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A Prospective Trial of Infliximab Therapy for Refractory Uveitis
Preliminary Safety and Efficacy Outcomes
Eric B. Suhler, MD;
Justine R. Smith, MBBS, PhD;
Michael S. Wertheim, MBChB, MRCOphth;
Andreas K. Lauer, MD;
Daryl E. Kurz, MD;
Terri D. Pickard, COT;
James T. Rosenbaum, MD
Arch Ophthalmol. 2005;123:903-912.
ABSTRACT
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Objective Infliximab, a monoclonal antibody against tumor necrosis factor  , is approved by the US Food and Drug Administration for treatment of numerous autoimmune disorders. We conducted a prospective, open-label phase 2 clinical trial to assess the effectiveness of infliximab in treating refractory autoimmune uveitis.
Methods We prospectively enrolled 23 patients from the uveitis clinic of the Casey Eye Institute, Portland, Ore, into this trial. All patients meeting eligibility criteria received 3 infliximab infusions at weeks 0, 2, and 6. Clinical success was ascertained at week 10. Patients meeting initial criteria for success received an infusion at week 14 and every 8 weeks thereafter, with dose escalation permitted for breakthrough inflammation, and underwent outcome measurements at week 50.
Results All patients underwent outcome assessment at week 10. Eighteen (78%) of these subjects met criteria for clinical success at this time. Success was judged by the composite clinical end point of visual acuity, control of intraocular inflammation, ability to taper concomitant medication therapy, and improvement in inflammatory signs on fluorescein angiography and/or ocular coherence tomography. Successful grading required improvement in at least 1 of 4 subcomponents and worsening in none. Seven of 14 patients enrolled for 1 year continued infliximab therapy and maintained their successful grading. Five did not complete 1 year of treatment because of significant adverse events, and 2 terminated treatment early for reasons unrelated to the study. Serious adverse events that were potentially related to infliximab included pulmonary embolus, congestive heart failure, lupus-like reaction in 2, and vitreous hemorrhage in 2 patients. Antinuclear antibodies developed in 15 of 20 enrolled patients receiving 3 or more infusions.
Conclusions Infliximab was an effective short-term immunosuppressive agent in most of the patients, with 18 of 23 meeting criteria for clinical success at week 10. Infliximab was effective in the long term in all patients able to complete 50 weeks of therapy. Although some patients achieved clear benefit, the rate of serious toxic effects was unexpectedly high. Further long-term studies are warranted to determine the safety and efficacy of infliximab in treating intraocular inflammation.
INTRODUCTION
The term uveitis is used clinically to describe a heterogeneous group of diseases characterized by inflammation of intraocular structures. Although frequently associated with systemic inflammatory or autoimmune diseases such as sarcoidosis, multiple sclerosis, Behçet disease, and the seronegative spondyloarthropathies, a significant number of cases defy disease classification and are labeled idiopathic. In general, noninfectious cases of uveitis are thought to represent immune-mediated disease, possibly triggered by environmental stimuli and mediated primarily by T cells in patients with an immunogenetic predisposition.1-2 The implication that cell-mediated immunity is involved in the pathogenesis of uveitis has provided a rationale for treatment with immunosuppressive medications such as corticosteroids, which have been shown to be effective in improving the signs and symptoms of ocular inflammation and the prognosis for preservation of visual acuity.3 The well-known adverse effects of long-term corticosteroid therapy, however, have led ophthalmologists to use corticosteroid-sparing agents to reduce the toxic effects associated with long-term corticosteroid use. Unfortunately, each of these agents is also associated with undesirable toxicity.4 Efforts are under way to identify more effective therapy, which would ideally focus on targeting specific mediators of the immune response, allowing for increased efficacy and decreased adverse effects of treatment.
One horizon being explored in the search for targeted immunosuppressive agents is blockade of tumor necrosis factor (TNF-). Tumor necrosis factor is an inflammatory mediator that plays an important pathogenic role in inflammatory diseases such as rheumatoid arthritis,5 fistulizing Crohn disease,6 and ankylosing spondylitis.7 Pharmacological blockade of this mediator has demonstrated benefit in all 3 of these diseases. In addition, ample evidence from animal and human studies implicates TNF as a potentially important mediator in uveitis.8-11 These results and the positive outcomes reported in clinical trials for other inflammatory diseases led us to initiate a prospective study to evaluate the safety and effectiveness of infliximab for the treatment of patients with chronic, vision-threatening, noninfectious uveitis that has been refractory to standard immunosuppressive therapy.
