- Email: [email protected]
Infliximab for the Treatment of Refractory Noninfectious Uveitis
Infliximab for the Treatment of Refractory Noninfectious Uveitis A Study of 88 Patients with Long-term Follow-up Jonathan N. Kruh, MD,1,2 Paul Yang, MD, PhD,1,2 Ana M. Suelves, MD,1,2 C. Stephen Foster, MD, FACS1,2,3 Objective: To establish the safety and efficacy of infliximab for the treatment of refractory noninfectious uveitis. Design: Retrospective, interventional, noncomparative cohort study. Participants: Eighty-eight patients from a single-center private practice. Methods: Patients with chronic, recalcitrant uveitis treated with infliximab (Remicade; Janssen Biotech, Inc., Titusville, NJ) were identified through an electronic medical record database. All charts were reviewed for sex, diagnosis, location of inflammation, presence of vasculitis, prior immunomodulatory treatments, duration of infliximab treatment, dose received, secondary side effects, and other medications continued while receiving treatment with infliximab. Main Outcome Measures: The primary outcome measures were the rate of remission, time to remission, relapse rate, failure rate, and patient tolerance. Additional analysis aimed to identity risk factors that would predict a higher success rate of infliximab to treat various types of noninfectious uveitis. Results: Of the 72 patients (81.8%) who achieved clinical remission while being treated with infliximab, 42 (58.3%) required additional immunomodulatory medications. At 7, 18.1, and 44.7 weeks, 25%, 50%, and 75% of patients, respectively, achieved clinical remission off all corticosteroids. Thirty-two patients (36.4%) experienced at least 1 side effect while on infliximab therapy, and 17 patients (19.3%) discontinued treatment secondary to 1 or more intolerable side effects. The most common adverse effects were skin rash (9.1%) and fatigue (8%). Factors associated with a higher chance to achieve clinical remission were nonidiopathic uveitis (P < 0.001), intermediate or panuveitis (P < 0.001), absence of vasculitis (P < 0.001), and a starting dose 5 mg/kg (P < 0.011). Conclusions: Infliximab induces a high rate of complete clinical remission in recalcitrant uveitis and is well tolerated by most patients. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2013;-:1e7 ª 2013 by the American Academy of Ophthalmology.
Noninfectious uveitis is a significant cause of blindness in developed countries. In the United States alone, it is estimated that 30 000 people are declared legally blind from uveitis annually.1 Recent studies indicate that the incidence may be even higher.2 Despite increasing awareness, the uveitic population continues to have a poor prognosis secondary to the complexity behind the pathophysiology, treatment, and management. Tumor necrosis factor (TNF)-a is a proinflammatory cytokine that is produced by multiple inflammatory cells, such as macrophages, T cells, and natural killer cells. It functions as a costimulator for T cells, B cells, cytotoxic T cells, and neutrophils.3 The effect of TNF-a on the immune system is broad and includes an increase in the levels of certain proinflammatory cytokines (e.g., interleukin [IL]-1 and IL-6), chemokine release, upregulation of IL-2 receptors, endothelial cell activation, leukocyte accumulation through the induction and maintenance of human leukocyte antigen (HLA) class II expression, angiogenesis, and 2013 by the American Academy of Ophthalmology Published by Elsevier Inc.
production of prostaglandin, and it promotes the survival and function of regulatory T cells.3e12 The induction of regulatory T cells may be especially useful in maintaining uveitic patients in remission; it has been shown that the ratio of regulatory T cells in the immune system may play a crucial role in the balance and management of an appropriate inflammatory response.12 Animal models have demonstrated that during the induction of experimental autoimmune uveitis, both aqueous and serum TNF-a levels increase.13 Elevated TNF-a levels also have been demonstrated in uveitic patients.14 The inhibition of TNF-a as therapy for ocular inflammatory disease was first shown to be effective in animal models of uveitis,15e17 possibly because of a reduction in leukocyte rolling, adhesion, and vascular leakage induced with endotoxin-induced uveitis in the rat model.18 With the development of biologic response modifiers and their successful use in rheumatologic conditions, agents such as antieTNF-a became an emerging option for uveitic ISSN 0161-6420/13/$ - see front matter http://dx.doi.org/10.1016/j.ophtha.2013.07.019
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Ophthalmology Volume -, Number -, Month 2013 patients who failed or did not tolerate conventional immunomodulatory therapy (IMT). Such therapy is used off label, and many reports now exist in peer-reviewed literature documenting uncontrolled case series’ experience with this treatment strategy for vision-threatening ocular inflammatory disease. Infliximab (Remicade; Janssen Biotech, Inc., Titusville, NJ) is a chimeric monoclonal antibody directed against TNF-a of predominantly human origin but that includes 2 murine antigen-binding sites.19 The efficacy of infliximab has been widely studied for the treatment of various types of chronic inflammatory diseases.20e24 Additional studies have shown the possible benefits of infliximab for the treatment of refractory cases of sarcoidosis,25,26 juvenile idiopathic arthritis (JIA),27,28 and Behçet’s disease.29e31 The use of infliximab to treat refractory cases of uveitis in humans has been examined in a small but growing number of case reports and small studies.32e41 The purpose of this report is to present our experience with the use of infliximab as treatment for recalcitrant noninfectious uveitis.
