The clinical effectiveness of intra-articular corticosteroids for arthritis of the lower limb in juvenile idiopathic arthritis: a systematic review

Juvenile Idiopathic Arthritis (JIA) is the most common rheumatic disorder in children, affecting approximately 1 in 1000 Australian children [1]. Lower limb arthritis is common in JIA regardless of disease classification, with the knee joint affected most frequently at disease onset (40-60% of cases) followed by the ankle (20-30% of cases) [2, 3]. Persistent synovitis in these joints is associated with pain, reduced joint ranges of motion, deformities, gait disruption, and poor functional status [4‐7]. Moreover, radiographic progression of the disease occurs early, and if not addressed may result in permanent joint destruction and poor functional outcomes [8, 9].

The primary aim of medical management in JIA is to suppress inflammation prior to the development of irreparable joint damage and functional limitation [10]. Recent improvements in the medical management of JIA have led to a greater emphasis on early diagnosis of JIA, early detection of synovitis, and subsequent prompt and aggressive systemic medical intervention via disease-modifying and/or biologic regimens to control the inflammatory disease process [11]. The introduction of such regimens have led to a relative increase in the number of patients achieving disease improvements characterised by low disease activity or remission [12]. However, in spite of promising signs of improvement, children may experience refractory disease, characterised by continued persistent synovitis, and/or serious adverse effects including hepato-toxicity and immuno-deficiency following administration of methotrexate and etanercept [13].

Intra-articular corticosteroid injections (IACIs) are often used as the main form of management in milder oligoarticular JIA, and also as an adjunct to systemic therapy in other JIA subtypes where localised synovitis is restricted to a single or a small number of joints [13, 14]. IACIs are administered to induce rapid relief of symptoms through resolution of localised synovitis, and in some cases may prevent the need for escalation of systemic therapy and associated increased risk of serious side-effects [14]. It is acknowledged that IACIs are also associated with adverse events, however, these may be relatively mild compared to those associated with systemic disease-modifying anti-rheumatic drugs (DMARDs) or biologics. These may include subcutaneous atrophy, hypopigmentation and/or post-injection pain [14, 15]. Several inconsistencies have been highlighted in studies of IACIs such as variable injection techniques, inclusion criteria, post-injection procedures, outcome measures, and follow-up period [14, 16, 17].

Previous systematic reviews have been conducted but they are now outdated and new studies of IACIs have been published since they were completed. The Cochrane Collaboration recommends that systematic reviews are updated biannually, and the most relevant and recent review was published seven years ago [18]. Two systematic reviews have been conducted to evaluate the evidence for IACIs in JIA; one which focused on IACIs for temporomandibular joint (TMJ) arthritis only [16]; and another which reviewed studies on lower limb IACIs for children with JIA and/or adults with rheumatoid arthritis (RA). However, ultimately they did not include any studies of JIA [17]. The recent systematic review of IACIs for TMJ arthritis [16] may not be directly relevant to this work as IACIs administered in the joints of the lower limb appear to be less efficacious than those administered in upper limb and non-weight-bearing joints [19]. Moreover IACIs administered to the knee joints appear to be more efficacious than those administered to the small joints in the foot, where the response is less predictable [19]. Two other reviews of the overall medical management of JIA adopted systematic approaches to conduct their literature search, but their restrictive inclusion criteria retrieved only two small randomised studies concerning IACIs and only limited conclusions were drawn [10, 20]. One other systematic review attempted to appraise the evidence for knee joint IACIs for a range of arthritis conditions including JIA, osteoarthritis (OA) and RA [21]. However, methodological problems were identified with this review including a single joint focus (knee), adult arthritis predominance for studies included, and violations of the detailed inclusion criteria. Narrative reviews have also been conducted and have provided useful summaries of the literature concerning IACIs in JIA [14, 22]. However, such reviews are often reinforced with the authors’ expert opinions and clinical experience and as a result may be vulnerable to bias [23].

Most research concerning IACIs efficacy to date appears to focus predominantly on the knee joint only, or a combination of several joints which differ in terms of anatomical complexity, and may include weight-bearing/non-weight-bearing joints which could impact on IACI efficacy. The reviews which have been published to date fail to account for the efficacy of IACIs for synovitis relief in other important lower limb joints, and thus the findings and conclusions drawn from these reviews are not necessarily generalizable. Lastly, it should be noted that standard clinical practice has changed in recent years with a greater emphasis being placed on image-guidance to aid the administration of intra-articular injection therapies [24‐26]. This advancement of clinical practice may have led to improvements in the effectiveness of IACIs on the basis of improved steroid placement accuracy and thus fewer reports of adverse events [24‐26]. The emergence of further evidence, introduction of new technologies and changing clinical practices has raised important new questions concerning lower limb IACI efficacy in JIA. Accordingly, the aim of this review is to systematically identify and critically evaluate the clinical effectiveness of IACIs administered to joints of the lower limb in people with JIA.