METHODS
ENROLLMENT CRITERIA AND STUDY SCREENING
All patients in this series were recruited from the uveitis clinic of the Casey Eye Institute, Portland, Ore, between October 1, 2001, and March 31, 2004. Approval was given by the institutional review board of the Oregon Health and Science University, Portland. Before enrollment, all patients provided a detailed medical history and underwent a complete ophthalmic examination and appropriate systemic evaluations to determine the etiology of their uveitis. To be considered for enrollment in this study, patients were required to have vision-threatening uveitis that was refractory to therapy with corticosteroids and at least 1 other immunosuppressive medication or to be intolerant of such therapy. Table 1 gives a complete list of inclusion and exclusion criteria.
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Table 1. Inclusion and Exclusion Criteria for Participation in Study
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All patients were required to undergo a protein purified derivative skin test and chest radiograph within 3 months of enrollment. Patients with latent tuberculosis (defined as a protein purified derivative skin conversion without radiographic or clinical evidence of pulmonary or disseminated disease) were enrolled only if they agreed to undergo concomitant chemoprophylaxis with antituberculosis therapy because of the known risk of tuberculosis reactivation associated with TNF inhibition.9-10 In addition, all patients underwent fluorescein angiography (FA), visual field testing, and electroretinography (ERG) at study enrollment. These 3 tests were repeated at weeks 10 and 50 for patients who reached these time points in the study. Finally, all patients with intermediate uveitis of the pars planitis subtype were required to undergo magnetic resonance imaging of the brain to rule out demyelinating disease, given the known association between pars planitis and multiple sclerosis11 and previous studies indicating that TNF blockade may worsen the course of demyelinating disease.12
TREATMENT PROTOCOL
Once enrolled, patients received 3 infliximab infusions at a dose of 3 mg/kg if they were using immunosuppressive drugs concurrently (n = 20), or at a dose of 5 mg/kg if they were not tolerating other immunosuppressives and infliximab treatment was consequently initiated as monotherapy (n = 3). Infusions were administered at weeks 0, 2, and 6 in a schedule similar to treatment protocols in published studies of infliximab therapy for rheumatoid arthritis and other inflammatory diseases.5 Patients who demonstrated a positive clinical response to infliximab at week 10 received an infusion at week 14 (8 weeks after the completion of the "loading" schedule) and every 8 weeks thereafter through the 12-month study period.
OPHTHALMIC EVALUATION
Ophthalmic evaluation included best-corrected visual acuity with spectacle correction and pinhole on Snellen eye charts, measurement of intraocular pressure, biomicroscopic evaluation, and dilated indirect ophthalmoscopy. Anterior chamber cell and flare and vitreous cell and haze were graded by means of the Nussenblatt standardized grading criteria.2 Specific notation of the presence or absence of cystoid macular edema (CME), active retinal vasculitis, and active chorioretinitis was also made. In addition, patients were requested to mark a point along a continuous 10-mm line to indicate the subjective quality of their vision that day, from worst to best (Likert or visual analog scale). Ophthalmic evaluation was mandatory within 1 week of infusion to assess the drug’s therapeutic benefit and to allow dose adjustments as needed. The protocol allowed for dose escalation up to a maximum of 10-mg/kg infusions given every 8 weeks.
SYSTEMIC EVALUATION AND LABORATORY MONITORING
Patients had a general physical examination and laboratory evaluation before each infusion. Preinfusion blood tests included a comprehensive metabolic panel, including liver function tests, and complete blood cell counts. Antinuclear antibodies (ANA) were obtained at each infusion except at week 2. If ANA titers were 1:160 or greater, a subsequent assay for anti–double-stranded DNA (anti-dsDNA) antibodies was performed. A complete ophthalmic evaluation and medical review was performed at study enrollment, at week 4 after infusion for safety, and then at week 10 after infusion, when the first outcome assessment was performed as described in the following section. After week 10, all patients had ophthalmic evaluations every 4 weeks for the remainder of the first year.
OUTCOME VARIABLES AND DEFINITIONS OF COMPOSITE CLINICAL END POINT
The primary outcome variable was a composite end point with the following 4 parts: visual acuity, control of inflammation, tapering of medication therapy, and reduction of CME. Cystoid macular edema was measured by means of FA and optical coherence tomography (OCT). Secondary outcome variables included the effects on intraocular pressure, visual fields, ERG, and subjective assessment of visual benefit using the visual analog scale.
