Treatment of rheumatoid arthritis with anakinra,a recombinant human interleukin‐1 receptor antagonist,in combination with methotrexate: Results of a twenty‐four–week,multicenter, randomized,double‐blind,placebo‐controlled trial

Objective

To evaluate the efficacy and safety of anakinra in combination with methotrexate (MTX) in patients with active rheumatoid arthritis (RA).

Methods

Patients with moderate‐to‐severe active RA who were receiving MTX for 6 consecutive months, with stable doses for ≥3 months (those with disease duration of >6 months but <12 years) were randomized into 6 groups: placebo or 0.04, 0.1, 0.4, 1.0, or 2.0 mg/kg of anakinra administered in a single, daily, subcutaneous injection. The primary efficacy end point was the proportion of subjects who met the American College of Rheumatology 20% improvement criteria (attained an ACR20 response) at week 12.

Results

A total of 419 patients were randomized in the study. Patient demographics and disease status were similar in the 6 treatment groups. The ACR20 responses at week 12 in the 5 active treatment plus MTX groups demonstrated a statistically significant (P = 0.001) dose‐response relationship compared with the ACR20 response in the placebo plus MTX group. The ACR20 response rate in the anakinra 1.0‐mg/kg (46%; P = 0.001) and 2.0‐mg/kg (38%; P = 0.007) dose groups was significantly greater than that in the placebo group (19%). The ACR20 responses at 24 weeks were consistent with those at 12 weeks. Similar improvements in anakinra‐treated subjects were noted in individual ACR components, erythrocyte sedimentation rate, onset of ACR20 response, sustainability of ACR20 response, and magnitude of ACR response. Anakinra was safe and well tolerated. Injection site reaction was the most frequently noted adverse event, and this led to premature study withdrawal in 7% (1.0‐mg/kg group) to 10% (2.0‐mg/kg group) of patients receiving higher doses.

Conclusion

In patients with persistently active RA, the combination of anakinra and MTX was safe and well tolerated and provided significantly greater clinical benefit than MTX alone.

     

Efficacy and safety of four doses of lumiracoxib versus diclofenac in patients with knee or hip primary osteoarthritis: A phase II,four‐week,multicenter, randomized,double‐blind,placebo‐controlled trial

Objective

To compare the efficacy and tolerability of the novel cyclooxygenase 2‐selective inhibitor lumiracoxib with placebo and diclofenac in osteoarthritis (OA).

Methods

Adults (n = 583) with knee or hip OA were randomized to receive for 4 weeks lumiracoxib 50, 100, or 200 mg twice daily or 400 mg once daily; placebo; or diclofenac 75 mg twice daily. Efficacy assessments included overall joint pain intensity and Western Ontario and McMaster Universities Osteoarthritis Index subscales; tolerability was evaluated by adverse event and physician reporting.

Results

All lumiracoxib doses were superior to placebo in relieving pain, improving stiffness, and improving physical function after 4 weeks. At study endpoint, pain relief was comparable among all lumiracoxib dosages and similar to diclofenac. Lumiracoxib tolerability was superior to diclofenac and comparable to placebo.

Conclusion

Lumiracoxib provides predictable and sustained relief from pain, stiffness, and impaired physical function in OA. Lumiracoxib shows clinically comparable efficacy and superior tolerability to diclofenac.

     

Anakinra,a recombinant human interleukin‐1 receptor antagonist (r‐metHuIL‐1ra), in patients with rheumatoid arthritis: A large,international, multicenter,placebo‐controlled trial

Objective

To evaluate the safety of anakinra (a recombinant human interleukin‐1 receptor antagonist) in a large population of patients with rheumatoid arthritis (RA), typical of those seen in clinical practice.

Methods

A total of 1,414 patients were randomly assigned to treatment with 100 mg of anakinra or placebo, administered daily by subcutaneous injection. Background medications included disease‐modifying antirheumatic drugs, corticosteroids, and nonsteroidal antiinflammatory drugs, alone or in combination. The primary end point was safety, which was evaluated by adverse events (including infections), discontinuation from study due to adverse events, and death.

