Intraarticular corticosteroid injections (IACIs) are often used as first-line therapy in patients with Oligoarticular JIA, in whom a limited number of joints are affected. IACIs are also used as adjunctive therapy in other subtypes of JIA to expeditiously control inflammation and decrease pain while awaiting systemic medications to take effect. IACIs have the benefit of quickly decreasing inflammation, thus minimizing the risk of morbidity associated with JIA, such as cartilage destruction, muscle wasting, and leg length discrepancies [1,2,3,4, 14]. Acquired leg length discrepancies in children with JIA are thought to result from stimulation of the growth plate due to the inherent hyperemia in the region secondary to synovial inflammation [4]. Intraarticular corticosteroids have been shown to effectively reduce synovial T lymphocytes and downregulate certain pro-inflammatory cytokines, including TNF-a, IL-1b, extranuclear HMGB-1, ICAM-1, and VEGF [15].
Historically, TH has been shown in several studies to have a longer duration of action and a superior side effect profile compared to other intraarticular corticosteroid formulations [10,11,12,13, 20]. TH was superior, even at lower doses, with effects lasting up to 24 months [10, 11].
Furthermore, it has been shown to be an effective therapy for inflammatory arthritis in all subtypes of JIA [21]. Aristospan, a formulation of triamcinolone hexacetonide (TH), was the preferred corticosteroid for intraarticular injection until it became unavailable in the United States almost a decade ago. Since that time, pediatric rheumatologists have been using Kenalog, a brand of triamcinolone acetonide (TA). However, there have been very few contemporary studies comparing the efficacy of the two.
The results from our study support the past comparative studies in pediatric rheumatology that have suggested superiority of TH compared to TA across all subtypes of JIA. TA dosing was approximately 50% higher than customary dosing (there is no established dosing regimen for TA), similar to prior studies comparing these two drugs, The median time to flare in joints treated with TH was 11 months in our study, which is similar to the mean time to flare reported by Eberhard et al. of 10.14 ± 0.49 months in the group injected with TH [13]. Lepore et al. reported a mean duration of remission of 13.9 months in knees injected with TH for patients with oligoarticular JIA [22]. This slightly longer duration of remission may be secondary to the isolation of knee injections, with previous studies suggesting IACIs were most effective in this joint [8, 13, 21]. Similar to us, both Eberhard et al. and Lepore et al. defined remission as a complete disappearance of clinical signs of inflammation. Other studies have reported much longer durations of remission. Zulian et al. compared the efficacy of TH and TA in oligoarticular JIA in a prospective study, with almost double the response rate with TH at 24 months [10]. Subsequently, Zulian et al. compared TA at twice the dose of TH in children with symmetric arthritis in a prospective double-blinded study, with similar findings [11]. However, the scale to assess for arthritis was different, allowing for a nominal degree of arthritis. In a retrospective study, Marti et al. reported a longer median duration of remission of 23.1 months for patients who underwent IACI with either TH or TA, but patients were often started on concomitant medications at time of injection [8].
The median time to flare in joints treated with TA in our study was 3 months, which is shorter than the mean time to flare of 7.75 ± 0.49 months reported by Eberhard et al. However, it should be noted that Eberhard et al. used 80 mg for the knee and 60 mg for the elbow, ankle, and wrist, which is higher than what was used in this study. Some studies suggest that higher doses of TA are needed to be effective, and while our dosing of TA was approximately 50% higher than customary dosing, the dosing in this study was 100% higher [10, 11, 13]. Additionally, every patient in our study who received TH had previously failed IACI with TA, suggesting a more refractory disease group and the potential for a more robust response if initially treated with TH.
Side effects of IACI are usually mild and temporary, with discomfort at the injection site being the most common [23]. Other reported side effects include mood and sleep alteration, appetite changes, menstrual irregularities, weight gain, and Cushingoid appearance, especially in young patients or in those getting multiple injections [24, 25]. Skin hypopigmentation and subcutaneous atrophy from leakage of the steroid along the needle track can also be seen, but these changes usually resolve with time [1, 25]. In our cohort, the use of TH for IACI was associated with more post-procedural discomfort, but fewer systemic side effects, likely due to increased intraarticular residence and less systemic absorption [25]. Compared to those who received TA, those who received TH had less post-procedural emotional lability, appetite changes and weight gain, flushing and malaise.
Limitations of this study include the small sample size and the retrospective nature of chart reviews. The sample size was limited by the availability of the medication, as the cost was not covered by insurance. Furthermore, there was often parental hesitance to use a medication that was not FDA-approved. Interestingly, more males than females received TH compared to TA, and the reason for this is unclear, i.e., if the medication was offered to more male patients, or if the parents of male patients were more likely to want to try it (as opposed to starting systemic therapy). We know that in this age group, in general, there is a female predominance, so that will be an interesting variable to evaluate going forward.
The majority of the patients in this study had Oligoarticular JIA (both persistent and extended), as is expected. Most of the patients that we treat who have either psoriatic or polyarticular JIA or have uveitis receive systemic therapy initially, and those patients that received concurrent joint injections were not included. The patients that were included in the study either received joint injections as initial management or if they flared on systemic therapy in which case they were only included if therapy did not change before or after they received joint injections. However, by excluding patients who concomitantly started or changed systemic therapy, we may have introduced some selection bias, as there was no standardization for stepwise escalation of therapy. This could suggest that patients with worse disease may have been quickly started on concomitant therapies and excluded from the study. However, we would argue that since all patients were required to have previously failed TA injections to qualify for TH injections, this may suggest that they had more severe or refractory disease at baseline.
A future goal is to conduct a prospective study evaluating the duration of remission of TH versus TA, when TH is used in steroid-naïve joints as opposed to being used as a second-line agent for intraarticular corticosteroid injections.
In conclusion, we confirm the finding that TH is superior to TA in terms of time to flare and associated side effects, and we advocate for increased availability of this product for our patients. At the time of this writing, Medexus Pharma is the sole pharmaceutical company with rights to sell this drug in the United States. They are currently importing Trispan from France, which is the same chemical formulation as Lederspan which was imported from Germany.
Literature to support the superiority of TH over TA could expedite the FDA approval of this medication and render it less cumbersome for pediatric rheumatologists to obtain.
