of a surrogate or intermediate clinical endpoint, for treatment of OA to alter disease progression, abnormal function or pathological changes in the morphology of the joint. In this white paper we define the concept and regulations regarding accelerated approval and propose two major study design scenarios for PMA trials in OA. The long-term goal is to discuss and refine these designs in consultation with regulatory agencies in order to facilitate development of drugs to fill the large unmet need in OA.

A critical review of clinical trials in systemic lupus erythematosus.

One challenge in caring for patients with systemic lupus erythematosus (SLE) is a paucity of approved therapeutics for treatment of the diverse disease manifestations. In the last 60 years, only one drug, belimumab, has been approved for SLE treatment. Critical evaluation of investigator initiated and pharma-sponsored randomized controlled trials (RCTs) highlights barriers to successful drug development in SLE, including disease heterogeneity, inadequate trial size or duration, insufficient dose finding before initiation of large trials, handling of background medications, and choice of primary endpoint. Herein we examine lessons learned from landmark SLE RCTs and subsequent advances in trial design, as well as discuss efforts to address limitations in current SLE outcome measures that will improve detection of true therapeutic responses in future RCTs.

OARSI Clinical Trials Recommendations: An abbreviated regulatory guide to the clinical requirements for development of therapeutics in osteoarthritis.

In this brief abbreviated review of regulatory issues regarding the development of drugs and or devices for the treatment of osteoarthritis (OA), the steps that are expected by both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) are discussed.

OARSI Clinical Trials Recommendations: Design and conduct of clinical trials for hip osteoarthritis.

The ability to assess the efficacy and effectiveness of an intervention for the treatment of hip osteoarthritis (OA) requires strong clinical trial methodology. This consensus paper provides recommendations based on a narrative literature review and best judgment of the members of the committee for clinical trials of hip OA. We provide recommendations on clinical trial design, outcome measures, including structural (radiography), and patient and physician global assessments, performance based measures, molecular markers and experimental endpoints including MRI imaging. This information can be utilized by sponsors of trials for new therapeutic agents for hip OA.

OARSI Clinical Trials Recommendations: Design and conduct of clinical trials for hand osteoarthritis.

Hand osteoarthritis (OA) is a very frequent disease, but yet understudied. However, a lot of works have been published in the past 10 years, and much has been done to better understand its clinical course and structural progression. Despite this new knowledge, few therapeutic trials have been conducted in hand OA. The last OARSI recommendations for the conduct of clinical trials in hand OA dates back to 2006. The present recommendations aimed at updating previous recommendations, by incorporating new data. The purpose of this expert opinion, consensus driven exercise is to provide evidence-based guidance on the design, execution and analysis of clinical trials in hand OA, where published evidence is available, supplemented by expert opinion, where evidence is lacking, to perform clinical trials in hand OA, both for symptom and for structure-modification. They indicate core outcome measurement sets for studies in hand OA, and list the methods and instruments that should be used to measure symptoms or structure. For both symptom- and structure-modification, at least pain, physical function, patient global assessment, HR-QoL, joint activity and hand strength should be assessed. In addition, for structure-modification trials, structural progression should be measured by radiographic changes. We also provide a research agenda listing many unsolved issues that seem to most urgently need to be addressed from the perspective of performing "good" clinical trials in hand OA. These updated OARSI recommendations should allow for better standardizing the conduct of clinical trials in hand OA in the next future.

Safety issues in the development of treatments for osteoarthritis: recommendations of the Safety Considerations Working Group.

