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58 Listrat et al.: Hyaluronan in osteoarthritis of the kneeResultsPATIENTS AND STUDY COURSEThe baseline characteristics of the 39 patientsenrolled in the study are summarized in Table Iand the parameters evaluating the symptomaticseverity and/or the structural severity of osteoarthritisusing clinical, radiological and arthroscopicalparameters are summarized in Tables IIand III.At entry, there was no statistically significantdifference between the two studied groups withregard to clinical and radiological variables (seeTables I and II). However, at arthroscopy, therewas a trend in favor of more severe disease in thecontrol group which was close to statisticalsignificance for the variable SFA scoring (P-valueof 0.058 when using ANOVA analysis).Three patients withdrew frorn the study duringthe 1 year of follow up: one in the hyaluronangroup (the patient refused to continue thetreatment due to'"'lack of pain) and two in thecontrol group [one because ofmoving, one becauseof surgery of the evaluated knee (osteotomy)].Therefore, 36 patients completed the 1 year of thestudv.EFFICACYClinical parametersImprovement was observed in both groups forpain and functional impairment but the differencesbetween groups did not reach statistical significance(see Table II). A statistically significantdifference between the two groups in favor ofHyalgan was found in the quality of lifeassessment. Moreover, 30% (six of 20) and 68.40/0(13 of 19) in Hyalgan and control groups,respectively, recei.ved a NSAID during the studywith the difference between groups being statisticallysignificant (P= 0.016). The mean daily intakewas 0.65 + 2.17 and 2.77 + 3.56 in the Hyalgan andthe control group, respectively , (P = 0.044). Anonstatistically significant trend in favor of a moreimportant analgesic rescue in the control groupwas observed. The paracetamol mean daily intakewas 0.22 + 0.41 and 0.49 + 1.01 in the hyaluronanand côntrol group, respectively.Structura.l par ametersThe' changes in severity of chondropathyevaluated by both X-rays and arthroscopy aresummarized in Table III. The chanses observed instructural variables indicate deterioration in bothgroups but to a lower extent in the hyaluronangroup. For the arthroscopic evaluation, thebetween-groups difference for the SFA scoringsystem and the overall assessment using the VASwere statistically significant in favor of Hyalgan,and this difference was close to statisticalsignificance for the SFA grading system (P = 0.0b2).Evaluation of joint space narrowing and jointspace width by radiography showed that thebetween-group differences for these parameters didnot reach statistical significance although deteriorationwas less in the Hyalgan group.The imbalance in the concomitant therapiesprompted a post-hoc exploratory analysis in orderto clarify the possible influence of NSAIfT intakeon the between-treatments difference. Results ofsimple regression analysis on the SFA score.including the treatment and the NSAID consump-\_-,/tion as main effects, and the treatment by NSAIDinteraction effect, showed that the effect of thetreatment was still statistically significant, andneither the NSAID effect or the interaction effectwas statistically significant.ACCEPTABILITYOne patient in the hyaluronan group refused tocontinue the course of intra-articular injectionsbecause he was free from pain. Moreover, eightout of the 20 hyaluronan treated patients (40%)reported pain during or immediately after theinjection for at least one of the nine injections fora total of 17 events (180 hyaluronan injections wereperformed during the study). In all cases, pain waslimited to the moment of injection or lasted for afew minutes after the injection. No acute hydarthrodialflare of osteoarthritis occurred durins .Jthe study.DiscussionThis study supports existing data concerning thebeneficial symptomatic effects of intra-articularinjections of hyaluronan in osteoarthritis of theknee; and suggests that repeated intra-articularinjections of hyaluronan might delay structuralprogression of the disease. It also suggests thatarthroscopy might be able to identify chondromodulatingagents; and confirms the feasibility ofusing arthroscopy as an outcome measure of kneeosteoarthritis.Arthroscopy, even simplified, can be consideredan aggressive method. However, in this study, thehigh percentage (36 out of Jg: g2oÂ) of patientscompleting the trial may be considered an ,