Intraocular inflammation was considered active or uncontrolled if the inflammatory activity was grade 1+ or greater (measured as anterior chamber cells and/or vitreous haze by means of the Nussenblatt standardized grading systems2) at any examination. Tapering of immunosuppressive therapy was attempted in patients with controlled intraocular inflammation. In general, prednisone therapy was tapered first unless it was medically necessary to first taper a concomitant immunosuppressive therapy owing to drug-related toxic effects. At each examination, the dose of prescribed immunosuppressive medications was recorded and patients were questioned about the development of any adverse effects.
The 4 components of our composite clinical end point each were graded dichotomously (yes or no for success). For visual acuity to be considered a success (ie, improved visual acuity), a patient had to have an improvement of at least 2 Snellen chart lines in at least 1 eye. Conversely, to have worsening visual acuity, patients had to drop 2 lines from baseline in at least 1 eye. Two lines of change was chosen as the standard for worsening or improvement because we believed that this was the minimum number of lines necessary to reflect a clinically significant change in visual acuity that was unlikely to be due to chance. Our standard is consistent with those in other recently published uveitis trials using biologic agents.13-14 A change in visual acuity of fewer than 2 lines was regarded as clinically inconsequential. Infliximab was defined as successful in controlling inflammation when patients with active disease at the outset of treatment ( 1+ inflammatory activity) achieved clinical quiescence (defined as reduction of anterior chamber cells or vitreous haze by 2 steps in 1 eye, using Nussenblatt criteria) on therapy. Infliximab was defined as an effective concomitant immunosuppressive-sparing agent if the dosage of prednisone or other immunosuppressive treatment could be reduced by 50% or greater with maintained control of the inflammation. Improvement in FA required improvement in CME and other signs of inflammation as graded in a masked fashion by one of the investigators (A.K.L.) using a standardized grading form (Figure 1). Improvement in CME as measured by OCT was also included as a component of the evaluation for the 18 patients in whom this technique was able to produce usable images.
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Figure 1. Standardized fluorescein angiography grading form used for this study. For all criteria, 0 indicates none; 1, mild; 2, moderate; and 3, severe. For media opacity, 0 indicates clear view of retinal capillaries; 1, dull view of vessels, but capillaries are appreciated; 2, unable to see retinal capillaries; and 3, unable to see secondary retinal vessels. For cystoid macular edema (CME; late angiographic phases), 0 indicates no perifoveal hyperfluorescence; 1, incomplete ring of leakage; 2, circumferential leakage; and 3, circumferential and broad leakage greater than the disc area. For disc hyperfluorescence (late angiographic phases), 0 indicates normal exit of fluorescein and normal staining of the scleral rim; 1, staining of the optic disc; 2, leakage at the optic disc; and 3, leakage with blurring of papillary vasculature. For retinal vascular hyperfluorescence (late angiographic phases), 0 indicates normal exit of fluorescein; 1, staining of vessels; 2, leakage; and 3, more leakage. For diffuse leakage, 0 indicates none; 1, small or isolated foci of leakage; 2, moderate; and 3, numerous or large areas of leakage. For choroidal filling defect, 0 indicates none; 1, small areas; 2, moderate; and 3, larger areas.
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RESULTS
The demographic information for enrolled patients is summarized in Table 2. Fifteen (65%) of the 23 patients enrolled were female. The age range was 10 to 75 years (mean age, 40 years; median age, 43 years). The intraocular inflammatory disease in each case was classified anatomically using the International Uveitis Study Group criteria.15 Panuveitis was the most common anatomic diagnosis (13/23 [57%]), followed by intermediate uveitis or pars planitis (8/23 [35%]) and posterior uveitis (2/23 [9%]). The most commonly diagnosed causes of secondary uveitis were Behçet disease (4/23 [17%]), sarcoidosis (3/23 [13%]), bird-shot chorioretinopathy (3/23 [13%]), pars planitis unrelated to multiple sclerosis (2/23 [9%]), multifocal choroiditis (1/23 [4%]), and Crohn disease (1/23 [4%]). Nine patients (39%) were classified as having idiopathic forms of uveitis. All patients had been treated unsuccessfully with at least 2 immunosuppressive agents (range, 2-6; mean, 2.7) for their uveitis.
