Rheumatology Research Unit, Repatriation General Hospital, 1Department of General Practice, Flinders University, 2Department of Radiology, 3Department of Immunology, Allergy and Arthritis and 4Department of Pathology, Flinders Medical Centre, Adelaide, South Australia.
Correspondence to:
M. Ahern, Rheumatology Research Unit, Repatriation General Hospital, Daws Road, Daw Park, South Australia 5041, Australia. E-mail: michael.ahern{at}rgh.sa.gov.au
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Abstract |
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Methods. Seventy-seven patients with OA of the knee were randomized to receive either 120 mg methylprednisolone acetate (MPA) or placebo following arthroscopy. Clinical assessments included severity of pain on movement and at rest, stiffness, the presence of joint effusions, range of movement, WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) score and Lequesne functional assessment. The outcome measures were evaluated at baseline and 2, 4, 8, 12 and 24 weeks. Further arthroscopies and synovial biopsies were performed at the time of clinical response and at relapse.
Results. An intention-to-treat analysis was performed on 71 patients (38 MPA, 33 placebo). Using the OARSI (Osteoarthritis Research Society International) response criteria, 58% of the steroid group vs 33% of the placebo group (adjusted relative risk = 2.38) (P = 0.004) responded at 4 weeks. At other time points, there were no significant differences between the treatment groups. There were no significant differences between the two treatment groups for pain, stiffness or WOMAC or Lequesne assessments at any time point.
Conclusions. The response to intra-articular corticosteroids following joint lavage is short-lived (24 weeks), achievement of an OARSI response criterion being the only difference between the two groups.
KEY WORDS: Osteoarthritis, Knee joint, Randomised trial, Intra-articular corticosteroids
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Introduction |
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Treatment of OA has not progressed at the same rate as our knowledge of the pathogenic mechanisms of OA, and the main pharmacological treatments remain analgesics and non-steroidal anti-inflammatory drugs (NSAIDs). However, the role of these two treatments in the management of OA has been questioned [68]. Corticosteroids are among the most powerful anti-inflammatory drugs available in rheumatology, yet the benefits and mechanisms of action of intra-articular (IA) corticosteroids in symptomatic OA remain controversial [1, 9]. The speed of onset of action of corticosteroids suggests a direct anti-inflammatory effect. Corticosteroids act directly on nuclear steroid receptors, leading to changes in lymphocyte function, white cell trafficking, cytokine levels and activity, and enzymes such as phospholipase A2. Thus, a theoretical rationale can be provided for an anti-inflammatory effect of IA corticosteroids in knee OA [9]. Most of the studies published on IA corticosteroids in the treatment of OA have shown short-lived positive effects; also, those studies which were placebo-controlled demonstrated a beneficial response to a placebo IA injection. Joint lavage or tidal irrigation have been reported to be beneficial in the management of OA, although the results of published studies are conflicting [10, 11].
Recently, the first randomized controlled study comparing joint lavage and IA corticosteroids, alone and in combination, in patients with symptomatic OA of the knee joint was published [10]. This study concluded that both joint lavage and IA corticosteroids relieved pain for up to 4 weeks but had no effect on function. This multicentre study had a number of potential problems, including a design with four treatment arms, the use of a non-arthroscopic lavage and joint injection technique, and reliance on a radiological definition of OA. We now report the results of a single-centre study comparing arthroscopic joint lavage with and without IA corticosteroid treatment in a group of patients with symptomatic OA of the knee joint.
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Materials and methods |
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Clinical assessments
All assessments were performed by a single assessor, blinded to treatment allocation and arthroscopy results, at baseline (i.e. prior to arthroscopy) and weeks 2, 4, 8, 12 and 24. Standardized questionnaires were administered at each assessment, including the WOMAC (Western Ontario and McMaster Universities Osteoarthritis) index (containing separate subscores for pain, stiffness and disability) and the Lequesne functional index. Pain at rest and on movement and stiffness were assessed on a 10 cm visual analogue scale (VAS), the patient being asked to assess only the target knee joint. In addition, the target knee joint was assessed for the presence of a joint effusion and the range of movement was measured using a goniometer. Patients were classified as having responded to treatment or relapsed by an independent observer, blinded to arthroscopy results and treatment group, according to the following predetermined criteria: response was based on a >30% reduction in VAS pain on movement compared with baseline, and relapse was based on an increase in VAS pain on movement to <20% of baseline measurement. In addition, patients were assigned an OARSI (Osteoarthritis Research Society International) response category based on the criteria recently ratified at the 2002 OMERACT (Outcome Measures in Rheumatology) meeting (reduction of at least 20% in pain VAS and an absolute change of >10 mm and/or an improvement in function of >20% and an absolute change of 10 units compared with baseline).
All patients entered in the study had a further arthroscopy and synovial biopsy at the time of clinical response and at symptom relapse as defined above. Relapse patients were offered active treatment with 120 mg methylprednisolone acetate at the time of the arthroscopy and were followed again with the same assessments until further symptom relapse, without revealing the original treatment allocation to the patient or assessor.
