Background
Pediatric non-infectious uveitis [NIU] is an important cause of visual morbidity in children, with prevalence in the United States of 29/100,000 [
1]. Ocular inflammation can be associated with systemic disease, most commonly Juvenile Idiopathic Arthritis [JIA] [
1] or may be idiopathic. Vision loss from ocular complications such as band keratopathy, synechiae, cataracts, glaucoma, cystoid macular edema and hypotony occur in up to 75% of patients [
2‐
5]. Visual acuity worse than 20/40 and 20/200 occurs in approximately 20 and 5% of patients respectively even with advances in therapeutic options [
6]. Therefore, timely diagnosis and initiation of an effective management protocol are strongly indicated.
While local and systemic therapy with corticosteroids may be utilized as initial treatment, ocular [
7,
8] and systemic [
9] side effects of long-term administration warrant early implementation of corticosteroid-sparing therapy to improve visual outcomes [
8,
10]. Most commonly, methotrexate is used as initial treatment in children, with response rate ranging from 50 to 75% of patients [
6,
11]. For those who do not respond or incompletely respond, escalation to a biologic response modifier such as the tumor necrosis factor-alpha [TNF-α] inhibitors, adalimumab [ADA, Humira™] and infliximab [IFX, Remicade™], is appropriate to attempt to control disease activity [
12‐
15].
Cytokines like TNF-α have been shown to play a role in the pathogenesis of uveitis, as evidenced by elevated TNF-α levels in the aqueous humor [
16,
17]. IFX is a chimeric human/murine monoclonal antibody to TNF-α, that binds to free and membrane-bound forms and initiates a conformational change that inhibits binding to TNF receptors [
18]. IFX has been used for pediatric uveitis for many years with variability in reported response rates ranging from 0 to 100% [
19‐
26], with average response rate of 72% based on meta-analysis by Simonini and colleagues in 2014 [
26].
To successfully manage and to treat uveitis, frequent appointments and complicated medication regimens are often needed. Adherence to both treatment and follow-up evaluations are paramount to treatment success of uveitis [
27,
28]. Children represent a vulnerable population, and treatment success may largely depend on the partnership between the caregivers and the clinicians to promote adherence. Uveitis with or without JIA has the potential to leave residual and permanent disability, which has life-long consequences for these children. One of the benefits of IFX is that the clinician can track infusion administration. Therefore, understanding the impact of adherence on treatment efficacy and disease control is an important endeavor. In this study, we evaluate the long-term use of IFX to sustain control of inflammation and impact of treatment adherence in a single center study of children with recalcitrant NIU. The number of patients in this study is larger than relevant publications in the literature.
Discussion
IFX has a long track record of efficacy for treating pediatric uveitis [
19‐
26], however, several key findings can be learned from this study: [1] IFX was efficacious for long-term control of disease in the majority of this population and represented a viable alternative for those who had failed treatment with ADA for either uveitis and/or joint disease; [2] Topical corticosteroid and glaucoma medication was reduced on IFX; [3] Treatment adherence is key to achieving optimal effectiveness.
Firstly, we found a high level of IFX effectiveness in our patient population. Twelve of the 14 patients who failed ADA treatment prior to IFX had active uveitis or required > 2 drops of PA/day to control disease. After changing to IFX, all but one patient was controlled at their most recent visit and all had a steroid regimen of ≤2 drops of PA/day with half of the patients discontinuing ocular steroids entirely. This study did not directly compare efficacy of ADA to IFX; however, this study supports previous studies that changing TNF-alpha inhibitors represents a viable option for those failing ADA as initial treatment [
35].
Significant variability of IFX response rate for pediatric uveitis is present in the literature ranging from 0 to 100% [
19‐
26,
36‐
39], with average of response rate of 72% based on a meta-analysis by Simonini and colleagues in 2014 [
26]. Historically, the frequency and dosage has been variable for uveitis extrapolating from the treatment of other autoimmune disorders such as rheumatoid arthritis and inflammatory bowel disease, in which dosages of 3–5 mg/kg dosed every 6 to 12 weeks are adequate to control disease [
40‐
43]. Several pediatric uveitis studies that report less favorable results and/or loss of effectiveness with IFX dosed at 5 mg/kg dose every 6–8 weeks after initial q2week loading doses [
20,
36‐
38]. Previous literature suggests that higher dosages of IFX at an infusion frequency of every 4 weeks may be needed to effectively control pediatric uveitis [
22,
39].
Higher concentrations may allow more adequate penetration of the ocular compartment as compared to joint or gastrointestinal system. The pharmacokinetic and pharmacodynamic aspects of biologic response modifiers are complex and individualized optimal dosing predictions have only been determined for inflammatory bowel disease [
44,
45]. For non-infectious pediatric uveitis, optimal dosing of IFX and treatment interval has been determined empirically. A well-designed prospective trial may help to guide patient-specific dosing for non-infectious uveitis based on pharmacokinetic and pharmacodynamic parameters.
Importantly, no severe adverse events occurred in the present study. The frequency of HACAs in our population [15%] was less than that observed in prospective pediatric cohorts with JIA with or without uveitis [23–37%] reported previously [
46,
47]. The lower frequency observed is likely an underestimate as HACAs were measured only in those failing therapy. Alternatively, higher and more frequent dosing used to treat uveitis may be protective against antibody formation as demonstrated by Aeschilmann and colleagues [
46]. The routine use of methotrexate or other DMARDs while on an IFX may also prevent antibody formation. Randomized protocols combined with routine serum IFX levels and HACAs are needed to delineate the role of dosage and frequency of IFX and use of concomitant DMARDs in preventing HACA formation.