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Table 2. Demographics of Enrolled Patients
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Eighteen (78%) of 23 patients met a priori criteria for clinical success 10 weeks after the initiation of therapy. With regard to the 4 subcriteria of our composite index, 8 (44%) of 18 patients had improved visual acuity, 9 (50%) had control of active inflammation, 10 (56%) were able to reduce the dose of 1 or more concomitant medications by 50%, and 11 (61%) had improvement in their FA/OCT grading. The subcriteria met by each patient are summarized in Table 3. Briefly, of the 18 patients graded as successfully treated, 5 patients met 3 of 4 subcriteria; 10 met 2 criteria; and 3 met a single criterion, the minimum required for continued participation (Table 3).
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Table 3. Variables Defining Clinical Success in Enrolled Patients at Week 10 Outcome Measurement
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Ten (43%) of the 23 patients had active intraocular inflammation at the outset of therapy, defined as the presence of 1+ or greater anterior chamber cell and/or vitreous haze using standardized grading criteria. Within this group, 9 patients (90%) achieved control of inflammation with infliximab after 10 weeks in the study. The single patient in this group (patient 19) for whom infliximab did not control inflammation did not demonstrate improvement in vitreous haze and FA grading. This was partially due to dense posterior subcapsular cataracts and fixed vitreous opacities. This patient indicated subjective benefit; however, owing to the lack of objective improvement in visual acuity, vitreous haze, tapering of medicine dose, or FA findings, treatment was not graded as a success. One patient (patient 12) with quiet intraocular inflammation at study enrollment had a severe bilateral flare at week 8, without a demonstrable increase in vitreous haze but with a marked increase in CME and concomitant decrease in visual acuity. This patient discontinued study participation, and recovery of baseline visual acuity was achieved with high-dose oral and periocular corticosteroids. The remaining patients had controlled inflammation at study outset and were enrolled for other indications, including the potential to taper concomitant medication therapy and thereby limit steroid or other medication-associated toxic effects.
Ten patients were able to taper therapy with at least 1 systemic medication by at least 50% during the first 10 weeks of study enrollment. Six patients were able to taper their daily corticosteroid dose. In this group, the average starting daily dose was 30 mg (dose range, 3.75-80 mg), and was reduced to 7 mg daily (dose range, 1.25-20 mg) during the 10 weeks. Two of these patients were able to taper therapy with an additional medicine, with 1 patient tapering azathioprine sodium therapy by 25% and the other discontinuing cyclosporine therapy. Three patients who were not receiving prednisone at the study outset tapered their cyclosporine use (2 discontinued and 1 reduced the dose by 80%), and 1 patient reduced mycophenolate mofetil use from 2 to 1 g/d. At 10 weeks, 1 patient’s treatment was not graded as a success because of a misunderstanding of the initial tapering instructions whereby prednisone therapy was tapered from 20 to 15 mg (25%). Although study treatment was characterized as a failure, this patient continued to receive study infusions per protocol with the goal of tapering prednisone use to less than 10 mg/d. By week 50, the prednisone dosage was tapered to 8 mg/d (60% reduction).
Eight patients (10 affected eyes in total) met the criteria for improved visual acuity. In this subgroup, improvement ranged from 2 to 8 Snellen chart lines. The visual acuity in 1 patient (patient 12) worsened significantly (20/25 OD and 20/50 OS to 20/100 OU), leading to study termination. Visual acuity remained stable in the affected eyes of others in this group. Among this group, there was no clear trend toward improvement or decline of visual acuity observed in a graphic display (Table 4 and Figure 2).
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Table 4. Visual Acuity at Weeks 0 and 10
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Figure 2. Visual acuity before and after infliximab therapy at 10 weeks. Logarithm of the minimum angle of resolution (logMAR) equivalents was calculated from visual acuity recorded on standard clinic Snellen charts as follows: 20/15 indicates –0.1; 20/20, 0.0; 20/30, 0.2; 20/40, 0.3; 20/50, 0.4; 20/60, 0.5; 20/70, 0.55; 20/80, 0.6; 20/100, 0.7; 20/150, 0.85; 20/200, 1.0; and 20/400, 2.0. All visual acuity measurements worse than 20/400 (ie, counting fingers, hand motions, light perception, and no light perception) were arbitrarily classified as 2.5. Each eye of treated patients is plotted singly; however, points on the scatterplot may represent multiple eyes of patients or patients with identical pretreatment and posttreatment acuities.