Radiological investigations
The knee joints of all patients were examined using a standard technique to obtain anteroposterior and lateral views of both knees, which were graded by a single radiologist, blinded to all other aspects of the study, using the method of Kellgren and Lawrence [16].
Randomization
Randomization was computer-generated by a member of the hospital pharmacy department, who also prepared a blinded intra-articular injection to be given at the conclusion of the initial knee arthroscopy. The treatments were either 120 mg methylprednisolone acetate or a placebo solution of normal saline. The randomization code was kept in a sealed envelope in a locked filing cabinet and was not revealed until the conclusion of the study.
Statistical analysis
The main statistical analyses were performed to assess the effect of joint lavage with and without IA corticosteroids on response rates. The primary outcome measure was the response rate according to predetermined criteria of >30% reduction in VAS pain on movement compared with baseline. Because previous randomized control trials of intra-articular steroids in OA of the knee showed short-term efficacy, we were particularly interested in responses at 2 and 4 weeks. A sample size calculation based on previous studies [10], assuming a type I error () of 0.05 and type II error (ß) of 0.20, 48% response rate in the placebo group and 83% response rate in the IA corticosteroid group, gave a total number of 66 patients (two-sided estimate).
Statistical analyses of the effects of corticosteroid injections were based on an intent-to-treat strategy, so that all patients entered into the study who received an intra-articular injection at the conclusion of the knee joint arthroscopy were included in the analysis. In the event of relapse as defined above, the last documented outcome variables were carried forward. A preliminary analysis was performed to compare the baseline characteristics of the two treatment groups using the t-test for two independent samples for continuous variables (tests for normality at baseline were applied) and the 2 test for categorical variables.
In comparing the treatment response (primary outcome measure), the presence or absence of joint effusions and OARSI responses, we used a generalized linear model with log link and binary error distribution to model the relative risk. The relative risk was adjusted for severity of X-ray grade and baseline score. A modified Bonferroni approach was used to correct for multiple comparisons [17]. To assess the baseline predictors of success (OARSI response at 4 weeks) in the corticosteroid-treated group, we used a generalized linear model with binary error distribution and log link.
When comparing continuous variables over time, we used a repeated measures analysis of variance (SPSS, version 10.0, Chicago, IL, USA) with X-ray grade/severity and treatment group the between-subject factors.
Survival curves over time in the study were estimated using the KaplanMeier method. The survival time was the interval from the time of randomization to the time for relapse of pain in the target knee joint, according to the definition above. Placebo and IA corticosteroid groups were compared using the log-rank test. A Cox regression model was used to estimate the influence of radiological severity. Time in the study was censored at 24 weeks.
All analyses were performed two-sided with the minimum significant level set at 5%.
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Results |
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Table 2 shows the mean clinical and functional parameters at baseline and at the different time points in the study. A repeated measures analysis of variance was used to test for the between-group differences over time whilst adjusting for X-ray severity, for the variables of pain, stiffness, range of movement and function. There were statistically significant improvements in pain at rest (P = 0.003), WOMAC difficulty score (P = 0.01) and Lequesne score (P = 0.007) for time (Fig. 2) and near-significant improvements for stiffness (P = 0.069), pain on movement (P = 0.068) and WOMAC pain score (P = 0.081). However, there was no significant difference between the two groups (IA corticosteroids and placebo) for any of these parameters.
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We then analysed the results of this study using the newly defined OARSI response criteria for OA. At 4 weeks, after adjusting for severity of the radiological score, there was a 2.4-fold increase in the probability (95% CI 1.314.33) of being a responder in the IA corticosteroid group compared with the placebo group (P = 0.004). There were no significant differences between the two treatment groups at any of the other time points (Table 3A). Knee effusions decreased in both treatment groups, with a maximum effect at the 2-week assessment. After adjustment for X-ray severity, the presence of effusions at baseline and the number of comparisons, there was no statistical significance between the treatment groups at any of the time points (Table 3B), but there was a trend for fewer joint effusions in the IA corticosteroid group at 2, 4 and 8 weeks. Using a generalized linear model, we assessed the baseline characteristics of those patients injected with corticosteroid, to determine predictors of success as defined by the OARSI response at 4 weeks. The only predictor was the severity of OA assessed by radiology, the more severe disease being less likely to have an OARSI response [relative risk (RR) 0.59, 95% CI 0.3560.996; P < 0.05). On the other hand, grading of cartilage damage at arthroscopy did not predict the 4-week OARSI response (RR 0.79; P = 0.3); nor did the duration of symptoms (RR 0.91; P = 0.6).
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Discussion |
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Part of the explanation for the failure to demonstrate greater efficacy of IA corticosteroids in our study could be the magnitude and carry-over effects of the arthroscopy and lavage, overwhelming any possible smaller benefits of steroids. It is probable that the magnitude of the arthroscopy benefits was due to the open nature and placebo effect of that component of the study. Since the design of our study, two recent controlled studies have been published involving patients with OA of the knee [18, 19]. Both studies showed an improvement in pain scores and in one of the studies there was no difference between real and placebo/sham arthroscopy, demonstrating the potential for placebo effect with arthroscopic surgery [18]. Our results are consistent with this study [18].
