A multicenter, randomized controlled trial comparing a single intra-articular injection of Gel-200, a new cross-linked formulation of hyaluronic acid, to phosphate buffered saline for treatment of osteoarthritis of the knee.

OBJECTIVE: To compare the safety and efficacy of a single intra-articular (IA) injection of a new cross-linked hyaluronic acid product, Gel-200, with phosphate buffered saline (PBS, control) in a multi-center randomized controlled trial in patients with symptomatic osteoarthritis (OA) of the knee. DESIGN: Patients were randomized 2:1 to receive a single injection of Gel-200 or PBS, after joint aspiration. The primary measure of effectiveness was Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscores by 100-mm Visual Analog Scale (VAS); secondary outcomes included: total WOMAC, physical function, and stiffness subscores; patient and physician global assessments of disease activity, Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society International (OMERACT-OARSI) strict responders, as well as safety of Gel-200. RESULTS: Of 379 patients randomized, safety was evaluated in 377 and efficacy in 375 (98.9% randomized) in the intent-to-treat population. Effectiveness of Gel-200 by WOMAC pain subscores was statistically significant at week 13 (P=0.037). Mean improvements from baseline in WOMAC pain subscores consistently favored Gel-200 at each visit. Effectiveness of Gel-200 treatment was statistically significant over weeks 3-13 by WOMAC total score, physical function, and physician global evaluations (P<0.05). The number of "strict" OMERACT-OARSI responders was statistically significant from weeks 6 to 13 (P=0.022). Adverse events were not significantly different between treatment groups, including serious adverse events considered related to study treatment. CONCLUSIONS: This trial demonstrated that a single injection of Gel-200 was well tolerated and relieved pain associated with symptomatic OA of the knee over 13 weeks. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NTC 00449696.

Effectiveness and Safety of a Multicenter Extension and Retreatment Trial of Gel-200 in Patients with Knee Osteoarthritis.

OBJECTIVE: To assess the continued effectiveness and safety of Gel-200 following observation and open-label retreatment in an extension protocol following a randomized, double-blind, phosphate buffered saline (PBS)-controlled trial (initial treatment trial). DESIGN: Patients who completed initial blinded treatment were allowed to enroll into this extension protocol that permitted retreatment with Gel-200 when eligibility criteria were met. Retreatment was administered with a Gel-200 injection, without knowledge of initial treatment assignment (Gel-200 or PBS). Retreated patients were followed for up to 13 weeks. In the extension phase, durability of response following the first injection was analyzed by time to retreatment eligibility. During separate extension and retreatment phases, responses were assessed by WOMAC pain, stiffness, and physical function subscores, total score, and global assessments of disease activity (patient, physician) as well as safety of Gel-200. RESULTS: In the extension phase, time-to-event analyses through 26 weeks following the initial injection showed statistically significantly longer times to retreatment in patients receiving Gel-200 compared with PBS (P < 0.05). Retreatment with Gel-200, e.g., a second injection, resulted in statistically significant improvements from retreatment baseline in all outcome measures (P < 0.0001). The incidence and type of adverse events after retreatment were comparable to those observed following initial injection of Gel-200 without allergic reactions, including "pseudosepsis" or unanticipated treatment-related serious adverse events. CONCLUSIONS: These data demonstrate that a single injection of Gel-200 resulted in durable effectiveness through 26 weeks and that repeated treatment with Gel-200 relieved symptomatic osteoarthritis with a favorable safety profile.

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.

Circulating intercellular adhesion molecule-1 in patients with systemic sclerosis.

In view of recent data demonstrating increased expression of intercellular adhesion molecule-1 (ICAM-1) in the skin of patients with systemic sclerosis (SSc) we studied whether levels of soluble ICAM-1 (s-ICAM-1) shed into the circulation are increased in patients with this disorder. We also compared blood levels of s-ICAM-1 in SSc with those in systemic lupus erythematosus (SLE) and we investigated any possible association of s-ICAM-1 with soluble IL-2 receptor (s-IL 2R) levels, the latter being considered as a marker of lymphocyte activation. Patients with SSc had increased levels of sICAM-1 compared with healthy control subjects (mean +/- SEM, 587 +/- 34 versus 373 +/- 27 ng/ml, P < 0.0001). Patients with diffuse rapidly progressive disease had the highest s-ICAM-1 levels. No association was observed between the extent of skin or internal organ involvement and s-ICAM-1 levels. Patients with digital ulcers had significantly elevated s-ICAM-1, but not s-IL 2R, levels. No correlation was detected between individual s-ICAM-1 and S-IL 2R levels in SSc patients. These novel findings suggest that circulating s-ICAM-1 levels may be a useful marker of endothelial activation in SSc; however, further studies are needed to determine the role of ICAM-1 in the pathogenesis of this disorder.

Does the acetyl group of aspirin contribute to the antiinflammatory efficacy of salicylic acid in the treatment of rheumatoid arthritis?

In a multicenter, double-blind, parallel-group study, 233 patients with classical or definite RA who demonstrated disease flare during a prestudy washout period were randomized to 12 weeks of treatment with either the nonacetylated salicylate, salsalate (salicylsalicylic acid), or aspirin. Of the 150 patients who completed the study, 83 received salsalate and 67 were treated with aspirin. Doses of the two drugs were calculated to provide equal amounts of bioavailable salicylic acid. The efficacy of salsalate and aspirin, as measured by all the usual variables, was equivalent but aspirin-treated patients had a higher incidence of severe gastrointestinal problems. Thus, this study demonstrated that the acetyl group of aspirin does not enhance the anti-inflammatory efficacy of salicylic acid in RA.

Systemic sclerosis and pregnancy complicated by obstructive uropathy.

A patient with progressive systemic sclerosis whose twin pregnancy was complicated by obstructive uropathy due, in part, to a noncompliant abdominal wall is reported. The effects of progressive systemic sclerosis on pregnancy and those of pregnancy on progressive systemic sclerosis are reviewed and discussed.