Results

Safety was evaluated in 1,399 patients (1,116 in the anakinra group and 283 in the placebo group; 15 patients were randomized but did not receive any study drug) during the initial 6‐month, double‐blind, placebo‐controlled phase of this long‐term safety study. Baseline demographics, disease characteristics, and concomitant medications were similar between the 2 groups. The study group included patients with numerous comorbid conditions and a wide range of RA disease activity. Serious adverse events occurred at a similar rate in the anakinra group and the placebo group (7.7% and 7.8%, respectively). Serious infectious episodes were observed more frequently in the anakinra group (2.1% versus 0.4% in the placebo group). The rate of withdrawal due to adverse events was 13.4% in the anakinra group and 9.2% in the placebo group.

Conclusion

Results from this large, placebo‐controlled safety study demonstrate that anakinra is safe and well tolerated in a diverse population of patients with RA, including those with comorbid conditions and those using multiple combinations of concomitant therapies. Although the frequency of serious infection was slightly higher in the anakinra group, no infection was attributed to opportunistic microorganisms or resulted in death.

     

Long‐term safety and maintenance of clinical improvement following treatment with anakinra (recombinant human interleukin‐1 receptor antagonist) in patients with rheumatoid arthritis: Extension phase of a randomized,double‐blind,placebo‐controlled trial

Objective

To demonstrate the long‐term efficacy of anakinra, a human recombinant interleukin‐1 receptor antagonist, in patients with rheumatoid arthritis (RA), and to assess the long‐term safety of anakinra at different daily doses.

Methods

The efficacy and safety of anakinra were previously demonstrated in a double‐blind, placebo‐controlled, 24‐week evaluation in 472 patients with active RA. Of 345 patients who completed the placebo‐controlled phase of the study, 309 continued in a 52‐week, multicenter, double‐blind, parallel‐group extension phase of the study. Patients received subcutaneous injections of anakinra (30, 75, or 150 mg) once daily. Efficacy was assessed among the 309 patients for the first 24 weeks of the extension phase (48 weeks total therapy), using the American College of Rheumatology composite score (ACR20), its components, and radiographs of the hands and wrists. Safety was assessed in all 472 patients over the entire 52‐week extension phase (76 weeks total exposure).

Results

A total of 218 patients completed the extension phase. Of the 91 patients who withdrew prematurely, 46 did so following adverse events, and 26 withdrew because of lack of efficacy. Among patients receiving anakinra who entered the extension phase, the level of improvement was maintained for 48 weeks. The ACR20 response was 51% at week 24 and 46% at week 48, and this effect was consistent across all dose groups. The durability of the response to anakinra was further demonstrated in an evaluation of the sustained ACR20 response, which was similar during the first and second 24‐week periods (36% and 42%, respectively). At week 48, ACR50 and ACR70 responses were demonstrated in 18% and 3% of patients, respectively, who continued taking anakinra (all dose groups) and in 20% and 1% of patients, respectively, who were originally receiving placebo and then were randomized to all doses of anakinra. Anakinra was well tolerated for 76 weeks. The only side effects that appeared to be treatment‐related were skin reactions at the injection site. There was no evidence of decreased tolerance, an increased number of withdrawals, or an increased incidence of clinical complications associated with extended anakinra therapy.

Conclusion

The clinical benefits of treatment with daily self‐administered subcutaneous injections of anakinra in a cohort of patients with active RA were maintained for up to 48 weeks. Anakinra was well tolerated over 76 weeks. These observations support the long‐term use of anakinra for the treatment of patients with RA.

     

A randomized controlled trial to evaluate the slow‐acting symptom‐modifying effects of colchicine in osteoarthritis of the knee: A preliminary report

Objective

To determine if colchicine added to nimesulide may have a beneficial effect on osteoarthritis (OA) of the knee.

Methods

Colchicine 0.5 mg twice daily or placebo was added to nimesulide (a nonsteroidal antiinflammatory drug) in 36 patients with OA of the knee in a randomized, double‐blind, placebo‐controlled trial over a 5‐month period.

Results

The 30% improvement rate at 20 weeks was higher in the colchicine group than in the control group receiving placebo, as measured by total Western Ontario and McMaster University Osteoarthritis scores (57.9% versus 23.5%) and visual analog scale for index knee pain (52.6% versus 17.6%) (primary measures of response). The significance persisted on combined analysis by Mantel‐Haenszel test (P = 0.062). Comparison of means also showed significant improvement in the colchicine group versus the control group in a multivariate analysis performed using T² test (P = 0.0115).

