IASI is commonly used to relieve symptoms of knee OA; however, factors that predict response are poorly characterized, making it difficult to select patients who are most likely to be successfully treated using this approach. While this systematic review uncovered inconsistent findings across studies, there were several features that were reported by one or more studies as enhancing the likelihood of IASI response.
Although the mechanism of the therapeutic effect of CSs in knee OA is unclear, it is likely related in part to their potent anti-inflammatory effect. In this context, it is perhaps surprising that there was no consistent link between synovitis or presence of effusion on outcome [4
]. Indeed, in one study, the absence of synovitis was linked with a beneficial effect [4
]. The difference in the findings of the two studies that used US-assessed synovitis [4
] also raises questions about whether their findings were attributable to different patient characteristics and disease severity, different trial design or different criteria for defining responder status. The Pendleton et al.
] study was the larger of the two and included power Doppler assessments of synovitis, suggesting that its null findings may be more generalizable.
Methodological limitations in relation to defining the predictor variables may be another explanation for inconsistencies across studies. To assess knee synovitis, direct visualization and measurement of synovitis through sonography or other imaging is preferable. In the case of effusion, unsuccessful aspiration may also not always indicate the absence of effusion [36
]. Needle placement outside the joint, loculated or highly viscous SF, obese knees and errors from injectors all affect the ability to aspirate fluid [37
]. Even when the needle has been successfully placed within the joint capsule, it can move into the synovium or fat pad, resulting in a dry tap [38
]. Medial knee plica can also obstruct aspiration [38
], and it has been reported that fluid may be inaccessible if present in low volume [37
]. In relation to SF, small effusion volumes may not be readily detectable during clinical assessment. When using US to assess the presence of knee effusion, SF volume <7 ml, which is equivalent to about 2 mm thickness, may not be discernible during scanning [39
]. In some knees, effusion may be localized in the suprapatellar pouch or the medial or lateral recesses of the knee [40
], hence restricting US assessment to only one region may result in false-negative findings.
Surprisingly, there were only a few studies that formally studied the effect of the severity of joint and cartilage degeneration in knee OA on treatment response. Trials that used KL grading of knee OA appeared to find positive findings [14
], while those that used other scoring systems had null results [5
]. Smith et al.
] also did not find arthroscopic grading of cartilage damage associated with treatment response, despite the fact that the same trial found more severe disease, as assessed radiographically, to be associated with a worse response. This trial was an investigation of the effect of IASI given at the time of arthroscopy, where the adjunct treatment of arthroscopy could be a variable affecting outcome.
One major reason for null findings of studies is that most of the studies included in our review had too few subjects to be likely to detect significant risk factor effects, even if these effects were of clinical importance. We estimate that a sample size of 93 would be needed to ensure an 80% likelihood of detecting a factor with a prevalence of 50% to increase the odds of response to steroids 2-fold. Only 1 of the 11 studies had a sample size that was this large. The small-study bias could partially explain the conflicting results for the different predictors.
We are unable to evaluate whether the duration of follow-up in our studies accounts for some of the null findings in terms of predictors. The studies in general examined patients anywhere from 1 week to several weeks after injection, but a few studies looked at patients as late as 6 months after injection. In these latter studies, there were earlier evaluations and we focused on them, to be consistent.
Another consideration is whether the different steroids used in the trials partially explain the conflicting results for each outcome. Triamcinolone acetate, MPA and TH are said to share similar potency with similar recommended dosing [42
]. Trials that have evaluated different steroid preparations in knee OA have not found significant differences among the various IA steroids [15
]. However, one trial indicated that TH might act more quickly and could lead to a greater reduction in pain than MPA in the first 3 weeks after the injection [32
]. The studies reviewed in this article of IASI predictors were primarily those using MPA, TH and TA (see ) and differences in steroids should not have affected the results examining other predictors, although we cannot exclude the possibility that differences in doses across the studies would have affected the durability or intensity of steroid response. None of the studies we reviewed formally evaluated dose response for the commonly used IA steroid preparations in knee OA.
The sparse evidence for factors that may influence IASI reflected from this systematic review is partly because predictor factors are understudied. We could only identify 11 publications, of which many of them evaluated predictor factors as part of a secondary or post hoc analysis of the data. Secondly, predictor factors are poorly studied in trials. Many of the trials identified in this review were RCTs but the design of placebo/control comparisons of treatment effects of steroids means that evaluation of predictors of response to IASI can be made on one group only, the group that received the IASI, while the control/placebo group is disregarded. As evaluation of the predictor factors was now confined to the treatment group, this reduced further the sample size on many of the already small trials such that even if there is a predictor factor present, the power of the study would not be sufficient to detect it. This raises the question of whether RCT is the primary design for predictors of response. A longitudinal design such as observational studies, in contrast, may have allowed study of a wider spectrum of the disease and overcome some of the main constraints faced by RCTs.
To find additional studies, we expanded the search to trials that compared other agents such as hyaluronate with steroids in knee OA, but we were unable to find predictor studies on IASI among them. The use of Jadad scores may not provide the best evidence for quality [46
] but our findings using scoring systems for individual items evaluating quality did not differ much from the Jadad scores, since many of these trials lacked aspects of methodological rigour.
Other potential predictors, including previous knee injections, BMI, knee joint misalignment, use of walking aids, presence of muscle atrophy and also socio-economic factors have not been investigated. Future studies should include sufficient numbers of patients to provide adequate power and a longitudinally designed large observational study may be more appropriate to study IA steroid predictor factors. There should be clear information about the methods used to determine putative predictors and also details about the intervention, including delivery of therapy and whether or not US was used. Standardized outcomes should be reported, including pain, stiffness and function.
In summary, to our knowledge this is the first systematic review that attempts to investigate factors that may predict response to IASI in knee OA. Because of heterogeneity (in exposures), it was not possible to pool data across studies. Data from individual publications, although not consistent across studies, indicated there could be a number of predictors of response to IASI, including effusion, withdrawal of fluid from the knee, absence of synovitis, delivering injections under US guidance, structural severity of disease and pain. Further studies using standardized methods of assessment are needed to confirm these predictor factors and to characterize treatment response to IASI in patients with knee OA. Such data will be of help in better targeting therapy to those most likely to benefit.