Methods Study Population and Data Collection A review of medical records from the Massachusetts Eye Research and Surgery Institution from October 2005 to May 2012 identified 88 patients with a history of chronic noninfectious uveitis who were treated with infliximab. Inclusion criteria consisted of having had noninfectious uveitis resistant to other therapy, both corticosteroids and conventional immunomodulatory agents, started on intravenous infliximab at the Massachusetts Eye Research and Surgery Institution. All patients had active inflammation at the time of their first infusion. Patients who had received a fluocinolone acetonide intravitreal implant (Retisert; Bausch & Lomb, Inc., Rochester, NY), who were infused offsite, or who had incomplete data or a follow-up period <5 months were excluded from the study. Baseline data collected included sex, diagnosis, location of uveitis, presence of vasculitis, prior local or systemic corticosteroid treatment, and prior systemic immunomodulatory treatment. Categorization of uveitis location was based on that defined by the Standardization of Uveitis Nomenclature Working Group,42 except that optic nerve head or retinal vessel inflammation was included as sufficient to satisfy the posterior components of panuveitis. Local corticosteroid use included topical, subtenon, transseptal, intracameral, and intravitreal routes of administration. At each visit, all patients underwent a detailed ophthalmic evaluation and systemic review. This included visual acuity, intraocular pressure, and slit-lamp biomicroscopy. During each follow-up visit, ocular inflammation was assessed by the primary investigator (C.S.F.) and graded according to the Standardization of Uveitis Nomenclature criteria.41 Remission was a clinical decision made by the principal investigator (C.S.F.) that was based on corticosteroid-free resolution of aqueous or vitreous cell (<0.5þ), vitreous haze, and fluorescein leakage on angiography (e.g., optic disc, macula, retinal vessels, chorioretinal lesions). All patients exhibiting a posterior component to their uveitis were required to demonstrate an absence of optic disc staining, active macular edema, and vasculitis on fluorescein angiography. Clinical remission was defined as no disease activity while taking infliximab, and durable remission was defined as no disease activity after successful treatment and discontinuation of infliximab. Relapse was defined as increased
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anterior/posterior segment cell (<0.5þ) or evidence of inflammation on fluorescein angiogram as previously outlined. Therapeutic failure was defined as insufficient control of inflammation within 6 months of starting treatment with infliximab or 3 relapses while on infliximab. Infliximab was discontinued immediately in patients who failed therapy or had significant side effects. Patients were allowed a bridging period of 180 days from the beginning of their treatment with infliximab to be weaned off concomitant immunomodulatory medications. If patients continued on any additional immunomodulatory medication past 180 days, they were included in the category of patients who required infliximab þ additional therapy. At every infusion visit, the patient was assessed for treatment response and side effects. The starting dose and the maximum dose during each treatment period were recorded. All patients included in this study adhered to the tenants of the Declaration of Helsinki. Informed consent was obtained from all study subjects, and institutional review board approval was in place before commencement of the study.
Infliximab Protocol The protocol used in this study included a loading dose of infliximab administered at 0, 2, and 6 weeks, and then every 4 weeks until clinical remission was achieved. All patients were started on an initial dose of 4 to 6 mg/kg. Before starting treatment and during each follow-up visit, routine blood monitoring was performed to check for blood dyscrasia and liver toxicity. This included a complete blood count including differential and aspartate aminotransferase and alanine aminotransferase. Additional testing included tuberculosis screening with intradermal purified protein derivative and assessment for the development of drug-induced lupus with clinical assessment and antinuclear antibody testing before starting infliximab and every 6 months while on infusion therapy. The infusion interval and dose were adjusted according to patient response and side effects. After achieving clinical remission, the infusion interval was slowly prolonged at 2-week increments. We typically maintained any given infusion frequency for a minimum of 4 infusions before attempting to stretch the interval further. If the patient remained in remission after 4 infusions at an interval of 10 to 12 weeks, the drug was discontinued. The decision of when to complete treatment was individualized and based on prior response and total length of treatment time.