Conclusion

Among patients with OA of the knee, the group receiving colchicine plus nimesulide exhibited significantly greater symptomatic benefit at 20 weeks than did the control group receiving nimesulide plus placebo.

     

The safety of anakinra in high‐risk patients with active rheumatoid arthritis: Six‐month observations of patients with comorbid conditions

Objective

To determine in a placebo‐controlled, double‐blind trial the safety profile of daily anakinra (Kineret) use in patients with active rheumatoid arthritis (RA) and concurrent comorbid conditions.

Methods

In 169 centers in 9 countries, 1,414 patients with active RA were randomly assigned to receive either anakinra (100 mg) or placebo treatment (4:1 anakinra‐to‐placebo allocation ratio), with study drug administered by daily subcutaneous injection for 6 months. The current post hoc analysis assessed baseline comorbid conditions, and patients were considered at high risk for the occurrence of adverse events if they had a history of at least one of the following: cardiovascular event, pulmonary event, central nervous system–related event, infection, diabetes, malignancy, or renal impairment. Within each treatment group (anakinra or placebo), incidence rates were summarized for serious adverse events, infectious events, and serious infectious events in high‐risk patients and compared with these incidence rates in patients without comorbid conditions.

Results

The majority of patients in the trial had one or more comorbid conditions. In these high‐risk patients, there were no differences in the incidence of serious adverse events or infectious events between treatment groups. The incidence of serious infectious events with anakinra use was similar between high‐risk patients (2.5%) and the entire study population (2.1%) and was not attributable to any single comorbidity.

Conclusion

Results of the analysis of adverse events in patients with active RA and coexisting comorbidities suggest that the favorable safety profile of anakinra is maintained in a high‐risk patient population.

     

Safety and efficacy of long‐term intraarticular steroid injections in osteoarthritis of the knee: A randomized,double‐blind,placebo‐controlled trial

Objective

To evaluate the safety and efficacy of long‐term intraarticular (IA) steroid injections for knee pain related to osteoarthritis (OA).

Methods

In a randomized, double‐blind trial, 68 patients with OA of the knee received IA injections of triamcinolone acetonide 40 mg (34 patients) or saline (34 patients) into the study knee every 3 months for up to 2 years. The primary outcome variable was radiologic progression of joint space narrowing of the injected knee after 2 years. Measurements of minimum joint space width were performed by an automated computerized method on standardized fluoroscopically guided radiographs taken with the patient standing and with the knee in a semiflexed position. The clinical efficacy measure of primary interest was the pain subscale from the Western Ontario and McMaster Universities OA Index (WOMAC). Efficacy measures of secondary interest were the total score on the WOMAC, physician's global assessment, patient's global assessment, patient's assessment of pain, range of motion (ROM) of the affected knee, and 50‐foot walking time. Clinical symptoms were assessed just before each injection.

Results

At the 1‐year and 2‐year followup evaluations, no difference was noted between the two treatment groups with respect to loss of joint space over time. The steroid‐injected knees showed a trend toward greater symptom improvement, especially at 1 year, for the WOMAC pain subscale, night pain, and ROM values (P = 0.05) compared with the saline‐injected knees. Using area under the curve analyses, knee pain and stiffness were significantly improved throughout the 2‐year study by repeated injections of triamcinolone acetonide, but not saline (P < 0.05).

Conclusion

Our findings support the long‐term safety of IA steroid injections for patients with symptomatic knee OA. No deleterious effects of the long‐term administration of IA steroids on the anatomical structure of the knee were noted. Moreover, long‐term treatment of knee OA with repeated steroid injections appears to be clinically effective for the relief of symptoms of the disease.

     

Effects of intraarticular glucocorticoids on macrophage infiltration and mediators of joint damage in osteoarthritis synovial membranes: Findings in a double‐blind,placebo‐controlled study

Objective

To investigate the effects of intraarticular glucocorticoid treatment on macrophage infiltration, the expression of the chemokines monocyte chemoattractant protein 1 (MCP‐1) and macrophage inflammatory protein 1α (MIP‐1α), and the expression of matrix metalloproteinases 1 and 3 (MMPs 1 and 3) and their inhibitors, the tissue inhibitors of metalloproteinases 1 and 2 (TIMPs 1 and 2), in osteoarthritis (OA) synovial membranes.