Although the design of our study was different from that of the study by Ravaud et al. [10], it is possible to compare some of the key outcome measures in both studies. The study by Ravaud et al. was double-blind in relation to IA corticosteroids and open with regard to joint lavage (similar to our study) but had four treatment groups, with between 21 and 28 patients in each group. Ravaud demonstrated that the effects of joint lavage and intra-articular corticosteroid injection were additive rather than synergistic. The definition of response (at least 30% reduction in pain score) was identical to that used in our study, but the response rate in our study was lower in both the joint lavage (at arthroscopy) group and the joint lavage with IA corticosteroids group (42 and 39% respectively) at 24 weeks compared with the study of Ravaud et al. (48% for the joint lavage group and 54% for the joint lavage with IA corticosteroid group). The reasons for these differences in response rate between the two studies are unclear and are not readily explained by the differences in study design (percutaneous lavage and corticosteroid injection vs arthroscopic procedures). Similar response rates were seen at earlier time points with each treatment group in both studies. For joint lavage + placebo, the response rates were 55% at 2 weeks, 58% at 4 weeks and 55% at 12 weeks in our study compared with 48% at 1 week, 48% at 4 weeks and 48% at 12 weeks in the study by Ravaud et al. In contrast, our study demonstrated a smaller response to IA corticosteroids and joint lavage (68% at 2 weeks, 66% at 4 weeks, 47% at 12 weeks) compared with that seen in the study by Ravaud et al. (83% at 1 week, 71% at 4 weeks, 54% at 12 weeks). It is likely that these differences reflect differences in the lavage technique, differences in the population studied (although the baseline demographic data are similar in the two studies), the IA corticosteroid preparation, and the fact that our study design was directed to obtaining synovial tissue. The survival curve for the randomized patients showed that the patients in the IA corticosteroid group stayed in the study longer than the placebo-treated patients. The survival time was taken as the time to relapse, defined by a return to within 20% of baseline on movement in the target knee joint. The differences in times to relapse are due to the rapid relapse in the placebo group, although this is not reflected in the mean scores for pain on movement in Table 2, where there are no significant between-group differences over time.
Unlike the study of Ravaud et al. [10], this study did demonstrate a significant improvement in both functional indices [WOMAC difficulty score (P = 0.01) and Lequesne functional index (P = 0.007)] with time, but did not demonstrate any differences between the two treatment groups. It is unclear why there is a difference between the two studies in the effect of joint lavage and IA corticosteroids on functional outcomes for OA of the knee joint, but it is unlikely to be due to any significant difference between the patient populations in the two studies or the study design.
When the treatment groups were offered IA corticosteroid treatment following relapse, a majority of patients in both treatment groups accepted IA corticosteroid treatment at the time of a further knee arthroscopy. Both groups responded similarly to IA corticosteroids and had a similar time to relapse. This demonstrated that there was no fundamental difference between the two groups in the ability to respond to IA corticosteroids and also that retreatment with IA corticosteroids does not result in any alteration of the clinical response to that treatment.
We recognize that there are problems with interpreting the clinical responses in this study, as the design of the study was predominantly for the purpose of securing synovial biopsies at baseline, at the time of clinical response and at relapse in order to define the mechanisms underlying the response of knee joint OA to both joint lavage and IA corticosteroids. This necessitated the use of knee joint arthroscopy with associated joint lavage at baseline, at the time of clinical response and at relapse. This could have resulted in an increased use of joint lavage in one of the treatment groups if there was a significant difference between the joint lavage (placebo) and the IA corticosteroids + joint lavage (active) groups. Since there were minimal significant differences between the two treatment groups in this study, it is unlikely that this aspect of the study design has affected the conclusions of the study. We have attempted to nullify the effects of further arthroscopy and lavage at the time of relapse by documenting the outcome variables prior to the procedure and carrying them forward in the statistical analysis.
A selection bias may have been introduced because 61% of the patients assessed for eligibility did not participate in the study. This high rate of non-participation resulted from the demands of our study (at least two arthroscopies) and a 50% chance of receiving a placebo intra-articular injection. Also, patients entering the study may have had high expectations of benefit from the arthroscopy and lavage, with resultant expectation bias. These biases could potentially influence the validity of the results or their generalizability.
One of the aims of this study was to define end-points that could distinguish between patients given corticosteroids or placebo following arthroscopy. The end-point that we have selected for further studies is the response criteria at 4 weeks. Further studies will attempt to characterize features of the OA synovium that could predict the response to intra-articular steroids at 4 weeks.
In conclusion, joint lavage by arthroscopy produced a clinical improvement in patients with symptomatic OA of the knee joint, consistent with a placebo response with mild additional benefits from IA corticosteroids persisting for up to 4 weeks. The clinical benefits were more likely to be seen in those patients with less severe OA of the knee as defined radiologically.
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Acknowledgments |
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References |
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