Data Analysis Statistical analysis was performed using the Stata software program, version 12 (StataCorp LP, College Station, TX). Percentages of categoric variables were computed, and means and standard deviations of quantitative variables were used as summary measures. Cox proportional hazards regression (survival) analysis was used to identify factors that were associated with the occurrence of clinical remission. The following variables were included in the Cox regression analysis: sex; vasculitis; location of inflammation; duration of uveitis before treatment; presence or absence of a diagnosis (birdshot chorioretinopathy, idiopathic, JIA, HLAB27); prior corticosteroid use (topical, transseptal triamcinolone [Kenalog; Ranbaxy Laboratories Inc., Haryana, India], subtenon, intracameral, intravitreal), prior systemic medications (corticosteroid, methotrexate [MTX], cyclophosphamide, mycophenolate, azathioprine, cyclosporine A [CSA], adalimumab, nonsteroidal anti-inflammatory drugs [NSAIDs], daclizumab, etanercept, sirolimus, chlorambucil); continued medications while taking infliximab (MTX, mycophenolate, azathioprine, CSA, NSAIDs, local corticosteroid); presence or absence of a side effect; starting dose; and highest dose. Some variables were not included because of small cell frequency. A backward elimination process was used
Kruh et al
Infliximab for Refractory Uveitis
Table 1. Patient Characteristics, Diagnosis, and Location of Uveitis
Table 2. Prior and Continued Medications While on Infliximab Variable
Variable Sex Female Male Race Caucasian African American Hispanic Asian Diagnosis Idiopathic JIA Birdshot chorioretinopathy HLA-B27 Sarcoidosis Behçet’s disease Presence of vasculitis Present Absent Location of inflammation Anterior Panuveitis Posterior Intermediate
No. (n [ 88)
%
68 20
77.3 22.7
75 8 4 1
85.2 9.0 4.5 1.1
34 16 13 6 6 3
38.6 18.2 14.8 6.8 6.8 3.4
46 42
52.9 47.1
36 28 17 7
40.9 31.8 19.3 8.0
HLA ¼ human leukocyte antigen; JIA ¼ juvenile idiopathic arthritis.
where variables that were not significant were dropped or removed from the regression model one at a time, starting with the least significant variable. Dropping of variables stopped when the regression model contained variables that were all significantly related to the outcome. A P value of <0.05 was considered statistically significant.
Results Descriptive Analysis Eighty-eight patients were included in the study, of whom 68 (77.3%) were female and 20 (22.7%) were male. The largest number had anterior uveitis and a diagnosis of idiopathic cause. Table 1 shows a detailed description of the location of uveitis, presence of vasculitis, and most frequent diagnoses. The mean follow-up of those who achieved remission was 28.75 months (range, 5e86.5 months). Table 2 details the medications used before and during infliximab treatment. The most commonly prescribed medications before infliximab treatment were topical corticosteroids (78.4%) and MTX (65.95%). The average number of failed treatments per patient in our study was 3 (Table 2).
Efficacy and Safety Seventy-two of the 88 patients (81.8%) achieved complete clinical remission while being treated with intravenous infliximab. Thirtythree patients (37.5%) were able to discontinue all additional topical or oral corticosteroids and other IMT within 180 days of beginning infusion therapy. Of the 55 patients (62.5%) who required additional medications, the most commonly continued drugs were MTX (26.1%) and topical corticosteroids (20.5%). From a total of 15 013 person-days at risk among all patients, the incidence density of the remission rate was 47 per 10 000 person-days, with a median
No. (n [ 88)
%
69 26 13 2 1
78.4 29.5 14.8 2.3 1.1
58 47 40 38 24 12 8 6 4 4 3
65.9 53.4 45.5 43.2 27.3 13.6 9.1 6.8 4.5 4.5 3.4
55 12 23 18 10 8 5 4
62.5 13.6 26.1 20.5 11.4 9.1 5.7 4.5
Prior corticosteroid use Topical Transseptal Intravitreal Subtenon Intracameral Prior systemic medication Methotrexate Mycophenolate Corticosteroid Cyclosporine NSAIDs Azathioprine Chlorambucil Adalimumab Cyclophosphamide Etanercept Sirolimus Continued systemic medication Continued other medicines Mycophenolate Methotrexate Local corticosteroid Systemic corticosteroid Cyclosporine NSAIDs Azathioprine NSAID ¼ nonsteroidal anti-inflammatory drug.