Methods

Forty patients underwent arthroscopic biopsy before and 1 month after intraarticular injection of glucocorticoids. Twenty‐one patients received 120 mg of methylprednisolone acetate (Depo‐Medrol; Upjohn, Kalamazoo, MI), and 20 patients received placebo (1 patient received placebo in 1 knee and methylprednisolone acetate in the other). Immunoperoxidase staining for the expression of CD68, MCP‐1, MIP‐1α, MMP‐1, MMP‐3, TIMP‐1, and TIMP‐2 was performed, and the immunostaining was quantified by color video image analysis.

Results

CD68, MCP‐1, MIP‐1α, MMP‐1, MMP‐3, TIMP‐1, and TIMP‐2 immunostaining was observed in all synovial membranes. Intraarticular glucocorticoid treatment was associated with a small (30%) but statistically significant (P = 0.048) reduction in CD68+ macrophage staining in the synovial lining layer, but there was no change in the CD68 expression in the synovial sublining layer. No significant differences were observed for MCP‐1, MIP‐1α, MMP‐1, MMP‐3, TIMP‐1, and TIMP‐2 immunostaining in the synovial lining or sublining layers.

Conclusion

Intraarticular glucocorticoids may reduce CD68+ macrophage infiltration into the synovial lining layer, but not the expression of MCP‐1, MIP‐1α, MMP‐1, MMP‐3, TIMP‐1, and TIMP‐2 in the synovial membrane, in patients with OA.

     

Cannabinoid‐mediated antinociception is enhanced in rat osteoarthritic knees

Objective

To determine whether local administration of the cannabinoid 1 (CB₁) receptor agonist arachidonyl‐2‐chloroethylamide (ACEA) can modulate joint nociception in control rat knee joints and in experimental osteoarthritis (OA).

Methods

OA was induced in male Wistar rats by intraarticular injection of 3 mg of sodium mono‐iodoacetate, with a recovery period of 14 days. Electrophysiologic recordings were made of knee joint primary afferent nerve fibers in response to normal rotation and noxious hyperrotation of the joint both before and after close intraarterial injection of different doses of ACEA.

Results

Local application of the CB₁ agonist significantly reduced the firing rate of afferent nerve fibers by up to 50% in control knee joints (n = 19) and up to 62% in OA knee joints (n = 29; P < 0.01). Coadministration of the CB₁ receptor antagonist AM251 or the transient receptor potential vanilloid 1 (TRPV‐1) ion channel antagonist SB366791 significantly reduced the desensitizing effect of ACEA. The CB₁ receptor antagonist AM251 by itself had no effect in the control joint but significantly increased the firing rate of afferent nerve fibers in the OA joint.

Conclusion

These findings indicate that activation of peripheral CB₁ receptors reduces the mechanosensitivity of afferent nerve fibers in control and OA knee joints. Blockade of either the CB₁ receptor or the TRPV‐1 channel significantly reduced the efficacy of ACEA, which suggests that both receptors are involved in cannabinoid‐mediated antinociception. The increased nerve activity observed following CB₁ receptor antagonism suggests a tonic release of endocannabinoids during OA. As such, peripheral CB₁ receptors may be important targets in controlling OA pain.

     

The role of interleukin‐1β in arthritic pain: Main involvement in thermal,but not mechanical,hyperalgesia in rat antigen‐induced arthritis

Objective

Interleukin‐1β (IL‐1β) is considered a pronociceptive cytokine, but its role in the generation of arthritic pain is unknown. The aim of this study was to investigate the role of IL‐1β in arthritic pain and to explore the antinociceptive potential of the IL‐1 receptor type I (IL‐1RI) antagonist anakinra.

Methods

Antigen‐induced arthritis (AIA) was induced in rats. Expression of IL‐1RI in the dorsal root ganglia (DRGs) was determined, and the effects of anakinra on inflammation, pain‐related behavior, and receptor expression were assessed. In cultured DRG neurons, the effect of IL‐1β on the expression of the transient receptor potential vanilloid 1 (TRPV‐1) ion channel was examined. Recordings of action potentials from joint nociceptors were made after intraarticular injection of IL‐1β into the rat knee joints.