OBJECTIVE: The symptomatic treatment of osteoarthritis (OA) remains to be improved, as many patients do not respond well to current palliative therapies and/or suffer unacceptable adverse events. Given the unmet need for innovative, effective and well-tolerated therapies, it is important to develop the means to estimate the ongoing safety profile of novel therapeutic agents over short- and longer term use. DESIGN: Methods are presented to estimate the number of serious adverse events (SAEs) of interest considered as "acceptable" per 1000 patient-years exposure and to estimate the numbers of patient-years needed in a randomized controlled trial (RCT) to meet objectives. As exposure is increased, more evidence is accrued that the overall risk is within study limits. It is equally important that requirements for delineating the safety of promising new therapies not create barriers that would preclude their development. Therefore, ongoing surveillance of occurrence of SAEs of interest during clinical development is proposed, for example after every incremental 500 patient-years exposure are accrued. RESULTS: This paper and others in this special issue focus on identification of safety signals for symptomatic treatments of OA. Much less information is available for agents aimed at slowing/preventing structural progression but it is expected that a higher risk profile might be considered acceptable in the context of more promising benefit. CONCLUSION: This paper provides a proposal and supporting data for a comprehensive approach for assessing ongoing safety during clinical development of both palliative and disease-modifying therapies for OA.

Outcome measures in placebo-controlled trials of osteoarthritis: responsiveness to treatment effects in the REPORT database.

INTRODUCTION: Treatment response in randomized clinical trials (RCT) of osteoarthritis (OA) has been assessed by multiple primary and secondary outcomes, including pain, function, patient and clinician global measures of status and response to treatment, and various composite and responder measures. Identifying outcome measures with greater responsiveness to treatment is important to increase the assay sensitivity of RCTs. OBJECTIVE: To assess and compare the responsiveness of different outcome measures used in placebo-controlled RCTs of OA. SEARCH STRATEGY: The Resource for Evaluating Procedures and Outcomes of Randomized Trials database includes placebo-controlled clinical trials of pharmacologic treatments (oral, topical, or transdermal) for OA identified from a systematic literature search of RCTs published or publicly available before August 5, 2009, which was conducted using PubMed, the Cochrane collaboration, publicly-available websites, and reference lists of retrieved publications. DATA COLLECTION AND ANALYSIS: Data collected included: (1) pain assessed with single-item ratings and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale; (2) patient and clinician global measures of status, improvement, and treatment response; (3) function assessed by the WOMAC function subscale; (4) stiffness assessed by the WOMAC stiffness subscale; and (5) the WOMAC and Lequesne Algofunctional Index composite outcomes. Measures were grouped according to the total number of response categories (i.e., <10 categories or ≥10 categories). The treatment effect (difference in mean change from baseline between the placebo and active therapy arms) and standardized effect size (SES) were estimated for each measure in a meta-analysis using a random effects model. RESULTS: There were 125 RCTs with data to compute the treatment effect for at least one measure; the majority evaluated non-steroidal anti-inflammatory drugs (NSAIDs), followed by opioids, glucosamine and/or chondroitin, and acetaminophen. In general, the patient-reported pain outcome measures had comparable responsiveness to treatment as shown by the estimates of treatment effects and SES. Treatment effects and SESs were generally higher for patient-reported global measures compared with clinician-rated global measures but generally similar for the WOMAC and Lequesne composite measures. CONCLUSIONS: Comparing different outcome measures using meta-analysis and selecting those that have the greatest ability to identify efficacious treatments may increase the efficiency of clinical trials of treatments for OA. Improvements in the quality of the reporting of clinical trial results are needed to facilitate meta-analyses to evaluate the responsiveness of outcome measures and to also address other issues related to assay sensitivity.

A modified Delphi exercise to determine the extent of consensus with OMERACT outcome domains for studies of acute and chronic gout.

OBJECTIVES: To reach consensus with recommendations made by an OMERACT Special Interest Group (SIG). METHODS: Rheumatologists and industry representatives interested in gout rated and clarified, in three iterations, the importance of domains proposed by the OMERACT SIG for use in acute and chronic gout intervention studies. Consensus was defined as a value of less than 1 of the UCLA/RAND disagreement index. RESULTS: There were 33 respondents (61% response rate); all agreed the initial items were necessary, except "total body urate pool". Additional domains were suggested and clarification sought for defining "joint inflammation" and "musculoskeletal function". Items that demonstrated no clear decision were re-rated in the final iteration. There were six highly rated items (rating 1-2) with four slightly lower rating items (rating 3) for acute gout; and 11 highly rated items with eight slightly lower ratings for chronic gout. CONCLUSIONS: Consensus is that the following domains be considered mandatory for acute gout studies: pain, joint swelling, joint tenderness, patient global, physician global, functional disability; and for chronic gout studies: serum urate, gout flares, tophus regression, health-related quality of life, functional disability, pain, patient global, physician global, work disability and joint inflammation. Several additional domains were considered discretionary.