time of disease remission of 127 days. At 7 and 44.7 weeks, 25% and 75% of patients, respectively, achieved clinical remission (Fig 1). After achieving clinical remission, the rate of continued remission without a relapse while on therapy was 84.7% and 75.6% at 6 months and 12 months, respectively (Table 3). Patients who relapsed typically did so when the interval between infusions was increased. A relapse then triggered a return to the previous shortened infusion interval. Some 45% of patients had a history of systemic corticosteroid use (intravenous methylprednisolone or oral prednisone). On induction of infliximab therapy, 6 patients were receiving intravenous infusions of methylprednisolone (1000 mg) and 16 patients were receiving oral prednisone (mean, 13 mg/day; range, 2e40 mg/day). At 6 months on treatment, no patient required intravenous methylprednisolone and only 6 of 16 patients required oral prednisone. The mean dose of prednisone for patients continuing to take oral prednisone at 6 months was 4.6 mg/day (range, 1e7 mg), a reduction of 64.2%. At 9 months, of the 6 patients who required oral prednisone at 6 months, 2 were discontinued from the study, deemed failures, and 3 patients continued on daily oral prednisone, 4.3 mg/day (range, 1e7 mg/day). There was no change in the data at 12 months. A corticosteroid-sparing effect was achieved in all patients who responded to infliximab therapy. Side effects induced from infliximab were closely monitored during each patient visit. Most patients (63.6%) did not experience any side effects. The most common adverse effects experienced were rash and fatigue, noted in 8 patients (9.1%) and 7 patients (8%), respectively. Of the 32 patients who experienced any side effects, the effects were considered transitory or mild in 15 and the patients wanted to continue therapy. The remaining 17 patients discontinued treatment secondary to side effects, which were as follows in order of decreasing incidence: rash (n¼4), transitory
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Ophthalmology Volume -, Number -, Month 2013
Figure 1. KaplaneMeier curve of time to clinical remission.
increased liver function test (LFT) results (n¼2), autoimmune hepatitis (n¼1), infusion-related reaction (n¼3), fatigue (n¼2), chronic infection (n¼2), nausea (n¼1), myalgia (n¼1), and druginduced lupus (n¼1) (Table 4, available at http://aaojournal.org). The mean time to the development of a side effect that necessitated discontinuation was 39.2 weeks (range, 2e113 weeks).
Factors Affecting Remission The incidence density of the remission rate was higher among male subjects (52.9/10 000 person-days), subjects without vasculitis (53.7/10 000 person-days), subjects with birdshot chorioretinopathy (55.2/10 000 person-days), subjects without idiopathic uveitis (52.2/10 000 person-days), subjects with JIA (48.6/10 000 persondays), and subjects without HLA-B27 (48.1/10 000 person-days). Remission incidence also was highest among those with anterior uveitis and a 4- to 6-year history of uveitis (Table 5). Incidence density of remission was higher among those with prior topical (51.1 cases per 10 000 person-days) and subtenon corticosteroid use. The relapse rate was higher among those with prior topical, intravitreal, and intracameral use. Lower percentages of relapse were observed in those who had transseptal triamcinolone (Kenalog) and subtenon injection. Patients who used prior systemic medications overall had a lower incidence rate of clinical remission compared with those who had not. Of those patients, patients taking mycophenolate, azathioprine, and CSA had a higher incidence rate of remission than those who were not taking these medications (Table 6, available at http://aaojournal.org). The percentage of incidence of relapse was higher among patients with prior use of MTX and daclizumab but lower with prior use of corticosteroid, mycophenolate, azathioprine, CSA, and NSAIDs. For patients who required additional immunomodulatory treatment while taking infliximab, those with the highest incidence rate of remission were as follows, in order of most effective: mycophenolate (74.5 cases per 10 000 person-days), azathioprine Table 3. Remission Rate While on Therapy Remission Remission Remission Remission
at at at at
6 mos (n ¼ 72 (95% CI) 12 mos (n ¼ 56 (95% CI) 18 mos (n ¼ 32 (95% CI) 24 mos (n ¼ 24 (95% CI)
CI ¼ confidence interval. n ¼ patients at risk for relapse.
4
61 32 24 16
(84.7%) (75.6%) (56.4%) (53.4%)
(61.8 cases per 10 000 person-days), CSA (56.9 cases per 10 000 person-days), and MTX (49.7 cases per 10 000 person-days) (Table 7, available at http://aaojournal.org). The lowest incidence rates of relapse were in patients receiving CSA (14.3 cases per 10 000 person-days) and mycophenolate (27.3 cases per 10 000 person-days). Incidence density of the remission rate also was higher among patients without side effects (52.1 cases per 10 000 person-days). The analysis of factors associated with a higher rate of first clinical remission showed the absence of idiopathic diagnosis (hazard ratio [HR], 3.15), standard and higher starting dose of infliximab (HR, 5.24 and 2.58, respectively), absence of vasculitis (HR, 6.8), and panuveitis or intermediate uveitis (HR, 5.37). Absence of some systemic medications before infliximab was also associated with clinical remission, in particular, no treatment with adalimumab (HR, 15.21), MTX (HR, 4.23), corticosteroid (HR, 3.54), or sirolimus (HR, 13.57). Use of local corticosteroids during infliximab treatment greatly increased the risk of not achieving clinical remission. Those not using a local corticosteroid were 61.44 times more likely to achieve clinical remission than those using a local corticosteroid while taking infliximab (Table 8).