Results

AIA generated pronounced and persistent mechanical and thermal hyperalgesia, and IL‐1RI expression in the lumbar DRGs was significantly up‐regulated. Treatment with anakinra did not significantly reduce the severity of arthritis or mechanical hyperalgesia, but did result in a pronounced reduction in thermal hyperalgesia. In cultured DRG neurons, IL‐1β up‐regulated the expression of TRPV‐1, a major transduction molecule involved in thermal hyperalgesia. During AIA, anakinra treatment down‐regulated the expression of TRPV‐1, consistent with the pronounced reduction in thermal hyperalgesia. IL‐1β increased the mechanosensitivity of C‐fibers of the joint, but reduced the mechanosensitivity of Aδ‐fibers, thus having opposite effects on these mechanonociceptive nerve fibers.

Conclusion

In the context of arthritic knee pain, IL‐1β and IL‐1 receptors appear to be involved in thermal, rather than mechanical, hyperalgesia. Therefore, neutralization of IL‐1β may be mainly antinociceptive in disease states characterized by thermal hyperalgesia, but not in disease states mainly characterized by mechanical hyperalgesia.

     

Long‐term effects of chondroitins 4 and 6 sulfate on knee osteoarthritis: The study on osteoarthritis progression prevention,a two‐year,randomized, double‐blind,placebo‐controlled trial

Objective

To assess the long‐term effects of chondroitins 4 and 6 sulfate (CS) on the radiographic progression of, and symptom changes associated with, knee osteoarthritis (OA).

Methods

We performed an international, randomized, double‐blind, placebo‐controlled trial in which 622 patients with knee OA were randomly assigned to receive either 800 mg CS (n = 309 patients) or placebo (n = 313 patients) once daily for 2 years. Radiographs of the target knee, using the Lyon schuss view, were obtained at the time of enrollment and at 12, 18, and 24 months. The minimum joint space width (JSW) of the medial compartment of the tibiofemoral joint was assessed by digital image analysis. The primary outcome was the loss in minimum JSW over 2 years.

Results

The intent‐to‐treat analysis demonstrated a significant reduction (P < 0.0001) in minimum JSW loss in the CS group (mean ± SEM −0.07 ± 0.03 mm) as compared with the placebo group (−0.31 ± 0.04 mm). The percentage of patients with radiographic progression ≥0.25 mm was significantly reduced in the CS group compared with the placebo group (28% versus 41% [P < 0.0005]; relative risk reduction 33% [95% confidence interval 16–46%]). The number of patients needed to treat was 8 (95% confidence interval 5–17). Pain improved significantly faster in the CS group than in the placebo group (P < 0.01). There were no differences in safety between groups.

Conclusion

The long‐term combined structure‐modifying and symptom‐modifying effects of CS suggest that it could be a disease‐modifying agent in patients with knee OA.

     

Long‐term efficacy of the interleukin‐1 receptor antagonist anakinra in ten patients with neonatal‐onset multisystem inflammatory disease/chronic infantile neurologic,cutaneous, articular syndrome

Objective

Cryopyrin‐associated periodic syndromes (CAPS) are a group of rare autoinflammatory diseases. Neonatal‐onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic, cutaneous, articular syndrome (CINCA syndrome) is the most severe phenotype, with fever, rash, articular manifestations, and neurologic and neurosensory involvement. CAPS are caused by mutations in CIAS1, the gene encoding NLRP3, which plays a critical role in interleukin‐1 (IL‐1) processing. Anakinra, an IL‐1 receptor antagonist, has been shown to be an effective treatment; however, data on long‐term efficacy and safety have been sparse. This study was undertaken to assess the long‐term efficacy and safety of anakinra treatment in patients with NOMID/CINCA syndrome.

Methods

We retrospectively analyzed the medical records of NOMID/CINCA syndrome patients referred to 2 centers, who had started anakinra treatment before June 2007.