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Of the 2 patients who discontinued infliximab therapy during the first 10 weeks, 1 patient (patient 12) with bird-shot chorioretinopathy had increased CME and decreased visual acuity in both eyes at week 8, and 1 patient with idiopathic intermediate uveitis (patient 16) experienced a pulmonary embolus at week 6. Two other patients withdrew from the study shortly after week 10, despite meeting criteria for clinical success. These included patient 9, who wished to join a different clinical trial for the treatment of fibromyalgia, and patient 10, who had positive test findings for illegal drugs and did not adhere to other protocol requirements. The reasons for patient discontinuation from the study by week 10 are summarized in Table 5.
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Table 5. Failures at Week 10 Outcome Measurement
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As of this writing, 14 patients have been enrolled in the study for at least 1 year. Of these patients, 7 have continued to receive infliximab and maintained their successful grading in each of the criteria met at their week 10 grading. Five patients stopped infliximab therapy owing to significant adverse effects, and 2 dropped out for reasons unrelated to the study. Table 6 summarizes the reasons for study termination after 10 weeks. No patients had deterioration of ERG findings, visual fields, or intraocular pressure control requiring discontinuation of infliximab therapy. Ocular adverse effects of infliximab therapy were limited to 2 patients with preexisting posterior pole ocular neovascularization in whom vitreous hemorrhages developed. One patient had recurring vitreous hemorrhages that transiently reduced visual acuity in the affected eye but did not affect final visual acuity. In the other patient, the hemorrhage did not clear and required vitrectomy and concomitant cataract extraction. These adverse events, and others characterized as severe that did not prompt study termination, are listed in Table 7.
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Table 6. Failures After Week 10 Outcome Measurement
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Table 7. Significant Adverse Effects Not Requiring Study Discontinuation
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Four patients, all with different diagnoses, were reported to demonstrate clinically significant improvement on ERG findings at 10 weeks. Only 1 of these patients had continued ERG improvement at 50 weeks. Two patients showed a clinically insignificant mild reduction in ERG function. There were no other significant ERG changes during the study. Similarly, regular Humphrey visual field testing was performed in all patients, and no patient had a clinically significant decrement in Humphrey visual field results.
Regular laboratory monitoring performed on subjects revealed that detectable ANA titers developed in 15 of the 20 patients who completed 3 infusions during 10 weeks in the study. Only 1 of these patients had detectable ANA titers on study enrollment (1:80). This patient experienced an 8-fold increase in the titer (1:640) while receiving infliximab therapy. Of the 15 patients with detectable ANA titers, 7 reached a titer of 1:160, which mandated anti-dsDNA antibody testing. Five of these 7 patients had detectable anti-dsDNA antibodies. Rheumatic symptoms developed in 2 of these patients related temporally to the development of the positive ANA finding. A symmetric polyarthritis that resolved after therapy with prednisone and the discontinuation of infliximab therapy developed in 1 patient with an ANA titer of 1:2560. In the other patient, an ANA titer of 1:640 and a migratory arthritis developed. Both patients were also noted to have elevated antistreptolysin O titers at the time of the onset of symptoms. There was no clear relation between the development of ANAs and ocular therapeutic response and no other adverse effects except those already noted. Table 8 compares the peak ANA titers of patients enrolled compared with the ANA titers measured at baseline before receiving infliximab.
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Table 8. ANA Titers at Baseline and Highest Levels in Study
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Patients were asked to assess their visual symptoms using a visual analog scale (Figure 3A) on each visit. Comparison of this subjective visual analog data at weeks 0, 10, and 50 is summarized in Figure 3B.
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Figure 3. Patient self-assessment of their quality of vision. A, Visual analog scale used at each visit to measure patient perception of visual function. B, Scatterplot demonstrating the patient’s perception of visual function using the visual analog scale (graded on a continuous scale of 0-10 on the scale illustrated in part A) at weeks 0, 10, and 50 in the study.
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COMMENT
Infliximab is a monoclonal IgG1 antibody against TNF-, which binds circulating and cell-surface cytokine. It is currently approved by the US Food and Drug Administration for the treatment of rheumatoid arthritis,5 fistulizing Crohn disease, and ankylosing spondylitis and is being investigated for treatment of numerous other inflammatory diseases implicated in uveitis, including Behçet disease and sarcoidosis.
