Other retrospective studies have supported the efficacy of infliximab for Behçet’s disease-associated panuveitis and retinal vasculitis.22–26 Outcome measures have differed between these retrospective case series, making comparisons between studies difficult. Improvement in visual acuity, decreased intraocular inflammation, and reduction of daily corticosteroid requirements have been reported. However, the development of ocular and systemic tuberculosis in 1 patient26 and an episode of thoracic herpes zoster in another patient25 required systemic antimicrobial therapy.

Besides Behçet’s disease-associated uveitis, sarcoid-associated uveitis has also been treated successfully with infliximab therapy. Cruz et al.27 reported the successful use of infliximab (3 mg/kg infusions given at day 0, week 2, and week 6) in 2 patients with retinal vasculitis and multisystem sarcoidosis. Other patients with sarcoidassociated uveitis have also experienced therapeutic benefit with infliximab.17,24,28

Other retrospective case series have reported a therapeutic benefit of infliximab for JIA-associated uveitis.29,30 Richards et al.30 reported improved control of intraocular inflammation in 6 of 6 patients treated with infliximab and maintenance low-dose immunosuppression. This study suggested a role for infliximab as adjunctive therapy in JIAassociated uveitis. Rajaraman et al.29 also evaluated infliximab for pediatric uveitis due to a variety of etiologies, including JIA-associated uveitis (3 patients), pars planitis (1 patient), retinal vasculitis (1 patient), and idiopathic uveitis (1 patient). All patients demonstrated improvements in intraocular inflammation while on infliximab and 5 of 6 patients were able to wean completely off corticosteroid therapy by the end of the study period evaluated (mean follow-up 48 weeks). Vitreous hemorrhage developed in 1 patient while another patient experienced a transient upper respiratory infusion reaction.

The use of high-dose infliximab (10–20 mg/kg) for pediatric patients with refractory uveitis was reported by Kahn et al.31 In 17 patients evaluated, 13 individuals demonstrated quiescence of inflammation following two infliximab infusions, and the remaining 4 patients achieved this outcome after three to seven infusions. All patients receiving oral steroids before therapy discontinued steroid treatment over a period varying between 2 weeks and 2 years, and 15 of 17 patients were tapered off topical corticosteroids. No significant adverse events were noted, although 2 patients developed autoantibody formation (i.e., positive antinuclear antibody or anti-dsDNA), although no features of lupus were noted in either patient.31

One prospective noncomparative case series of infliximab as monotherapy for HLA-B27-associated anterior uveitis demonstrated a rapid decrease in anterior-chamber inflammation in 7 patients treated with infliximab (10 mg/kg) infusions.32 However, 1 patient required a second infusion after 3 weeks because of a flare-up, and median time to relapse in the 4 patients was 5 ± 6.4 months.

Besides these reports of its efficacy for intraocular inflammation, infliximab has also been successfully utilized for the treatment of scleritis and peripheral ulcerative keratitis due to a variety of etiologies, including Wegener’s granulomatosis, RA, and relapsing polychondri- tis.33–37 The efficacy of infliximab for posterior scleritis in a pediatric patient has also been reported.38

Contraindications

Infliximab is contraindicated in patients with known hypersensitivity to known murine proteins or any component of infliximab.39 Infliximab is also contraindicated in patients with New York Heart Association class III or IV congestive heart failure.

Ocular complications and toxicity

Ocular complications attributed to infliximab therapy have rarely been reported in the literature; however, recurrence of disease following infliximab cessation has been reported and should be discussed with patients prior to discontinuation of medication.20,32 Herpetic keratitis,21 vitreous hemorrhage,17,29 optic neuritis,40 and ocular tuberculosis26 have been reported during infliximab therapy.

Systemic complications and toxicity

A number of systemic complications have been associated with infliximab therapy, the most concerning of which include reactivation of latent tuberculosis, exacerbation of congestive heart failure, unmasking of demyelinating disease, the development of autoantibody formation (i.e., antinuclear antibodies, anti-dsDNA antibodies), and the formation of anti-infliximab antibodies.41 In the pediatric population, reports of hepatosplenic T-cell lymphoma following infliximab therapy for Crohn’s disease have been extremely concerning.42 The possible contribution of anti-TNF therapy to increased lymphoma risk in RA patients is unclear at this time. Increased risk of lymphoma has been associated with RA independent of anti-TNF therapy, but further studies are needed.43–46 Severe hepatotoxicity complicating infliximab therapy has also been reported both with and without concomitant use of other medications with known hepatotoxicity.47 Thoracic herpes zoster, herpetic keratitis, nonocular herpetic infection, and optic neuritis have also been reported rarely following infliximab therapy for ophthalmic disease.

Drug interactions

Specific drug interactions, including interactions of infliximab with methotrexate, have not been studied extensively. However, many patients with RA or Crohn’s disease have been on other immunosuppressive medications in combination with infliximab. RA patients have been treated with infliximab and methotrexate whereas Crohn’s disease patients have been treated with infliximab while concomitantly using a number of other medications, including antibiotics, antivirals, corticosteroids, 6-mercaptopurine, azathioprine, and aminosalicylates.39

Summary

Infliximab, a mouse–human chimeric monoclonal antibody targeting TNF-α, has been utilized successfully for the treatment of a number of systemic autoimmune conditions, including RA, Crohn’s disease, Behçet’s disease, and psoriatic arthritis. The efficacy of infliximab for a number of uveitic syndromes, including Behçet’s disease-associated panuveitis and retinal vasculitis, JIA-associated anterior uveitis, and HLA-B27-associated uveitis, is supported by limited prospective studies and a number of retrospective case series and interventional case reports. The utility of infliximab for scleritis and peripheral ulcerative keratitis due to a number of etiologies has also been described in several retrospective case series. Currently, doses used by ocular inflammatory specialists range from 3 to 10 mg/kg intravenous infusion, although higher doses of infliximab have been rarely reported. While the efficacy of infliximab for a number of sight-threatening ocular inflammatory syndromes appears promising, a thorough medical workup and caution are advisable because of serious adverse events reported in the literature, including reactivation of latent tuberculosis, unmasking of demyelinating disease, hepatosplenic lymphoma in pediatric patients, lupus-like syndrome, congestive heart failure exacerbations, and the possible association of infliximab with an increased risk of lymphoma in RA patients.

ADALIMUMAB (HUMIRA)

Pharmacology and mechanism

Adalimumab is a fully human, anti-TNF-α IgG1 monoclonal antibody, which blocks the interaction of TNF-α with p55 and p75 cell surface receptors.

Adalimumab is typically administered as a 20or 40-mg dose via subcutaneous injection either weekly or every other week. The subcutaneous route of administration may be favorable to infliximab, which requires an intravenous infusion.

The terminal half-life of adalimumab ranges from 15 to 19 days and early phase I trials demonstrated no significant pharmacokinetic advantage to weight-based dosing strategies.48

Diseases Retinal in Mechanisms and Drugs • 4 section