Results

There were 10 patients with NOMID/CINCA syndrome who had been treated with anakinra. The patients' ages at the time anakinra treatment was initiated ranged from 3 months to 20 years. They had been followed up for 26–42 months. Sustained efficacy in the treatment of systemic inflammation and, in some cases, neurologic involvement and growth parameters, was achieved. The dosage of anakinra required for efficacy ranged from 1 to 3 mg/kg/day in the 8 oldest patients and from 6 to 10 mg/kg/day in the 2 youngest. Residual central nervous system inflammation and deafness persisted in some patients, especially if there had been a delay in diagnosis and treatment. Secondary amyloidosis persisted in cases in which it was present at treatment initiation, but no new lesions developed. No effect on overgrowth arthropathy was observed. Adverse events consisted of mild injection‐site reactions.

Conclusion

The present results indicate that anakinra treatment is effective over the long term in NOMID/CINCA syndrome. However, treatment has to be initiated before irreversible lesions develop, and, particularly in very young patients, dosage adjustment is required.

     

Antiinflammatory and chondroprotective effects of intraarticular injection of adipose‐derived stem cells in experimental osteoarthritis

Objective

In experimental collagenase‐induced osteoarthritis (OA) in the mouse, synovial lining macrophages are crucial in mediating joint destruction. It was recently shown that adipose‐derived stem cells (ASCs) express immunosuppressive characteristics. This study was undertaken to explore the effect of intraarticular injection of ASCs on synovial lining thickness and its relation to joint pathology in experimental mouse OA.

Methods

ASCs were isolated from fat surrounding the inguinal lymph nodes and cultured for 2 weeks. Experimental OA was induced by injection of collagenase into the knee joints of C57BL/6 mice. OA phenotypes were measured within 8 weeks after induction. Histologic analysis was performed, and synovial thickening, enthesophyte formation, and cartilage destruction were measured in the knee joint.

Results

ASCs were injected into the knee joints of mice 7 days after the induction of collagenase‐induced OA. On day 1, green fluorescent protein–labeled ASCs were attached to the lining layer in close contact with macrophages. Thickening of the synovial lining, formation of enthesophytes associated with medial collateral ligaments, and formation of enthesophytes associated with cruciate ligaments were significantly inhibited on day 42 after ASC treatment, by 31%, 89%, and 44%, respectively. Destruction of cartilage was inhibited on day 14 (65%) and day 42 (35%). In contrast to early treatment, injection of ASCs on day 14 after OA induction showed no significant effect on synovial activation or joint pathology on day 42.

Conclusion

These findings indicate that a single injection of ASCs into the knee joints of mice with early‐stage collagenase‐induced OA inhibits synovial thickening, formation of enthesophytes associated with ligaments, and cartilage destruction.

     

Randomized,double‐blind,placebo‐controlled glucosamine discontinuation trial in knee osteoarthritis

Objective

To assess the efficacy of glucosamine sulfate in knee osteoarthritis (OA).

Methods

A 4‐center, 6‐month, randomized, double‐blind, placebo‐controlled glucosamine discontinuation trial was conducted in 137 current users of glucosamine with knee OA who had experienced at least moderate improvement in knee pain after starting glucosamine. Study medication dosage was equivalent to the dosage of glucosamine taken prior to the study (maximum 1,500 mg/day). Followup continued for 6 months or until disease flare, whichever occurred first. The primary outcome was the proportion of disease flares in the glucosamine and placebo groups using an intent‐to‐treat analysis. Secondary outcomes included time to disease flare; analgesic medication use; severity of disease flare; and change in pain, stiffness, function and quality of life in the glucosamine and placebo groups.

Results

Disease flare was seen in 28 (42%) of 66 placebo patients and 32 (45%) of 71 glucosamine patients (difference ?3%; 95% confidence interval [95% CI] ?19, 14; P = 0.76). In the Cox regression analysis, after adjustment for sex, study site, and OA radiographic severity, time to disease flare was not significantly different in the glucosamine compared with placebo group (hazard ratio of flare = 0.8; 95% CI 0.5, 1.4; P = 0.45). At final study visit, acetaminophen was used in 27% and 21% of placebo and glucosamine patients, respectively (P = 0.40), nonsteroidal antiinflammatory drugs were used in 29% and 30% (P = 0.92), and both were used in 20% and 21% (P = 0.84). No differences were found in severity of disease flare or other secondary outcomes between placebo and glucosamine patients.