The innate heterogeneity of uveitis makes it a challenge to study therapeutically. Our study incorporated several unique aspects. First, we used a composite definition of success. This definition of success parallels the goal that might be sought by a treating physician in clinical practice. Many uveitis clinical trials limit enrollment to patients with active disease with the goal of controlling inflammation16 or to patients with controlled disease with the goal to reduce other immunosuppressive therapies.17 In this study, our outcome instrument allowed us to accommodate either clinical problem as it would arise in a practice setting. Neurological toxic effects of TNF inhibitors have been a major clinical concern,12 and our study is the first to prospectively use ERG and visual field testing to reassure physicians that neurological injury, manifested by retinal or optic nerve dysfunction, is not intrinsic to infliximab therapy.
Our 10-week success rate of 78% exceeds the response rate reported for many commonly used interventions for uveitis, including oral cyclosporine or corticosteroids18 or periocular corticosteroid injections.19 In many instances we observed success in patients who had been treated unsuccessfully with several different immunosuppressive therapies. On the other hand, only 50% of patients in our study were able to maintain infliximab therapy for at least 1 year. This outcome was secondary to a high frequency of adverse events. Among the 23 patients who underwent evaluation, 7 experienced serious adverse events, including 3 serious thromboses, 2 vitreous hemorrhages, 1 malignancy, 1 new onset of congestive heart failure, and 2 possible instances of drug-induced lupus.
Since the inception of our trial, a number of smaller prospective studies have been published investigating the effect of TNF blockers in uveitis. Etanercept, a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75-kDa (p75) TNF receptor linked to the Fc portion of human IgG1, has been used with mixed levels of success in the treatment of uveitis. Reiff et al16 published a prospective series of juvenile idiopathic arthritis and uveitis in 10 patients, in whom etanercept was deemed effective in 10 of 16 affected eyes within 12 weeks, with rebound inflammation occurring in some patients discontinuing the therapy. In 2 small, double-masked, placebo-controlled uveitis studies by Foster et al17 and Smith et al,14 etanercept did not demonstrate a significant effect in allowing tapering of methotrexate therapy in patients with juvenile idiopathic arthritis whose inflammation was well controlled and active, respectively; however, both trials were underpowered to detect a small to moderate effect of treatment. Using a fusion protein consisting of the p55 receptor for TNF, Murphy and colleagues20 found that 12 of 17 treated patients reported complete resolution of inflammation, and 11 of 17 were able to taper therapy consisting of other immunosuppressive agents. Five patients reported adverse effects, including mild infusion reactions or transient leukopenia.
In a small prospective study of infliximab for uveitis, Joseph and colleagues21 found infliximab to be effective in 4 of 5 patients with refractory uveitis. The fifth patient was found to have occult tuberculosis, reinforcing the necessity of screening for this disease in patients in whom TNF blockade is considered.21 A second, retrospective case series from Murphy and colleagues22 described the treatment of 3 patients with uveitis and 4 with scleritis, with 6 of the 7 exhibiting improvement after an average of 7 infliximab infusions. One patient experienced an infusion reaction that required discontinuation of therapy. No other adverse effects were observed.
Sfikakis and colleagues23 reported the results of a prospective study in which 25 patients with Behçet uveitis were treated with a single infliximab infusion at the time of a clinical flare. All patients were described as having a complete response, with resolution of retinitis and vitritis observed within 28 days. Moreover, 15 patients from the same cohort with recent disease recurrence continued a 32-week protocol during which they received infliximab infusions at weeks 4, 8, 16, and 24. The ocular disease remained quiescent in 9 of these patients throughout the study period, and the overall frequency of flares, compared with the 6 months before infliximab therapy, was reduced from 2.5 to 0.5 flares in 6 months. Significant disease flares were controlled with more frequent doses of infliximab in 3 patients. El-Shabrawi and Hermann24 have reported that anti-TNF therapy may be useful for the treatment of refractory anterior uveitis related to HLA-B27, although because of the efficacy of topical corticosteroid therapy, we would reserve its use for those with posterior involvement in most cases. Case reports and small case series have also reported clinical success in treating uveitis associated with Crohn disease25 and juvenile idiopathic uveitis.26 In addition, the scientific literature is replete with case reports and series extolling the benefits of infliximab for uveitis and nonocular manifestations of Behçet disease.27-29