OMERACT: an international initiative to improve outcome measurement in rheumatology.

OMERACT is the acronym for an international, informally organized network aimed at improving outcome measurement in rheumatology. Chaired by an executive committee it organizes consensus conferences in a 2-yearly cycle that circles the globe since 2002. Data driven recommendations are prepared and updated by expert working groups. Recommendations include core sets of measures for most of the major rheumatologic conditions. Since 2002 patients have been actively engaged in the process. OMERACT 8 will take place in Malta, May 2006 (www.omeract.org).

Unresolved issues in the role of cyclooxygenase-2 in normal physiologic processes and disease.

Originally suggested to function mainly in inflammatory situations, recent data have implied important roles for the cyclooxygenase-2 isoenzyme in reproductive biologic processes, renal and neurologic function, and the antithrombotic activities of endothelial cells. As cyclooxygenase-2-specific inhibitors have recently become available as analgesic and anti-inflammatory drugs, a comprehensive view of this rapidly evolving field is necessary to anticipate both the potential therapeutic benefits and toxic effects associated with these agents.

Procollagen type I carboxy-terminal extension peptide in serum as a marker of collagen biosynthesis in bone. Correlation with Iliac bone formation rates and comparison with total alkaline phosphatase.

We measured iliac bone formation rates on all surfaces after double tetracycline labeling, serum levels of type 1 procollagen carboxy-terminal extension peptide (pColl-I-C), and serum levels of total alkaline phosphatase activity (TAP) in four normal subjects and in 44 patients with various forms of metabolic bone disease. In three patients with enzymatic evidence of liver disease both biochemical serum markers were disproportionately raised. In a patient with idiopathic axial osteosclerosis serum pColl-I-C was selectively increased by more than ten-fold. In the remaining 44 subjects pColl-I-C and TAP levels correlated significantly with each other (r = 0.70) and both showed the same directional changes and broadly similar correlations with iliac bone formation rate expressed in different ways. In general, pColl-I-C levels correlated better with cancellous bone formation rates and TAP levels cortical bone formation rates. There was a modest improvement in prediction of bone formation rate with multiple regression using both markers. In 15 patients with typical uncomplicated postmenopausal osteoporosis, neither biochemical marker, singly or jointly, correlated significantly with any expression of bone formation rate. Disadvantages to the use of pColl-I-C as a marker include a significant contribution to the serum level from type 1 collagen biosynthesis in tissues other than bone, and (probably) variable metabolic clearance. For both biochemical markers the most consistently high correlations (r = 0.77-0.79) were found with total bone formation rate for the entire biopsy core volume, which is the best estimate available from a biopsy of formation rate at the bone organ level of organization in vivo. The core volume as a referent also allows the amount of bone formed on cortical, endocortical, and cancellous surfaces to be compared. Measurement of serum pColl-I-C levels merits further study as a noninvasive index of bone metabolism. Differences between normal and abnormal subjects in the relationships between a variety of biochemical markers and a variety of histologic indices have the potential for providing insight into the pathogenesis of osteoporosis.

Changes in serum levels of type I and III procollagen extension peptides during infusion of human parathyroid hormone fragment (1-34).

Parathyroid hormone (PTH) inhibits collagen synthesis in vitro, in organ or cell culture and cell-free translation systems. We have designed studies to measure the effects of PTH on collagen synthesis in vivo in humans, utilizing measurements of the serum levels of procollagen extension peptides during and after infusion of synthetic human PTH (hPTH) fragment (1-34). Radioimmunoassays for the carboxy-terminal peptide of type I procollagen (pColl-C) and the amino-terminal peptide of type III procollagen (pColl-III-N) were used to measure acute changes in serum during and after hPTH(1-34). In all six osteoporotic subjects and two normal individuals, serum levels of pColl-I-C were decreased by 16 hr of infusion and returned towards normal 14 hr after the infusion was discontinued; serum levels of pColl-III-N did not change significantly during the infusion, but were increased at 14 hr after the infusion was discontinued. The PTH-induced decrease in levels of pColl-I-C correlated with an increase in blood levels of ionized calcium. In all but two subjects the serum levels of 1,25-dihydroxy vitamin D [1,25(OH)2D] were also increased during the period when serum levels of pColl-I-C were decreased. These results are compatible with the conclusion that infusion of PTH acutely inhibits type I (bone) collagen synthesis, but not type III collagen synthesis. These effects could be direct or indirect, related in part to PTH-induced increased 1-alpha-hydroxylation of 25-(OH) vitamin D and the resultant increased serum levels of 1,25(OH)2D.