Conclusion

In patients with knee OA with at least moderate subjective improvement with prior glucosamine use, this study provides no evidence of symptomatic benefit from continued use of glucosamine sulfate.

     

Diet‐induced obesity significantly increases the severity of posttraumatic arthritis in mice

Objective

Obesity and joint injury are primary risk factors for osteoarthritis (OA) that involve potential alterations in the biomechanical and inflammatory environments of the joint. Posttraumatic arthritis is a frequent long‐term complication of intraarticular fractures. Obesity has been linked to primary OA and may potentially contribute to the development of posttraumatic arthritis by a variety of mechanisms. The objectives of this study were to determine whether diet‐induced obesity influences the severity of posttraumatic arthritis in mice and to examine the interrelationships between joint degeneration and serum levels of the inflammatory cytokines and adipokines that are involved in this response.

Methods

C57BL/6 mice were fed either normal chow (13% fat) or a high‐fat diet (60% fat) starting at 4 weeks of age. At 16 weeks of age, half of the mice in each group were subjected to a closed intraarticular fracture of the left knee. At 8 weeks postfracture, knee OA was assessed by cartilage and synovium histology in addition to bone morphology. Serum cytokine concentrations were determined with multiplex assays.

Results

Fractured knee joints of mice receiving a high‐fat diet showed significantly increased OA degeneration compared with nonfractured contralateral control knees, while fractured knee joints of mice receiving a low‐fat diet did not demonstrate significant differences from nonfractured contralateral control knees. A high‐fat diet increased serum concentrations of interleukin‐12p70 (IL‐12p70), IL‐6, and keratinocyte‐derived chemokine while decreasing adiponectin concentrations. Joint injury also increased IL‐12p70 concentrations in mice receiving a high‐fat diet. Systemic levels of adiponectin were inversely correlated with synovial inflammation in control limbs.

Conclusion

Diet‐induced obesity significantly increased the severity of OA following intraarticular fracture. Obesity and joint injury together can alter systemic levels of inflammatory cytokines such as IL‐12p70.

     

Comparing the efficacy of cyclooxygenase 2–specific inhibitors in treating osteoarthritis: Appropriate trial design considerations and results of a randomized,placebo‐controlled trial

Objective

To compare the efficacy of the cyclooxygenase 2 (COX‐2)–specific inhibitors celecoxib and rofecoxib in treating the signs and symptoms of osteoarthritis (OA).

Methods

In this randomized, placebo‐controlled, double‐blind, multicenter study, 475 patients with OA of the knee received either celecoxib 200 mg/day (n = 189), rofecoxib 25 mg/day (n = 190), or placebo (n = 96) for 6 weeks. Arthritis assessments were performed at baseline, week 3, and week 6 (or at the time of early termination).

Results

In primary measures of efficacy (OA pain score on a 100‐mm visual analog scale [VAS] and total domain score on the Western Ontario and McMaster Universities Osteoarthritis Index), celecoxib 200 mg/day and rofecoxib 25 mg/day demonstrated similar efficacy. At week 6, celecoxib was associated with a 34‐mm mean improvement on the VAS for OA pain, compared with 31.6 mm for rofecoxib and 21.2 mm for placebo. The difference between celecoxib and rofecoxib was −2.5 mm, with an upper limit of the 95% confidence interval of 2.7 mm and within the prespecified definition of noninferiority. Secondary measures of efficacy showed similar results. All differences in primary and secondary measures of efficacy between the 2 active treatments and placebo were statistically significant (P < 0.02), whereas all of the comparisons of efficacy between celecoxib and rofecoxib met the predefined criteria for noninferiority. All treatments were well tolerated throughout the study, with similar proportions of patients withdrawing due to adverse events.

Conclusion

Celecoxib 200 mg/day and rofecoxib 25 mg/day are equally efficacious in treating the signs and symptoms of OA.

     

Effect of hyaluronic acid in symptomatic hip osteoarthritis: A multicenter,randomized, placebo‐controlled trial

Objective

To evaluate the efficacy and tolerability of a single intraarticular (IA) injection of hyaluronic acid (HA) for the treatment of hip osteoarthritis (OA).