Osteoarthritis and Cartilage Vol. 5 No. 3 159argument favoring the good acceptability of thistechnique.The results obtained in this study suggest thatthis technique is capable of demonstrating statisticallysignificant changes in chondropathy in arelatively low number of patients (l/= = 17) andover a l-year period. Sensitivity to change is oneof the major characteristics of an outcomevariable. The results obtained in this study suggestthat arthroscopic parameters are more sensitivethan radiological parameters to evaluate thechanges in structural damage observed in osteoarthritis.Although this was not its primary objective, thisstudy confirms the beneficial clinical effects ofintra-articular injections of hyaluronan in kneeosteoarthritis. However. the study design (openprocedure to collect the clinical parameters,systematic articular lavage in all patients at entry)may have influenced the final results.The choice of the number of injections withineach course (three) and the interval between eachcourse (3 months) was based on data previouslyreported in different clinical studies suggestingthat at least three injections (once a week during2 weeks) are necessary to improve the clinicalmanifestations of osteoarthritis, and that thisimprovement persists several months after cessationof treatment [2]35 and reviewed in 261.It should be noted that the intra-articularinjections were performed in the hyaluronantreatment group even though the patients werepainless. The acceptability of this procedureappeared good as only one patient refused tocontinue the injections because he was free frompain.Comparison of the changes in severity ofchondropathy by treatment group during the 1year ofthe study suggests that repeated intra-articularinjections might delay cartilage lesions due toosteoarthritis in humans. Although these resultshave been observed using rigorous methodology, anumber of aspects must be considered beforedrawing definite conclusions: (1) the imbalance inthe severity of chondropathy observed at entry;(2) the small number of evaluated patients; (3) theimbalance in the amount of rescue treatment. Forexample, one can argue that the progression ofthedisease is related to its severity at entry and/orthat NSAID intake might have a deleteriousstructural effect in osteoarthritis, as has beenrecently suggested [35]. We conducted variousstatistical analyses in order to take into accountthe imbalance in both the severity of chondropathyand the amount of rescue treatment in theinterpretation of the results. The results obtainedsuggest that in this study NSAID intake alonemight not represent an explanation for the level ofcartilage deterioration after 1 year of study.However, the possible role of other patientconditions and the suggested effect of thetreatment in reducing access to concomitanttherapies impose cautious consideration of thisresult. A direct answer concerning the possibleeffect of the NSAID alone, or in association withother treatments can only be provided by another,randomized factorial study where the two experimentalfactors (NSAID and other treatments) andtheir combinations are compared.Moreover, these results were obtained in a verysmall subgroup of patients. This small sample sizecannot exclude that the results obtained are due tochance alone. The particular characteristics oftherecruited patients preclude any extrapolation ofthe results to the general population of patientswith knee osteoarthritis.In case of a real effect of hyaluronan intraarticularinjections on structural damage, it mightbe of interest to evaluate different schedules ofadministration. In this study, we used a 3 monthrepetition of cycles of three intra-articularhyaluronan injections to severely symptomaticpatients. It might be interesting to evaluate theeffects of repetition of injection cycles performedonly in case of a clinical flare of the disease.In the light of these considerations, furtherstudies are required in order to confirm our resultsand to evaluate long-term monitoring of osteoarthritispatients using such local (intra-articular)therapy.References1. Lequesne M, Brandt K, Bellamy N, Moskowitz R,Menkes CJ, Pelletier JP, Altman R. Guidelines fortesting slow acting drugs in osteoarthritis. JRheumatol 1994;21(Suppl. 41):65-71.2. Group for the REspect of Ethics and Excellence inScience (GREES): osteoarthritis section. Recommendationsfor the registration of drugs used inthe treatment of osteoarthritis. Ann Rheum Dis1996;55:552-7.3. Paulus HE, Bulpitt KJ. Clinical trials of osteoarthritistherapeies. Br J Rheumatol 1993;32:529-31.4. Rosenbloom D, Brooks P, Bellamy N, Buchanan W.Clinical trials in the rheumatic diseases, PraegerEd., 1 vol-, New York. 1985;1$53.5. Dieppe P, Cushnaghan J, Jasani MK, McCrae F,Watt I. A two-year placebo-controlled trial ofnon-steroidal anti-inflammatory therapy in osteoarthritisof the knee joint. Br J Rheumatol1993;32:595$00.6. Onghena P, Van Houdenhove B. Antidepressantinducedanalgesia in chronic non-malignant pain:
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