Serum levels of type I and III procollagen fragments in Paget's disease of bone.

Patients with Paget's disease of bone were found to have elevated serum levels of type I procollagen carboxyterminal peptide (pColl-I-C) which correlated with other measurements of disease activity. The elevated levels of pColl-I-C decreased within hours after the injection of salmon calcitonin and within weeks after oral dichloromethylene diphosphonate treatment. The decrease in serum pColl-I-C after a single injection of salmon calcitonin was associated with a decrease in urinary hydroxyproline excretion, both of which rose toward pretreatment values within 7 h. The pColl-I-C levels remained normal for months after dichloromethylene diphosphonate therapy was discontinued. Using a RIA for the type III procollagen amino-terminal peptide (pColl-III-N), it was found that serum levels were also elevated in patients with Paget's disease. The levels of pColl-III-N also decreased after the injection of salmon calcitonin, but not to the same extent as those of pColl-I-C. After chronic therapy with dichloromethylene diphosphonate, serum levels of pColl-III-N decreased, but not into the normal range. We postulate that whereas pColl-I-C is derived from synthesis of mineralized bone collagen, pColl-III-N is derived from the loose fibrous stroma replacing marrow in areas closely associated with active Pagetic bone disease.

A rapid method for assessment of a macrophage chemotactant produced by SaD2 fibrosarcoma cells in vitro.

A new rapid method for assessing murine macrophage chemotaxis was developed using peritoneal exudate cells labeled with [5,6-3H]uridine in modified Boyden chambers with double polycarbonate filters. The method gave positive results with endotoxin-treated mouse serum and with serum-free culture supernatant of the DBA/2 SaD2 fibrosarcoma. These results correlated with results obtained with conventional microscopic assessment of chemotaxis. Using this method, the SaD2 supernatant was shown to be chemotactic rather than chemokinetic.

Role and regulation of cyclooxygenase-2 during inflammation.

Prostaglandins are formed from arachidonic acid by the action of cyclooxygenase (COX) and subsequent downstream synthetases. Recently, it has been found that there are two closely related forms of COX, which are now known as COX-1 and COX-2. Although both isoforms of this enzyme convert arachidonate to prostaglandins, there are significant differences in their distribution in the body and their roles in health and disease. The basis for these important differences lies in the genes for COX-1 and COX-2 and the regulation of these genes. COX-1, the predominantly constitutive form of the enzyme, is expressed throughout the body and provides certain homeostatic functions, such as maintaining normal gastric mucosa, influencing renal blood flow, and aiding in blood clotting by abetting platelet aggregation. In contrast, COX-2, the inducible form, is expressed in response to inflammatory and other physiologic stimuli and growth factors and is involved in the production of those prostaglandins that mediate pain and support the inflammatory process. All conventional nonsteroidal anti-inflammatory drugs (NSAIDs) nonspecifically inhibit both COX-1 and COX-2 at standard anti-inflammatory doses. The beneficial anti-inflammatory and analgesic effects occur through the inhibition of COX-2, but the gastrointestinal toxicities and the mild bleeding diathesis occur as a result of concurrent inhibition of COX-1. It is important that physicians fully understand the pharmacologic basis for the differential actions of NSAIDs when prescribing them for pain and inflammation. This understanding is also important so that physicians can critically evaluate the basis for, and the emerging data on, COX-2-specific inhibitors and their potential role in clinical medicine. Agents that would inhibit COX-2 while sparing COX-1 represent an attractive therapeutic development and could represent a major advance in the treatment of rheumatoid arthritis and osteoarthritis, as well as a diverse array of other conditions.