Discussion To the best of our knowledge, to date, this is the largest single-center case study evaluating the safety and efficacy of infliximab for the treatment of varying types of uveitis that have failed other IMT. In this 6.5-year study of a cohort of 88 patients with recalcitrant uveitis treated with infliximab, the rate of clinical remission was 81.8%, and most patients tolerated the treatment well. This was comparable to a 2-year prospective trial of infliximab for refractory uveitis, which reported a success rate of 77% (24/31 patients).43 However, of the 65 patients in our cohort who were able to continue receiving long-term treatment with infliximab without serious side effects, only 5 were successfully tapered off infliximab after receiving a prolonged course, averaging 97.5 weeks. Of these 5 patients, 3 remained in durable remission off all IMT and corticosteroids for an average follow-up time of 89.4 weeks after completion of infliximab therapy. The remaining 2 patients both had anterior uveitis (idiopathic and HLA-B27 associated) and relapsed 58 weeks after completing their course of infliximab. This leads to the question of whether a TNF inhibitorfree remission is a feasible treatment goal. Likewise, this is a subject of much debate in the field of rheumatology. A recent study evaluated patients with recalcitrant rheumatoid arthritis who achieved remission on a combination of infliximab and MTX. After discontinuation of infliximab, 67% of patients achieved infliximab-free remission at 12 months while continuing on MTX monotherapy.44 Previous studies have suggested that a higher dose of infliximab is typically necessary to induce remission in patients with refractory uveitis compared with other autoimmune diseases.37 This study also supports this idea because dosing patients at 5 mg/kg was shown to be statistically significant for the induction of clinical remission. In addition, the dosing regimen used in our study is more aggressive than most rheumatology protocols, with loading doses at 0, 2, and 6 weeks, followed by maintenance doses every 4 weeks.
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Infliximab for Refractory Uveitis
Table 5. Percentage of Remission and Relapse by Sex, Location of Inflammation, and Diagnosis Remission Variable Sex Female Male Vasculitis Absent Present Location of inflammation Anterior Posterior Intermediate Panuveitis Duration of uveitis Before infliximab 1e3 yrs 4e6 yrs >6 yrs Diagnosis Birdshot chorioretinopathy Absent Present Idiopathic Absent Present JIA Absent Present HLA-B27 Absent Present
Relapse
No.
%
Time at Risk (Days)
Incidence Rate (per 10,000 Person Days)
No.
%
55 17
80.9 85.0
11 991 3022
45.9 52.9
23 6
41.8 35.3
39 33
95.1 71.7
7077 7762
53.7 42.5
16 13
41.0 39.4
33 14 5 20
91.7 82.4 71.4 71.4
6171 3509 1346 3987
51.9 39.9 37.1 50.2
12 3 3 11
36.4 21.4 60.0 55.0
33 16 23
91.7 72.7 79.3
7673 2881 4298
43.0 55.5 51.2
14 7 8
42.4 43.8 34.8
60 12
80.0 92.3
12 840 2173
46.0 55.2
27 2
45.0 16.7
48 24
88.9 70.6
8999 6014
52.2 39.9
18 11
37.5 45.8
57 15
79.2 93.8
12 134 2879
47.0 48.6
24 5
42.1 33.3
66 6
80.5 100.0
13 525 1488
48.1 40.3
26 3
39.4 50.0
HLA ¼ human leukocyte antigen; JIA ¼ juvenile idiopathic arthritis.
