Medication use in juvenile uveitis patients enrolled in the Childhood Arthritis and Rheumatology Research Alliance Registry

CARRAnet was developed by the Childhood Arthritis and Rheumatology Research Alliance (CARRA) and is a multicenter registry of children with rare pediatric rheumatologic conditions (“CARRA registry” on https://​clinicaltrials.​gov). Over 50 pediatric rheumatology research centers in the United States and Canada have enrolled over 9000 children into the registry since its inception. Children were eligible to participate if they had 1 of 12 specified rheumatologic diseases that were being studied in the registry. The primary diagnosis at enrollment was determined by the child’s treating rheumatologist. The registry opened with recruitment of children with JIA in May 2010; recruitment of children idiopathic uveitis began in February 2012, at which time collection of detailed information on uveitis presentation and treatment was also introduced to the registry. Demographic and clinical data, including information on prior medication use and disease complications, were gathered by family interview, medical record review, and/or provider recall and subsequently entered into a secure online database. Consent/assent was obtained from all study participants.

After Institutional Review Board approval, we obtained de-identified enrollment data from children with JIA-associated and idiopathic uveitis who participated in the CARRA registry from June 2010 to September 2013. Although the registry was developed for prospective data collection, at the time of our inquiry, only data from a single, baseline registry enrollment visit was available for most patients. Data collected included uveitis type, number of affected eyes,duration of current episode (if active uveitis present), history of ocular complications, and current and prior medication use. Possible ocular complications listed included increased intraocular pressure, keratic precipitates, posterior synechiae, cataracts, macular edema, epiretinal membrane, snowbanks, snowballs, retinal vasculitis, macular atrophy, hypopyon, iris nodules, band keratopathy, and history of eye surgery. Information on topical therapies (steroid, mydriatic, and anti-glaucoma drops), systemic glucocorticoids, intra-ocular steroids, intravenous immunoglobulin, non-biologic disease-modifying antirheumatic drugs (DMARDs), and biologic agents were included in the registry. Long-term steroid use was defined as a history of systemic glucocorticoid treatment for > 1 month. Drug use was categorized as “current,” “past,” “never,” or “unknown.” For this analysis, “ever drug use” was defined as past and/or current use. Information on medication dose and dates of drug initiation/cessation were not included in the registry. Thus, while some longitudinal information regarding treatment could be inferred based on current and past use of medications, details such as duration of therapy were not available. For JIA patients, the indication for a systemic medication (arthritis vs. uveitis) was not recorded. Finally, data collection also included “ANA status,” where a positive response was defined as a history of testing positive for anti-nuclear antibody (ANA). Date of ANA testing was not included in the registry.

Demographic differences between JIA-associated and idiopathic uveitis groups were compared with Mann-Whitney U and chi-square tests. Univariate analysis was performed between first-use of oral MTX and subcutaneous MTX, and between biologic and non-biologic groups, using the Mann-Whitney U-test for median age and Fisher’s exact test for percentages. Multivariable logistic regression (backward selection) was applied to identify predictive factors, with the likelihood ratio test used to assess significance of the independent predictors [40]. Odds ratios and 95 % confidence intervals (CI) were derived for significant multivariable predictors of route of MTX administration and for use of biologics.

There were 92 children with idiopathic uveitis and 646 children with JIA uveitis identified in the CARRA registry (Table 1). Children with JIA uveitis were significantly younger at disease onset (median age 2.8 years) than children with idiopathic uveitis (median 8.5 years) (P < 0.001) (Table 1). Females were more frequently affected than males in both forms of the disease; however, patients with JIA uveitis were more likely to be female than those with idiopathic uveitis (78 % vs 55 %; P < 0.001) (Table 1). A greater percentage of patients with JIA uveitis (92 %) were Caucasian as compared to children with idiopathic uveitis (77 %) (P < 0.001) (Table 1).

Information on uveitis disease characteristics and ocular complications was available for all patients with idiopathic uveitis but only 69 of 646 patients with JIA uveitis. Therefore, our evaluation of uveitis features was limited to patients with idiopathic uveitis. Anterior uveitis was the most common subtype of the disease (62 %), followed by panuveitis (21 %), intermediate uveitis (13 %), and posterior uveitis (4 %). Most children with idiopathic uveitis (77 %) had bilateral involvement. Ocular complications were common and noted in 71 (77 %) children with idiopathic uveitis: 35 had cataracts, 26 had undergone eye surgery, 13 had abnormal corrected vision, and 3 were blind in the affected eye (Fig. 1). Other frequently reported complications included posterior synechiae, band keratopathy, macular edema, and keratic precipitates. The majority of patients (64 children) reported having more than one complication. Among JIA uveitis patients for whom ocular complication data was known, cataracts again were the most common complication, although overall complication rate was lower (Additional file 1: Figure S1).