Secondly, there were relatively few ocular complications and surgical interventions in our patients during IFX treatment: no patients developed band keratopathy, CME or new diagnoses of glaucoma suspect or glaucoma while on IFX. The two patients’ cataracts that required surgery while on IFX were already present prior to the initiation of IFX, and IFX was utilized to control disease prior to the indicated surgery. Likewise, one of the patients who required glaucoma surgery while on IFX had surgery within 3 months of starting IFX. The high rate of inflammatory control and low incidence of complications provides further support for IFX effectiveness at this dosing and frequency.
Coinciding with decreased incidence of ocular complications, IFX treatment minimized known detrimental complications associated with prolonged steroid usage, such as OHT, glaucoma, and cataract development [
3‐
6,
9]. Although some patients were “quiet” and/or “controlled” at baseline, the high steroid burden required to control disease represented an insufficient long-term treatment plan, as patients on chronically high doses of topical corticosteroids are more likely to suffer complications [
7,
48]. In order to capture the effectiveness of IFX in patients who had quiet disease at baseline due to aggressive topical and systemic treatment regimens, we utilized steroid burden [drug, potency, dose, and frequency] as a measurement marker. All of the patients who were controlled at the most recent visit on IFX were on ≤2 drops of PA, and a majority were in steroid-free remission. Interestingly, glaucoma medication paralleled the reduction in corticosteroids, likely reflecting resolution of ocular hypertension associated with reduced chronic corticosteroid use [
48]. The reduction in topical corticosteroid therapy further supports long-term control on IFX compared to baseline.
Finally, this is the first study to our knowledge that assesses the impact of treatment adherence on disease activity in children with uveitis. Patients had a 10.4-fold increased risk of having active disease with incomplete adherence documented at any given visit while on IFX. Treatment adherence as defined by the World Health Organization is a “patient-centered term” describing “the extent to which a person’s behavior – taking medication, following a diet, and/or executing lifestyle, corresponds with the agreed recommendations from a health care provider” [
49]. Treatment adherence has been extensively studied in the adult population, most notably for patients treated for primary open angle glaucoma [
50‐
53]. For example, in the adult glaucoma literature, simplified dosing regimens and/or decreased frequency of dosing has been shown to improve reports of adherence [
54,
55]. Likewise, recommendations have been proposed to increase adherence in the adult population with uveitis [
28]. However, risk factors and interventions for incomplete treatment adherence have not been rigorously studied in children with uveitis.
Children represent a unique population: parents or guardians schedule and transport children to appointments and/or infusions, and treatments often depend on parents to administer medications at home in most cases. Adherence may be even more difficult to discern in older children or teenagers who self-administer drops or treatment, where adherence is a shared responsibility. The asymptomatic nature of JIA-like chronic iridocyclitis in which inflammation may be indolent and effects of damage may not be appreciated until the disease advances further, complicates treatment adherence. Therefore, further research is clearly needed to determine the risk factors for incomplete treatment adherence and barriers to adherence in children with uveitis. To address incomplete adherence, a multi-disciplinary approach that includes a pediatric rheumatologist and ophthalmologist combined with a social worker, devoted nurse and/or behavioral psychologist may prove beneficial. Some considerations include efforts in education of the disease process and consequences, reducing appointment burden by consolidating appointments/infusions, simplifying treatment protocols and uniform instructions and/or charts to document medication administration. Further research in this area will help to define risk factors and implement effective strategies to improve adherence.
Strengths of this study include patient numbers and longitudinal follow-up at a single center for biologic medication management and evaluation of adherence on treatment effectiveness. Because of previous reports of initial control on IFX with waning effectiveness with long-term follow-up [
36‐
38], we selected patients who had long-term follow-up of nine months or more. The long mean duration of follow-up is another strength of this study. A maintained response was observed in a vast majority of patients over the treatment interval. We did not include patients with short-term follow-up, as previous studies had demonstrated no difference between six months on IFX and one year.
Limitations of this study include its retrospective nature, heterogeneity of disease, and lack of a control group. As a practice pattern at CCHMC, patients with more severe disease tend to be placed on IFX as an initial TNF-alpha inhibitor since the high dose protocol yields rapid control and confirmed adherence. Thus, the successful outcomes in this study may actually be more significant due to this practice. Additionally, success with adherence may also be more significant in this group of patients since the highly adherent regimen of IFX infusions was used in patients that may have been selected due to higher risk of poor adherence. One of the other limitations to our statistical model was the variable appointment interval, which was based on disease activity. Therefore, a patient may have more visits a specific year compared to prior or future years. Likewise, in terms of incomplete treatment adherence, missed IFX infusions and doses of concurrent systemic therapy [i.e. MTX] have delayed and/or variable effects of an unknown duration on disease activity, and therefore the effects of interval incomplete adherence for any particular office visit may not by readily discernable for that specific visit. For example, a patient may miss an IFX infusion and be quiet on next follow-up, but then develop activity 2–3 months later after missing several doses. While side effects of IFX treatment were minimal, long-term toxicity [10–15 years] cannot be determined over the follow-up period. Larger, prospective trials are needed to confirm and expand on these findings.
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