In our report, there are a few important points to mention given the seemingly small number of patients who were able to achieve infliximab-free durable remission. First, the infliximab protocol in this study had a slow tapering scheme, so completing a course of therapy often can take 2 to 3 years. Thus, a longer follow-up period will be required to truly determine the rate of durable remission in this cohort. Second, of the 81.8% of patients who achieved clinical remission, 40.2% went on to have at least 1 relapse during their treatment. These relapses often occurred during the tapering protocol, suggesting that prolonged maintenance dosing for infliximab is perhaps necessary in many cases of recalcitrant uveitis. At the induction of infliximab therapy, 22 patients were actively receiving systemic corticosteroids. Of these, only 6 continued to require systemic corticosteroids at 6 months. After 6 months of treatment, the average decrease in oral prednisone was 64.2%. A 100% rate of corticosteroidsparing success was found in our study and in a prior study published by our group.32 This rate is superior to the rate published in the previous literature.44 The American College of Rheumatology guidelines advise the use of combination therapy in recalcitrant cases, mainly MTX with antieTNF-a or other biologics.45 Of note, patients who required combination IMT with
infliximab, mycophenolate, and CSA had the highest incidence rates of remission and the lowest incidence rates of relapse. This finding should be taken into consideration when deciding on a treatment protocol requiring infliximab therapy in combination with another immunomodulatory agent. As with all immunomodulatory medications, infliximab has potentially serious side effects that must be weighed against the possible benefits for each patient. In our study, 32 patients (36.4%) experienced at least 1 side effect while on infliximab therapy and 17 patients (19.3%) ultimately had to discontinue treatment secondary to serious side effects, which was similar to a prospective trial that reported a rate of 19.4% (6/31 patients).33,43 Despite the similar rate of infliximab-induced side effects in both studies, the rate of serious adverse events in our study was 2.3% versus 19.3% reported by Suhler et al.43 The most common side effects in our cohort were rash (9.1%), fatigue (8%), leukopenia (5.7%), chronic infection (4.5%), increased LFT results (4.5%), and infusion-related reactions (4.5%). No patients were diagnosed with lymphoma or leukemia throughout their treatment or follow-up period. Of the 8 patients who reported a rash while receiving treatment, 6 were discontinued from treatment secondary to their reported rash. The average time to discontinuation of
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Ophthalmology Volume -, Number -, Month 2013 Table 8. Factors Associated with Clinical Remission P Value
Variable
HR
Other than idiopathic cause Starting dose* Standard (5 mg/kg) High (>5 mg/kg) No vasculitis Panuveitis/intermediate inflammation No prior TSK (Kenalog; Ranbaxy Laboratories Inc., Haryana, India) corticosteroid treatment No prior intake of the following systemic medications Adalimumab Methotrexate Corticosteroid Sirolimus No local corticosteroid while on infliximab
3.15
0.001
5.24 2.58 6.80 5.37 3.43
<0.001 0.011 <0.001 <0.001 0.006
2.4e11.6 1.2e5.3 3.3e13.9 2.2e13.1 1.4e8.3
15.21 4.23 3.54 13.57 61.44
<0.001 <0.001 <0.001 0.001 <0.001
3.8e60.6 2.1e8.6 1.8e6.9 2.7e67.7 18.0e210.3
95% CI 1.6e6.1
CI ¼ confidence interval; HR ¼ hazard ratio; TSK ¼ transseptal triamcinolone. *Reference category: low (<5 mg/kg).
infliximab secondary to the development of rash was 39.8 weeks. Of these patients, 3 developed a hypersensitivity reaction to infliximab that resulted in a papular rash, 2 developed psoriasis, and 1 had a malar rash that led to the diagnosis of drug-induced lupus. Of the 2 patients who were able to continue treatment despite having a rash, 1 had a mild intermittent papular rash secondary to a hypersensitivity reaction and 1 developed a mild case of psoriasis. Drug-related, lupus-like illness is a significant adverse reaction of anti-TNF agents that improves after discontinuation of the medication and has been reported with infliximab in the treatment of refractory uveitis.33,43 We report a lower rate of 1 in 88 patients (1.1%) compared with 3 in 31 patients (9.7%) in the 2-year prospective trial by Suhler et al.43 The average time to discontinuation of infliximab secondary to elevated LFT results was 54 weeks. One of the 3 patients who discontinued infliximab because of an increase in LFT results went on to develop biopsy-proven autoimmune hepatitis after 24.8 weeks of treatment with infliximab. Three patients in our study had an infusion-related reaction at an average of 35.2 weeks. Each case was accompanied by tightness in the chest and flushed appearance. In addition, 2 patients had pruritus and 1 patient had neck stiffness. All 3 patients recovered quickly once infusion therapy was withdrawn, and there were no long-term effects. In conclusion, although our study is limited by the follow-up period and the retrospective design without a control group, we have shown that our infliximab protocol is highly effective in inducing clinical remission in refractory uveitis, with a relatively low rate of treatment-ending adverse events. Few patients achieved durable remission off infliximab during our follow-up period, but extended maintenance therapy may well be a necessary component in the treatment of recalcitrant uveitis. Continued follow-up of our cohort will be required to fully determine the long-term effects of infliximab, and our results will need to be confirmed by a larger multicenter study.
