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Success of Weekly Adalimumab in Refractory Ocular Inflammatory Disease

      Adalimumab (ADA, Humira, AbbVie, Chicago, IL) is the only systemic non-corticosteroid agent approved by the US Food and Drug Administration for the treatment of non-infectious intermediate, posterior and panuveitis. The dosage is based on 2 placebo-controlled phase III trials that used ADA on an every other week (EOW) schedule.
      • Jaffe G.J.
      • Dick A.D.
      • Brezin A.P.
      • et al.
      Adalimumab in patients with active noninfectious uveitis.
      ,
      • Nguyen Q.D.
      • Merrill P.T.
      • Jaffe G.J.
      • et al.
      Adalimumab for prevention of uveitic flare in patients with inactive non-infectious uveitis controlled by corticosteroids (VISUAL II): a multicentre, double-masked, randomised, placebo-controlled phase 3 trial.
      However, a meta-analysis showed that approximately 26% and 21% of patients failed to achieve short-term and long-term disease quiescence on this regimen, respectively.
      • Ming S.
      • Xie K.
      • He H.
      • et al.
      Efficacy and safety of adalimumab in the treatment of non-infectious uveitis: a meta-analysis and systematic review.
      In real-world practice, ADA is sometimes increased to weekly dosing, an off-label regimen, to attain better control of inflammation.
      Currently, the paucity of data validating weekly therapy makes dose escalation very challenging in clinical practice. Therefore, we evaluate the efficacy of weekly ADA in patients with inadequate control of inflammation on standard dosing.
      We conducted a retrospective review of all patients with ocular inflammation treated with ADA at Northwestern Memorial Hospital (Chicago, IL), from January 1, 2012, to April 1, 2019. This study was approved by the Institutional Review Board at Northwestern University and complied with the tenets of the Declaration of Helsinki.
      Inclusion criteria were any type of noninfectious ocular inflammation, in patients aged 2 years and older, who failed ADA EOW and were escalated to weekly dosing.
      The standard dose was 40 mg EOW for weight ≥30 kg and 20 mg EOW for weight <30 kg. The escalated dose was 40 mg every week for weight ≥30 kg and 20 mg every week or 40 mg EOW for weight <30 kg.
      Classification and grading of uveitis were based on the Standardization of Uveitis Nomenclature criteria. Treatment success was defined by anterior chamber (AC) grade ≤0.5+ cell, topical steroids ≤1 drop/day, oral steroids ≤5 mg/day, and improvement or resolution of the following: angiographic signs of inflammation, macular edema, chorioretinal lesions, orbital pain, and scleral injection in cases of scleritis. Patients with bilateral disease were deemed successful only if control was achieved in both eyes.
      Demographic and clinical data collected included type of disease, age, gender, concomitant immunomodulatory agents, steroid use, disease activity based on complete ophthalmic examination, and relevant imaging including fluorescein angiography and OCT.
      The main outcome measure was the number of patients with treatment success on weekly therapy. The follow-up time points were defined by contiguous windows (6±1 months, 12±1 months). The data were analyzed using descriptive statistics. The Kaplan–Meier method was used to visualize and estimate survival for the same 25 patients on every 2 weeks and on weekly ADA dosing. We defined baseline as the date the patient first started ADA, and then the date ADA was first escalated. Patients were censored at their last follow-up visit.
      Treatment responses to weekly therapy are summarized in Table 1. Fourteen of 25 patients (56%) achieved inflammatory control at 6 months. The median age was 12.5 years (range, 3–68 years), and 9 (50%) were female. No additional failures were observed at 12 months. One patient with juvenile idiopathic arthritis (JIA) was censored because of insufficient follow-up at 10 months. The median survival time was 4 months on EOW ADA (95% confidence interval [CI], 3.25–6 months) and 16.5 months on weekly ADA (95% CI, 5–∞ months). Twelve-month survival probability was 4% (95% CI, 1–27) on EOW and 56% (95% CI, 4–79) on weekly ADA (Fig S1, available at www.aaojournal.org).
      Table 1Treatment Success on Weekly Adalimumab Therapy
      6±1 Months Follow-up12±1 Months Follow-up
      Total patients, n2524
      Follow-up in mos, mean (range)6.1 (5.5–7)12.0 (11–13)
      Total success, n (%)14/25 (56)13/24 (54)
      Type of ocular inflammation, n (%)
       Anterior uveitis7/10 (70)6/9 (67)
       Panuveitis1/5 (20)1/5 (20)
       Scleritis2/4 (50)2/4 (50)
       Anterior/intermediate uveitis1/2 (50)1/2 (50)
       Intermediate uveitis1/2 (50)1/2 (50)
       Posterior uveitis2/2 (100)2/2 (100)
      Diagnosis, n (%)
       Idiopathic4/10 (40)4/10 (40)
       JIA5/6 (83)4/5 (80)
       Birdshot chorioretinopathy2/2 (100)2/2 (100)