Gastrointestinal toxic side effects of nonsteroidal anti-inflammatory drugs and cyclooxygenase-2-specific inhibitors.

Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat pain and inflammation but are frequently associated with gastrointestinal side effects, including life-threatening bleeding or perforation of gastroduodenal ulcers. Conventional NSAIDs are nonselective inhibitors of two isoforms of cyclooxygenase (COX): COX-1 and COX-2. The inhibition of COX-1 is believed to be responsible for inducing mucosal injury primarily by impairing prostaglandin-dependent mucosal protective mechanisms. The latest development in reducing the incidence of ulcers and ulcer complications associated with conventional NSAIDs is the use of recently approved COX-2-specific inhibitors (CSIs). This article critically reviews the data on gastrointestinal toxic side effects for conventional NSAIDs without as well as with prevention therapy. In addition, we compare these data with those for the CSIs, namely, celecoxib and rofecoxib. Finally, we offer recommendations on the clinical use of these drugs, emphasizing the need to balance clinical effectiveness with the avoidance of potential gastrointestinal side effects.

Viscosupplementation therapy with intra-articular hyaluronic acid. Fact or fantasy?

Pharmacologic therapy for osteoarthritis is presently only palliative and is based on the use of analgesic or anti-inflammatory agents. Simple analgesics, however, do not provide enough of an effect to satisfy the needs of many OA patients, and anti-inflammatory drugs that are currently available do not have favorable risk-to-benefit ratio in typical patients with OA. A need remains, therefore, for therapies that will be analgesic, appropriately anti-inflammatory when necessary, and that may favorably alter the natural history of the disease. The development of intra-articular hyaluronic acid (HA) supplementation was thought to fulfill these criteria. This therapy has been shown to modulate pain in OA of the knee and investigators have attempted to show that it have positive effects on articular cartilage biology. This article considers these claims for HA supplementation as an important therapy for the treatment of OA.

Economic and gastrointestinal safety comparisons of etodolac, nabumetone, and oxaprozin from insurance claims data from patients with arthritis.

This study was conducted to compare the effect of etodolac, nabumetone, and oxaprozin use on gastrointestinal (GI) safety and associated costs based on insurance claims information from practice settings. Data were obtained from a national claims database (MarketScan) for the years 1992 to 1994. The claims data of interest were for patients with arthritis who had used etodolac, nabumetone, or oxaprozin exclusively during a 9-month follow-up period (ONLY groups), or these drugs plus (PLUS groups) the other nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen, naproxen, diclofenac, sulindac, piroxicam, ketoprofen, or indomethacin. For each group, we obtained information on the use of inpatient and outpatient services for GI-related events and the associated costs. All GI admissions were classified as NSAID-induced or possibly NSAID-induced events based on International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9 CM) codes. All outpatient upper GI ulcers or bleeding episodes were also identified by specific ICD-9 CM code. There were no significant between-group demographic differences. The proportions of patients with NSAID-induced and possibly NSAID-induced GI admissions were 0.1% and 0.4% for the etodolac-ONLY, 0.3% and 1.0% for the nabumetone-ONLY, and 0.1% and 0.5% for the oxaprozin-ONLY groups, respectively (P > 0.05), and a similar pattern was observed among the PLUS groups. In outpatient settings, 3.9%, 4.2%, and 4.9% of the etodolac-, nabumetone-, and oxaprozin-ONLY patients, respectively (P > 0.05), and 6.0%, 5.3%, and 4.7% of the etodolac-, nabumetone-, and oxaprozin-PLUS patients, respectively, had at least one upper GI ulcer/bleeding claim (P > 0.05). The total health care costs for 9 months were approximately $3000 each for the etodolac-, nabumetone-, and oxaprozin-ONLY groups. Oxaprozin, nabumetone, and etodolac had similar GI-safety and associated-costs profiles based on information from practice settings. Also, in patients who used multiple NSAIDs, the groups did not differ in their GI-safety and cost profiles.