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20. Maini R, St Clair EW, Breedveld F, et al; ATTRACT Study Group. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomized phase III trial. Lancet 1999;354:1932–9. 21. Braun J, Brandt J, Listing J et al. Long-term efficacy and safety of infliximab in the treatment of ankylosing spondylitis: an open, observational, extension study of a three-month, randomized, placebo-controlled trial. Arthritis Rheum 2003;48:2224–33. 22. Girardin M, Manz M, Manser C et al. First-line therapies in inflammatory bowel disease. Digestion 2012;86(Suppl): 6–10. 23. Reinisch W, Van Assche G, Befrits R et al. Recommendations for the treatment of ulcerative colitis with infliximab: a gastroenterology expert group consensus. J Crohns Colitis 2012;6:248–58. 24. Sands BE, Anderson FH, Bernstein CN et al. Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med 2004;350:876–85. 25. Hostettler KE, Studler U, Tamm M, Brutsche MH. Long-term treatment with infliximab in patients with sarcoidosis. Respiration 2012;83:218–24. 26. Maneiro JR, Salgado E, Gomez-Reino JJ, Carmona L, BIOBADASER Study Group. Efficacy and safety of TNF antagonists in sarcoidosis: data from the Spanish registry of biologics BIOBADASER and a systematic review. Semin Arthritis Rheum 2012;42:89–103. 27. Ruperto N, Lovell DJ, Cuttica R, et al; Paediatric Rheumatology INternational Trials Organization (PRINTO), Pediatric Rheumatology Collaborative Study Group (PRCSG). Longterm efficacy and safety of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis: findings from an open label treatment extension. Ann Rheum Dis 2010;69:718–22. 28. De Marco G, Gerloni V, Pontikaki I et al. Long-term evaluation of infliximab in the treatment of persistently active juvenile idiopathic arthritis refractory to conventional therapy [in Italian]. Reumatismo 2007;59:50–6. 29. Adler S, Baumgartner I, Villiger PM. Behçet’s disease: successful treatment with infliximab in 7 patients with severe vascular manifestations. A retrospective analysis. Arthritis Care Res (Hoboken) 2012;64:607–11. 30. Naganuma M, Sakuraba A, Hisamatsu T et al. Efficacy of infliximab for the induction and maintenance of remission in intestinal Beçhet’s disease. Inflamm Bowel Dis 2008;14: 1259–64. 31. Pipitone N, Olivieri I, Padula A et al. Infliximab for the treatment of Neuro-Behçet’s disease: a case series and review of the literature. Arthritis Rheum 2008;59:285–90.
32. Artornsombudh P, Gevorgyan O, Payal A et al. Infliximab treatment of patients with birdshot retinochoroidopathy. Ophthalmology 2013;120:588–92. 33. Suhler EB, Smith JR, Wertheim MS et al. A prospective trial of infliximab therapy for refractory uveitis: preliminary safety and efficacy outcomes. Arch Ophthalmol 2005;123: 903–12. 34. Arida A, Fragiadaki K, Giavri E, Sfikakis PP. Anti-TNF agents for Behçet’s disease: analysis of published data on 369 patients. Semin Arthritis Rheum 2011;41:61–70. 35. El-Shabrawi Y, Hermann J. Anti-tumor necrosis factoralpha therapy with infliximab as an alternative to corticosteroids in the treatment of human leukocyte antigen B27-associated acute anterior uveitis. Ophthalmology 2002;109:2342–6. 36. Ohno S, Nakamura S, Hori S et al. Efficacy, safety, and pharmacokinetics of multiple administration of infliximab in Behçet’s disease with refractory uveoretinitis. J Rheumatol 2004;31:1362–8. 37. Sukumaran S, Marzan K, Shaham B, Reiff A. High dose infliximab in the treatment of refractory uveitis: does dose matter? ISRN Rheumatol [serial online] 2012; 2012:765380. Available at: http://www.hindawi.com/isrn/ rheumatology/2012/765380/. Accessed July 3, 2013. 38. Tynjälä P, Lindahl P, Honkanen V et al. Infliximab and etanercept in the treatment of chronic uveitis associated with refractory juvenile idiopathic arthritis. Ann Rheum Dis 2007;66:548–50. 39. Richards JC, Tay-Kearney ML, Murray K, Manners P. Infliximab for juvenile idiopathic arthritis-associated uveitis. Clin Experiment Ophthalmol 2005;33:461–8. 40. Seve P, Mennesson E, Grange JD et al. Infliximab in serpiginous choroiditis [letter]. Acta Ophthalmol 2010;88:e342–3. 41. Joseph A, Raj D, Dua HS et al. Infliximab in the treatment of refractory posterior uveitis. Ophthalmology 2003;110:1449–53. 42. Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol 2005;140:509–16. 43. Suhler EB, Smith JR, Giles TR et al. Infliximab therapy for refractory uveitis: 2-year results of a prospective trial [letter]. Arch Ophthalmol 2009;127:819–22. 44. Tanaka Y. Next stage of RA treatment: is TNF inhibitor-free remission a possible treatment goal? Ann Rheum Dis 2013;72(Suppl): ii124e7. 45. Singh JA, Furst DE, Bharat A et al. 2012 update of the 2008 American College of Rheumatology recommendation for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken) 2012;64:625–39.