Compared with other studies published on infliximab therapy for uveitis, we experienced a higher rate of significant adverse events. In many of these cases, causality is unclear. For example, the patient with a myocardial infarction (patient 8) was found to have a 95% stenosis of the left anterior descending coronary artery on catheterization, which almost certainly predated her 46-week involvement in our study. Similarly, patient 3, who had a pulmonary embolus approximately 4 weeks after terminating our study after 42 weeks, was morbidly obese and had a history of deep venous thrombosis preceding her use of infliximab by 6 years. The second patient with a pulmonary embolus (patient 16) was a smoker but had no other known risk factors. The patient with endometrial cancer (patient 15) had an abnormal Papanicolaou test result before entering the study, although this information was not available to us at her enrollment. The role of TNF blockers and indeed all immunosuppressives in the abrogation of native antitumor surveillance and possible increased risk of neoplasia is one that requires definitive study. Some adverse effects clearly are likely to have been related. For example, congestive heart failure, diagnosed by widening of the cardiomediastinal silhouette on chest roentgenography, elevated serum levels of brain natriuretic peptide, and symptomatic improvement with furosemide developed in patient 4 after almost 2 years of infliximab therapy. The risk of congestive heart failure exacerbation with infliximab is well described,30 although this patient had negative workup results for congestive heart failure 6 months before her diagnosis, including serum brain natriuretic peptide levels within the reference range and a normal echocardiogram finding. Drug-related lupus, as diagnosed in patient 6, is clearly related to TNF blockade31 and will be discussed in this section.
The 2 patients with vitreous hemorrhages due to premorbid ocular neovascularization present an interesting observation. It is well known that uveitic neovascularization will regress in many cases after institution of adequate immunosuppression.2, 32 In 1 of our 2 cases, our view to the retina was sufficiently clear to witness rapid regression of premorbid disc neovascularization in both eyes (Figure 4); such an evaluation in the second patient was limited by mature cataract and posterior synechiae. As is often the case in treatment of neovascular posterior pole disease, as the vessels regressed these patients sustained vitreous hemorrhages. Although this is considered a significant adverse event for the purposes of our study, this event was also proof of principle that the patient was immunosuppressed sufficiently to induce regression of neovascular disease. In 1 patient with bilateral active disease (patient 7), regression of neovascularization was associated with improved visual acuity, dramatic reduction of inflammatory flares, and elimination of Behçet disease–associated outbreaks of oral and genital ulceration.
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Figure 4. Sequential fundus photographs in patient 7. A and B, Neovascularization of the optic discs (arrows) bilaterally and vitreous haze before starting infliximab therapy. C and D, Resolution of vitreous haze 10 weeks after infliximab therapy. Arrows denote persistent neovascularization. E and F, Two years after treatment. Notable regression of neovascularization has occurred.
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As noted previously, we cannot definitively link the thrombotic events to infliximab therapy, and an increased risk of thrombotic adverse effects has not been detected in premarketing or postmarketing surveillance of infliximab (Greg Keenan, MD, oral communication, January 2004). One recently published animal study noted decreased thrombosis with the introduction of TNF,33 suggesting that blockade of native TNF might lead to increased thrombosis; however, this has not been demonstrated in any other animal or human study to our knowledge. A recent human study of patients with rheumatoid arthritis found that, after 6 months of treatment, anticardiolipin antibodies developed in 28% of infliximab- and 25% of etanercept-treated patients.34 In this study, thrombotic effects developed in 2 patients receiving TNF-blocking therapy; however, 2 patients with negative findings for anticardiolipin antibodies also had thrombotic adverse effects. The authors of this study concluded that development of anticardiolipin antibodies portended a worse prognosis for outcome and treatment-limiting infusion reactions. None of our patients with embolic adverse effects had anticardiolipin antibodies, and we did not routinely examine our other patients for these.