Data on medications ever used was available on all idiopathic and almost all (643/646) JIA uveitis patients (Tables 2 and 3). Use of DMARDs and biologic agents was similar in both groups. A majority of patients received a DMARD (83 % of idiopathic and 88 % of JIA uveitis patients). At least one biologic agent was used in 53 % of children with idiopathic uveitis and 56 % of children with JIA-associated uveitis. In patients with JIA uveitis, the indication for medication use was not specified and could have been due to either arthritis or uveitis disease activity. Therefore, in order to evaluate medication use for uveitis specifically, we restricted the remaining medication analysis to patients with idiopathic disease.

Topical steroid drops were used in 90 % of idiopathic uveitis patients, with hourly dosing employed at some point in the disease course in 26 % (Table 4). Of the 5 children who did not receive topical steroid drops, 4 were treated with oral or IV glucocorticoids. None of the idiopathic uveitis patients received intra-ocular steroid injections. Almost all (94 %) of idiopathic uveitis patients had received systemic glucocorticoids. Further, 38 % of idiopathic uveitis patients had received long-term systemic glucocorticoids.

Of the 92 idiopathic uveitis patients, 70 (76 %) received methotrexate (MTX), making it the most frequently utilized steroid-sparing agent. Overall, the oral and subcutaneous (SQ) forms of MTX were used at similar rates (Table 2). In 96 % of patients who had received MTX, it was possible to determine the initial route of MTX administration prescribed to treat idiopathic uveitis. SQ MTX was used first in 54 % of children, while oral MTX was prescribed first in 46 %. A minority (29 %) of patients had been trialed on both formulations (SQ to oral in 10 patients; oral to SQ in 7 patients; in 3 subjects the order could not be determined). By univariate analysis, the initial use of the SQ MTX was associated only with non-Caucasian race (P = 0.046). This relationship persisted in the multivariable analysis with adjustment for age at disease onset, ethnicity, race, gender, uveitis type, and ocular complications (P = 0.003) (Table 5). DMARDs other than methotrexate that were less frequently used in idiopathic uveitis patients included cyclosporine (N = 3), mycophenolate mofetil (N = 9), and sulfasalazine (N = 1) (Table 2).

Among the 49 idiopathic uveitis patients treated with a biologic medication, all received a tumor necrosis factor (TNF) inhibitor: infliximab (n = 36), adalimumab (n = 18), or golimumab (n = 1) (Table 3). Of these, all but 2 had also received methotrexate. In univariate analysis, patients who had received a TNF inhibitor were more likely to have a history of a cataract compared to patients who had never been exposed to a biologic agent (53 % vs. 21 %; P = 0.002) (Table 6). This association remained in multivariable analysis adjusting for age at disease onset, ethnicity, race, gender, uveitis type, ANA status, and ocular complications (odds ratio = 5.6; P = 0.001). In addition, multivariate modeling also revealed that a positive ANA, defined as a history of testing positive for ANA, was significantly associated with TNF inhibitor use after adjusting for other disease and patient characteristics (P = 0.04) (Table 6).

Six idiopathic uveitis patients were treated with multiple biologic agents. All of these patients had received both infliximab and adalimumab. In 5 of these patients, the order of TNF inhibitor use could be determined: 3 patients switched from adalimumab to infliximab, while 2 patients switched from infliximab to adalimumab.

Two patients included in the registry were treated with infliximab without a preceding DMARD. Neither of these patients had anterior uveitis, while both had ocular complications. The first patient was diagnosed with bilateral panuveitis and had developed snowballs and posterior synechiae. The second child had posterior uveitis complicated by retinal vasculitis and blindness in the affected eye.

Although the size of our idiopathic uveitis pediatric cohort was relatively large, interpretation of the impact of specific medications on patient outcome is limited by the lack of follow up. This was a relatively early cross-sectional look at enrollment data, but collection of data from follow up visits remains ongoing. We hope that over time, further analyses will allow more detailed examination of the factors that influence the selection of medications, as well as their efficacy.

The CARRAnet database did not include data on the indication for medication use in JIA uveitis patients. Therefore, it was not possible to determine if a medication was used for active arthritis and/or uveitis. Thus, we limited the majority of our analysis to idiopathic uveitis patients. It is unclear if our findings are applicable to JIA uveitis patients, given the differences in race, gender, and ANA status in both groups which may be associated with differences in disease severity, and subsequently medication use. The database also did not collect information on medication dosage, which can also vary greatly from provider to provider and also influence the decision for whether to move on to another agent. Future iterations of this database will hopefully allow more granular analysis of medication dosage.

Finally, our cohort may be influenced by selection bias, as these patients were all under the care of a pediatric rheumatologist. Patients with milder disease may be managed solely by ophthalmologists without coming to the attention of a rheumatology provider.