Using the detailed search strategy, a total of 568 articles were retrieved. The inclusion criteria were met by twenty-one studies (see Figure 1), and a description of each study is presented in Table 2. The majority of the studies were observational in nature, with only one RCT identified for inclusion. Therefore, meta-analyses were not possible as were originally intended. One study had high quality internal validity and twenty had low quality internal validity. Nine studies had high quality external validity and twelve had low quality external validity. There were no studies with both high quality internal and external validity (Table 3). From the assessed studies, nine outcome domains were identified which included tenderness/pain, swelling, synovitis, effusion, hyperthermia, sustained ‘clinical response’, joint range of motion (ROM), length discrepancy (leg length discrepancy or joint circumference), and imaging detectable outcomes. Leg length discrepancy (LLD) was defined as unequal length of the lower limb from the knee distally, as a result of knee synovitis and/or tibial growth disturbances. Qualitative syntheses of results are outlined below and presented in Table 4.

Weak levels of evidence were found for IACIs decreasing tenderness/pain, swelling, synovitis, clinical signs and symptoms, increasing joint (ROM) in lower limb joints and medical imaging disease-related outcomes such as joint effusion, synovial hypertrophy and erosion. Inconclusive evidence was present for IACIs reducing effusion, hyperthermia, LLD and knee circumference. The majority of studies were low quality observational studies with one low quality RCT, and as such these conclusions are based upon weak evidence only. Additionally, the majority of the studies identified by the search strategy presented results using descriptive statistics only, leading to uncertainty regarding the effectiveness of IACIs versus a suitable comparator.

The results of this contemporary review demonstrate similar issues raised by previous reviews concerning the lack of conclusive evidence in support of IACIs improving clinical outcomes [16, 17]. The adopted methodology of the most relevant previous systematic review appeared to be logical in restricting the inclusion criteria to RCTs in an attempt to increase the quality of evidence retrieved. However, at the time, there was a lack of published RCTs available for inclusion in this review and it subsequently concluded there was insufficient research to ascertain the effectiveness of IACIs for JIA. Observational studies were not considered by the authors as part of the inclusion criteria for that review, and as such potentially important studies were excluded which may have provided at least a weak level of evidence concerning IACI efficacy. In contrast, our review included observational studies and found weak evidence to suggest that sustained clinical response and improved joint ROM can be achieved following administration of IACIs to the joints of the lower limb in children with JIA.

A narrative literature review which adopted systematic search criteria on all medical treatment modalities for JIA including IACIs has previously been conducted [10]. The authors concluded there was significant evidence of efficacy for the use of IACIs in persistent oligoarticular JIA and moderate efficacy of IACIs for the use in polyarticular JIA based upon the findings of three studies [30, 46, 47]. However, this was not a true systematic review as the appraisal strategy did not adopt rigorous methods of quality assessment or evidence grading, and their conclusions were based solely upon effect sizes greater than 50% of patients. The lack of evidence grading introduces ambiguity to the conclusion of such reviews.

Our systematic review has utilised a specific quality assessment criteria with emphasis on the internal and external validity of the included studies [18]. Our study showed that while there was only one observational study with high internal validity [42], nine observational studies showed high external validity [19, 24, 26, 32, 34, 35, 40, 44, 46]. This may be explained by the fact that recruitment was largely conducted alongside standard practice within paediatric rheumatology outpatient clinics, thus increasing the clinical relevance of the results. This external validity criterion was also necessary to assess whether the study methodologies were pragmatic, as opposed to explanatory [48]. The pragmatic nature of these studies meant their conclusions were more likely to be applicable to the general population of children/adolescents with JIA to whom IACIs may be a possible treatment option.