       HLA-B271/2 (50)1/2 (50)
       RA1/1 (100)1/1 (100)
       TINU1/1 (100)1/1 (100)
       VKH syndrome0/1 (0)0/1 (0)
       Sarcoidosis0/2 (0)0/2 (0)
      HLA-B27 = human leukocyte antigen B27; JIA = juvenile idiopathic arthritis; RA = rheumatoid arthritis; TINU = tubulointerstitial nephritis and uveitis; VKH = Vogt–Koyanagi–Harada.
      The most common location of ocular inflammation in the success group was anterior uveitis (70% at 6 months, 67% at 12 months), and the most common diagnosis was JIA (83% at 6 months, 80% at 12 months). The median baseline level of AC inflammation was 2+ cells (range, 1–4+ cells). Seven patients using topical prednisolone, an average of 4.5 drops per day (range, 1–12 drops), were successfully tapered to an average of 0.75 drops daily (range of every other day to once daily). Seven of 14 patients (50%) were receiving concomitant antimetabolite therapy; no patient required dosage increase. Six patients were receiving methotrexate, a median dose of 17.5 mg weekly (range, 7.5–20 mg), and 1 patient was receiving mycophenolate mofetil.
      Eleven patients (44%) failed weekly ADA during the 12-month study period. The median age was 20 years (range, 2–68 years), and 9 (50%) were female. The median baseline level of AC inflammation was 2+ cells (range, 1–2+ cells). The most common location of ocular inflammation in the failure group was panuveitis (4/5 patients, 80%). Five of 6 patients (83%) had persistent vasculitis. Five of 11 patients (45%) were taking concomitant antimetabolite therapy. Two patients were receiving full-dose mycophenolate mofetil or mycophenolic acid, and 3 patients were receiving methotrexate, a median dose of 15 mg weekly (range, 10–25 mg). Six patients were using topical steroids and could not be tapered. No patient discontinued ADA because of intolerance or adverse events.
      In this retrospective study of patients with recalcitrant inflammation on standard EOW ADA dosing, escalation to weekly ADA resulted in control of ocular inflammation in more than half the patients.
      In the literature, only one study has evaluated the efficacy of weekly ADA for uveitis, but investigators did not try standard therapy first.
      • Erckens R.J.
      • Mostard R.L.
      • Wijnen P.A.
      • et al.
      Adalimumab successful in sarcoidosis patients with refractory chronic non-infectious uveitis.
      No clinical trials have used doses higher than 40 mg every 2 weeks or its equivalent dosing in children.
      • Jaffe G.J.
      • Dick A.D.
      • Brezin A.P.
      • et al.
      Adalimumab in patients with active noninfectious uveitis.
      ,
      • Nguyen Q.D.
      • Merrill P.T.
      • Jaffe G.J.
      • et al.
      Adalimumab for prevention of uveitic flare in patients with inactive non-infectious uveitis controlled by corticosteroids (VISUAL II): a multicentre, double-masked, randomised, placebo-controlled phase 3 trial.
      ,
      • Suhler E.B.
      • Lowder C.Y.
      • Goldstein D.A.
      • et al.
      Adalimumab therapy for refractory uveitis: results of a multicentre, open-label, prospective trial.
      ,
      • Ramanan A.V.
      • Dick A.D.
      • Jones A.P.
      • et al.
      Adalimumab plus methotrexate for uveitis in juvenile idiopathic arthritis.
      However, dose escalation is a reasonable next step as patients are already familiar with the medication and can avoid transitioning to infusion therapy, which has time-based and hospital-based nondrug costs.
      • Sussman D.A.
      • Kubiliun N.
      • Mulani P.M.
      • et al.
      Comparison of medical costs among patients using adalimumab and infliximab: a retrospective study (COMPAIRS).
      Although the small number of patients limits our ability to draw firm conclusions about which conditions are more likely to experience success, 5 of 6 patients (83%) with recalcitrant JIA anterior uveitis had a favorable response to weekly treatment. This fact may be hypothesis-generating, paving the groundwork for potential prospective studies on weekly ADA in patients with JIA uveitis.
      In conclusion, our series of 25 patients represents the first data describing success of weekly ADA treatment after failing EOW dosing for ocular inflammation. Although these results would ideally be confirmed in a controlled trial, our data suggest that increasing ADA to every week in patients with inadequate inflammatory control on EOW is a reasonable treatment option.

      Supplementary Data

      • Figure S1

        Kaplan–Meier plot of estimates of survival function for the same patients prescribed adalimumab (ADA) every 2 weeks and every 1 week. At every 2-week dosing, the median survival time was 4 months (95% confidence interval [CI], 3.25–6 months) and the 12-month survival probability was 4% (95% CI, 1–27). At every 1 week, the median survival time was 16.5 months (95% CI, 5–∞ months) and 12-month survival probability was 56% (95% CI, 4–79).

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