We routinely screened for ANA and found a relatively high prevalence among our study patients. Although this occurrence has not been reported in previous ophthalmic series, the rheumatic literature has extensively documented this finding in patients with rheumatoid arthritis and spondyloarthropathy, relating to duration and total dose of therapy.31, 35-36 In these studies, the development of ANAs was not linked to decreasing efficacy of treatment, the presence of neutralizing antibodies to infliximab, or other adverse effects. We measured concentrations of anti-dsDNA antibodies for screening in patients at greater risk for drug-related lupus, with positive results in several of our patients. Rheumatic symptoms in conjunction with elevated ANA and anti-dsDNA antibody levels developed in 2 patients. One individual (patient 6) had an ANA titer of 1:2560 and development of a symmetric polyarthritis consistent with drug-related lupus, which abated with the cessation of therapy and treatment with a slowly tapered dose of oral corticosteroids. In the second individual (patient 3), a migratory polyarthritis atypical for lupus developed, with an ANA titer of 1:640, which also resolved after the cessation of therapy. Interestingly, both patients were found to have positive titers for antistreptolysin O at the time of their illness, suggesting a possible infectious etiology or cofactor in the development of these adverse events. Two studies of infliximab for treatment of spondyloarthritis37 and psoriatic arthritis38 have described similar rates of toxic effects, with the former suggesting that streptococcal infection was the precipitating event in infectious complications, perhaps due to an impairment of specific host defense mechanisms. The 5 other patients with elevated ANA and anti-dsDNA antibody levels, however, were asymptomatic and continued in the study. As many of the other reported studies of infliximab for uveitis used a single or relatively few infusions, it is perhaps not surprising that they did not report this finding. It seems, based on our experience and from reports in the published rheumatic literature,37-38 that the development of ANAs is frequent in patients treated with repeated infusions of infliximab. The clinical significance of this finding in patients with uveitis requires further study.
To our knowledge, this is the largest published prospective study of patients with uveitis treated with multiple infliximab infusions. In addition, we studied a diverse group of ocular and systemic diseases and include the first published cases of the treatment of sarcoid uveitis and bird-shot chorioretinopathy in our report. In agreement with other researchers, we observed a high short-term rate of response to infliximab, with 18 of 23 patients responding to therapy at 10 weeks. We have followed up 7 patients who have continued to receive the therapy for 1 year or longer, and all of these patients have maintained a positive effect after 1 year or longer. Our increased incidence of adverse effects may be related to the nature of our tertiary referral population, which is by nature composed of patients with difficult or refractory disease. Patients were further selected by our stringent inclusion criteria, requiring failure of prednisone and at least 1 other agent, as well as by our protocol mandating longer-term infusions. It is also possible that uveitis has a unique toxicity profile owing to relatively low amounts of circulating substrate for TNF blockers compared with the rheumatic diseases. Nonetheless, infliximab shows significant promise as an immunosuppressive agent in the treatment of refractory uveitis, especially in diseases such as Behçet disease, where it is rapidly evolving toward the standard of care.39 We look forward to future randomized studies to clarify the role of infliximab, and TNF blockade in general, in the treatment of uveitis and other ocular inflammatory diseases.
AUTHOR INFORMATION
Correspondence: Eric B. Suhler, MD, Casey Eye Institute, 3375 SW Terwilliger Blvd, Portland, OR 97239-4197 (suhlere{at}ohsu.edu).
Submitted for Publication: November 4, 2004; final revision received March 7, 2005; accepted March 27, 2005.
Author Contributions: Drs Suhler and Smith contributed equally to and share first authorship on this manuscript.
Funding/Support: This study was supported by Centocor, Inc, Malvern, Pa; an unrestricted grant (Casey Eye Institute), a senior scholar award (Dr Rosenbaum), and a career development award (Dr Smith) from Research to Prevent Blindness, New York, NY; the Rosenfeld Family Trust, Portland, Ore; and Public Health Service grant 5 M01 RR000334 from the National Institutes of Health, Bethesda, Md (Oregon Health and Science University General Clinical Research Center).
Previous Presentation: This study was previously presented in part at the 76th Annual Meeting of the Association for Research in Vision and Ophthalmology; May 6, 2003; Fort Lauderdale, Fla; the 77th Annual Meeting of the Association for Research in Vision and Ophthalmology; April 28, 2004; Fort Lauderdale; and the 67th Annual Meeting of the American College of Rheumatology; October 26, 2003; Orlando, Fla.
Financial Disclosure: Dr Rosenbaum has served as a paid consultant to Centocor, Inc, Abbott Laboratories, and Amgen.
Author Affiliations: Uveitis (Drs Suhler, Smith, Wertheim, Kurz, and Rosenbaum and Ms Pickard) and Retina (Dr Lauer) Divisions, Casey Eye Institute, and Departments of Medicine and Cell Biology (Dr Rosenbaum), Oregon Health and Science University, and Department of Ophthalmology, Portland Veterans Affairs Medical Center (Dr Suhler), Portland, Ore. Dr Wertheim is now in academic practice training in Bristol, England; Dr Kurz is in private practice in Columbus, Ohio.
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