Due to the lack of multiple RCTs in this area, no meta-analysis could be conducted. This has implications for future research as high quality RCTs and meta-analyses are necessary to inform evidence-based clinical practice. Indeed a pragmatic RCT of IACIs versus a suitable comparator for the relief of localised synovitis could have sufficient external validity to inform and influence current practice and health policy in future. However, it is recognised that several clinical practice guidelines recommend use of IACIs in spite of the lack of high quality research evidence supporting their use [10, 20]. As such, it is acknowledged that a placebo- or sham-control arm for a parallel trial of IACIs may not be possible due to ethical restraints surrounding the withholding of standard care. A contextual problem with the lack of robust RCTs to evaluate IACIs at present exists with regards to recent changes to the Australian Medicare Benefits Schedule [49]. Evaluations of the cost-effectiveness of interventions are normally embedded within RCTs. At present, and to the best of the authors’ knowledge, an evaluation of the cost-effectiveness of IACIs in JIA has yet to be conducted. This raises an important issue; because presently people with arthritic conditions in Australia are potentially required to self-fund the cost of each individual IACI they receive [49], and doctors cannot yet provide sufficient guidance regarding this treatment based on robust evidence of clinical- and cost-effectiveness.

Two studies are frequently cited in reviews of IACIs in JIA and clinical practice guidelines to draw conclusions concerning this intervention [46, 47]. These prospective, randomised studies focus on the comparative efficacy of commonly used steroid preparations triamcinolone hexacetonide (TH) and triamcinolone acetonide (TA), concluding that TH was superior. However, a major limitation of these studies was that a non-treatment, placebo, or sham control arm by which to compare the effects of the IACI interventions was not possible due to ethical constraints. Moreover, participants included were not on stable medication for an appropriate period prior to enrolment, so both studies were vulnerable to confounding bias. New evidence has emerged since previous reviews have been published; however, limitations in these studies are still evident. The well documented restrictions of the commercial availability of TH resulted in this preparation being replaced by TA in at least one study included in this review [25]. A lack of standardisation of IACI interventions was identified amongst studies retrieved by our search criteria which may be problematic. Frequently studies do not describe their injection technique, which can vary between individual institutes [22]. Moreover, studies included in this review have utilised varying post-injection management strategies including physiotherapy rehabilitation [31], immobilisation [31, 34], and a period of non-weight-bearing or avoidance of physical activity [26, 37, 40, 45]. Despite this, other studies included did not describe a post-injection strategy [24, 35, 38, 42, 43]. These approaches appear to lack consensus, and at present there is a lack of evidence available to support a specific post-injection procedure.

A novel finding from this review was that several studies employed image-guidance to aid their IACIs [24‐26, 38, 42]. Ultrasonography-guided injections also have been identified as a useful imaging technique for IACIs as they permit the real-time guidance of the needle and allow confirmation of correct deposition of steroid [24, 35]. These studies concluded the use of imaging techniques ensured correct needle placement and guided IACIs were superior to standard ‘blinded’ injection and aspiration techniques. These studies also raise further questions surrounding image-guidance concerning whether or not image-guidance can reduce the rate of complications associated with IACIs. At present there have been no RCTs comparing guided and blindly administered IACIs in JIA.

The conclusions from this review contribute to the evidence base in support of current JIA management practices through aggressive and early intervention to reduce disease activity [11]. This highlights inconsistencies and evidence gaps concerning the efficacy of IACIs in JIA. It also provides valuable additional and contemporary information through a robust and systematic approach relative to previous reviews. While investigating the efficacy of IACIs, post-injection procedure was included in the study description as a contextual factor. This did not occur in previous reviews. Not all studies included a post-injection technique. Those studies that did include post injection procedure are described in Table 3. However, the lack of consistency among the described injection procedures makes it difficult for comparison to make a consensus. This is an area which requires further research.

There were a number of limitations for this systematic review that should be acknowledged. Language was limited to English which is generally not recommended, but is often difficult to overcome [50]. There were two identified studies which had to be excluded based on language barriers (Spanish and Russian languages) that could have potentially had an impact on the findings of this review. It is acknowledged that a number of studies were identified by hand-searching that were not identified using the detailed search strategy. The original search strategy was reviewed to investigate whether or not it was adequate. The minor problem with the search strategy was subsequently attributed to an indexing issue within the databases that could not be overcome by altering the search strategy. However, in spite of this limitation, the pragmatic nature of the reviewing strategy permitted important and relevant studies which met the inclusion criteria to be identified by hand.

In conclusion, there is conflicting and inconclusive evidence for the efficacy of lower limb IACIs for JIA. While there is enough quantity among the current body of knowledge to provide weak evidence in some outcome domains for generalised efficacy of IACIs administered to the lower limb, efficacy for duration of relief of synovitis in specific lower limb joints remains inconclusive. It is for this reason we conclude that more high quality studies are needed to definitively determine the efficacy of lower limb IACIs for improving outcomes associated with the JIA disease process.