Methods

A multicenter, randomized, parallel‐group, placebo‐controlled trial was conducted over 3 months. Patients (older than 30 years) with symptomatic hip OA (pain score of >40 mm on a visual analog scale [VAS]) and a Kellgren/Lawrence grade of 2 or 3 were randomly assigned to receive 1 fluoroscopically guided IA injection of HA (2.5 ml) or placebo (2.5 ml). Patients were followed up for 3 months. The main outcome measure was pain score on a VAS (100 mm) at month 3 compared with baseline. Secondary outcome measures were the proportion of responders defined by Osteoarthritis Research Society International criteria; Western Ontario and McMaster Universities Osteoarthritis Index subscores for pain, stiffness, and disability; and patient and physician global assessment. Randomization was computer generated. HA and placebo preparations were placed in numbered identical containers, and syringes were covered with masking tape. Physicians assessing outcomes were blinded with regard to group assignment.

Results

Eighty‐five patients were randomized to the HA group (n = 42) or placebo group (n = 43). Baseline characteristics were similar between the 2 groups. At 3 months, the decrease in pain score did not differ between the HA and placebo groups in the intent‐to‐treat analysis (mean ± SD decrease 7.8 ± 24.9 mm with HA versus 9.1 ± 27.4 mm with placebo; P = 0.98). The responder rates were 33.3% and 32.6% in the HA and placebo groups, respectively (P = 0.94). Other secondary end points did not differ between the groups, nor did use of rescue medication or frequency of adverse events.

Conclusion

Our findings indicate that a single IA injection of HA is no more effective than placebo in treating the symptoms of hip OA.

     

Tidal irrigation as treatment for knee osteoarthritis: A sham‐controlled,randomized, double‐blinded evaluation

Objective

To evaluate the effectiveness of tidal irrigation (TI) in comparison with a well‐matched sham irrigation (SI) procedure as a treatment for knee osteoarthritis (OA).

Methods

One hundred eighty subjects with knee OA were randomized to receive TI or SI, with clinical followup over the ensuing 12 months. The primary outcomes of interest were change in pain and function, as measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Subjects and the nurse assessor were blinded, and success of blinding was assessed.

Results

Although the study groups were otherwise comparable, the baseline WOMAC pain and physical functioning scores were higher (worse) in the SI group. After adjustment for baseline, there were no differences between the effects of SI and TI. Blinding was successful, with ∼90% of SI and TI subjects stating that they had received the TI procedure.

Conclusion

Most, if not all, of the effect of TI appears to be attributable to a “placebo response.”

     

The efficacy and safety of diacerein in the treatment of painful osteoarthritis of the knee: A randomized,multicenter, double‐blind,placebo‐controlled study with primary end points at two months after the end of a three‐month treatment period

Objective

To determine whether the efficacy of diacerein persists at 2 months after the end of a 3‐month treatment period, compared with placebo, in patients with painful knee osteoarthritis (OA).

Methods

After a 1‐week nonsteroidal antiinflammatory drug washout period, patients received either diacerein or placebo for 3 months, followed by an off‐treatment period of 3 months to determine the carryover effects of the drug. Although patients were followed up through month 6, the primary efficacy end point was the percent change from baseline in pain (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC] A) at month 5 (i.e., 2 months after the end of treatment) compared with placebo. The co–primary efficacy end point was the percent change from baseline in the total WOMAC score, also at month 5 versus placebo.

Results

Two hundred three patients were screened, and 168 patients with painful knee OA were randomized. One hundred sixty‐five patients were analyzed in an intent‐to‐treat analysis. At month 5, diacerein showed statistically significant superiority versus placebo as assessed with both the WOMAC A (P < 0.0001) and the total WOMAC (P < 0.0001), demonstrating the carryover effect of the drug. This superiority was already evident from month 2 for pain (P = 0.001) and month 1 for total WOMAC (P = 0.0021). Diacerein was safe and well tolerated. No serious or previously undocumented adverse events were observed during the study.

Conclusion

This is the first published study of a symptomatic slow‐acting OA drug in which the time of assessment of the primary outcome end points was 2 months after the end of a 3‐month treatment period. The results show that diacerein is safe and effective for the treatment of knee OA and has a long carryover effect.