We conducted a retrospective analysis of the case records of 9 patients with JIA-U who received care at the Department of Pediatric Rheumatology and Department of Ophthalmology at the Tokyo Medical and Dental University from April 2015 to August 2019 (107 JIA cases). The study was conducted in adherence with the guidelines of the Declaration of Helsinki, and written informed consent was obtained from each patient and their guardians. The IRB/Ethics Committee ruled that approval was not required for this study.
Figure 1 presents the 9 cases of JIA-U in order of age at onset, including 2 cases (Cases 4 and 9) in which uveitis preceded arthritis. Risk factors associated with the development of JIA-U included sex, JIA category, age at onset, the titer of anti-nuclear antibody (ANA), human leukocyte antigen B27 (HLA-B27) positivity, and rheumatoid factor (RF) negativity [2, 15–17]. These factors were reflected in our 9 JIA-U patients as follows: median age was 16.8 years (range 5.5–19.8 years), median disease duration was 12.5 years (range 3.5–24.7 years), the sex ratio was 1:8 (male:female), all patients presented with oligo-JIA (one presented with extended oligo-JIA), median age at uveitis onset was 5.0 years (range 3.0–13.0 years), the onset of uveitis preceded arthritis in 2 patients, 4 patients showed ANA positivity ( ≧ 1:160) (all patients presented with the homogeneous and speckled-pattern subtype), and all patients were negative for RF. It was difficult to determine the frequency of the HLA-B27 allele, because only 1 patient was tested (the patient was HLA-B27 negative).
All patients used topical glucocorticoid eye drops, 8 patients took methotrexate, and 7 were administered biologic drugs. The biologics prescribed were etanercept, infliximab, adalimumab, or golimumab. Six patients required ophthalmic surgery for cataracts, glaucoma, or iritis at an early age (≤ 18 years). Studies show the following regarding etanercept: it may induce JIA-U , shows no difference from placebo , and is inferior to adalimumab and infliximab ; Etanercept is therefore no longer considered a treatment for uveitis [21–23]. However, this information was not recognized at the time, and etanercept was used for one patient (case 2).
Two patients took golimumab (cases 2, 5) after approval by the hospital ethics committee for off-label use in Japan. These 2 patients had refractory JIA-U, which was not improved by adalimumab; however, golimumab treatment resulted in improved anterior chamber inflammation after 4 weeks, observed during slit-lamp examination (based on Standard Uveitis Nomenclature criteria) , and an improved inflammation grade, from 3 to 1.
Details on the 2 cases of blindness are described below.
Blindness case 1 (case 6)
A 29-year-old female patient, with no prior medical history, presented at 4 years of age with knee joint swelling and fever and was diagnosed with oligo-JIA. The arthritis disappeared within a month with nonsteroidal anti-inflammatory drug (NSAID) use. At age of 6 years, she was diagnosed with asymptomatic JIA-U; topical and systemic prednisolone use was commenced during exacerbations, but methotrexate or biologics was not prescribed (at the time as there were no indications for the use of biologics for the JIA). At age of 15 years, she complained of visual impairment, and had cataract surgery in her left eye (OS). She continued topical and systemic glucocorticoid therapy for 2 years, but her ocular inflammation was uncontrolled. At 18 years old, she was transitioned out of pediatric care and was treated as an adult patient. At that point, her BCVA was 0.02 in the right eye (OD) and 0.01 in the OS. Slit-lamp examination demonstrated 3 + anterior chamber cell/ 4 + anterior chamber flare OD, and 2 + anterior chamber cell/ 3 + anterior chamber flare OS. Soon after, cataract surgery in her OD was performed, and she was started on infliximab and methotrexate therapies. Her BCVA recovered to 0.7 (OD) / 0.08 (OS) when she was 19 years old. However, she developed depression and did not visit the outpatient clinic for 2 years. She stated that the rapid strengthening of treatment after the transition and the apathetic attitude of adult doctors kept her from returning to the hospital. She visited the hospital again at the age of 21 years with visual acuity to light perception bilaterally. Infliximab was restarted but was not effective, likely due to antibody production and the development of resistance. At the discretion of the attending physician and the patient, infliximab and methotrexate were considered invalidated; further treatment was withdrawn. At 27 years of age, she was referred to an ophthalmologist and a pediatric rheumatologist in our clinic for a second opinion. Although adalimumab (40 mg per 2 weeks) was started, no improvement was seen in the BCVA. Currently, she remains legally blind but continues anti-inflammatory treatment with adalimumab and methotrexate to prevent phthisis bulbi.
Blindness case 2 (case 8)
A 19-year-old female patient, with no previous medical history, presented at 5 years of age with right knee joint swelling and visual impairment (OS) and was diagnosed with oligo-JIA and JIA-U. The arthritis resolved within a year with NSAID, prednisolone, and methotrexate treatments, but ocular inflammation continued; thus, only methotrexate was continued thereafter. Ocular inflammation persisted, and surgeries were repeated. She underwent cataract surgery (OS) when she was 8 years old, iridotomy (OS) when she was 9 years old, and cataract surgery and peripheral iridectomy (OD) when she was 14 years old. Although she received repeated systemic prednisolone during exacerbations, she received no additional treatment with biologics. She was referred to a pediatric rheumatologist at our clinic at the age of 15 years. The patient was completely blind in OS, BCVA was 0.5 (OD), and slit-lamp examination demonstrated 4 + anterior chamber cell/ 4 + anterior chamber flare in OS and 1 + anterior chamber cell/1 + anterior chamber flare in OD. Immediately, peripheral iridectomy was performed and adalimumab (40 mg per 2 weeks) was prescribed, but the blindness did not improve. OS enucleation was performed at 17 years of age. The combination of adalimumab and methotrexate is currently being continued to control the inflammation of the OD that remains.