Footnotes and Financial Disclosures Originally received: January 28, 2013. Final revision: July 16, 2013. Accepted: July 16, 2013. Available online: ---.
3
Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.
Manuscript no. 2013-160.
1
Massachusetts Eye Research and Surgery Institution, Cambridge, Massachusetts.
2
Ocular Immunology Massachusetts.
and
Uveitis
Foundation,
Cambridge,
Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Correspondence: C. Stephen Foster, MD, FACS, 5 Cambridge Center, 8th Floor, Cambridge, MA 02142. E-mail: [email protected].
7
Noninfectious uveitis is a significant cause of blindness in developed countries. In the United States alone, it is estimated that 30 000 people are declared legally blind from uveitis annually.1 Recent studies indicate that the incidence may be even higher.2 Despite increasing awareness, the uveitic population continues to have a poor prognosis secondary to the complexity behind the pathophysiology, treatment, and management. Tumor necrosis factor (TNF)-a is a proinflammatory cytokine that is produced by multiple inflammatory cells, such as macrophages, T cells, and natural killer cells. It functions as a costimulator for T cells, B cells, cytotoxic T cells, and neutrophils.3 The effect of TNF-a on the immune system is broad and includes an increase in the levels of certain proinflammatory cytokines (e.g., interleukin [IL]-1 and IL-6), chemokine release, upregulation of IL-2 receptors, endothelial cell activation, leukocyte accumulation through the induction and maintenance of human leukocyte antigen (HLA) class II expression, angiogenesis, and 2013 by the American Academy of Ophthalmology Published by Elsevier Inc.
production of prostaglandin, and it promotes the survival and function of regulatory T cells.3e12 The induction of regulatory T cells may be especially useful in maintaining uveitic patients in remission; it has been shown that the ratio of regulatory T cells in the immune system may play a crucial role in the balance and management of an appropriate inflammatory response.12 Animal models have demonstrated that during the induction of experimental autoimmune uveitis, both aqueous and serum TNF-a levels increase.13 Elevated TNF-a levels also have been demonstrated in uveitic patients.14 The inhibition of TNF-a as therapy for ocular inflammatory disease was first shown to be effective in animal models of uveitis,15e17 possibly because of a reduction in leukocyte rolling, adhesion, and vascular leakage induced with endotoxin-induced uveitis in the rat model.18 With the development of biologic response modifiers and their successful use in rheumatologic conditions, agents such as antieTNF-a became an emerging option for uveitic ISSN 0161-6420/13/$ - see front matter http://dx.doi.org/10.1016/j.ophtha.2013.07.019
1
Ophthalmology Volume -, Number -, Month 2013 patients who failed or did not tolerate conventional immunomodulatory therapy (IMT). Such therapy is used off label, and many reports now exist in peer-reviewed literature documenting uncontrolled case series’ experience with this treatment strategy for vision-threatening ocular inflammatory disease. Infliximab (Remicade; Janssen Biotech, Inc., Titusville, NJ) is a chimeric monoclonal antibody directed against TNF-a of predominantly human origin but that includes 2 murine antigen-binding sites.19 The efficacy of infliximab has been widely studied for the treatment of various types of chronic inflammatory diseases.20e24 Additional studies have shown the possible benefits of infliximab for the treatment of refractory cases of sarcoidosis,25,26 juvenile idiopathic arthritis (JIA),27,28 and Behçet’s disease.29e31 The use of infliximab to treat refractory cases of uveitis in humans has been examined in a small but growing number of case reports and small studies.32e41 The purpose of this report is to present our experience with the use of infliximab as treatment for recalcitrant noninfectious uveitis.
Methods Study Population and Data Collection A review of medical records from the Massachusetts Eye Research and Surgery Institution from October 2005 to May 2012 identified 88 patients with a history of chronic noninfectious uveitis who were treated with infliximab. Inclusion criteria consisted of having had noninfectious uveitis resistant to other therapy, both corticosteroids and conventional immunomodulatory agents, started on intravenous infliximab at the Massachusetts Eye Research and Surgery Institution. All patients had active inflammation at the time of their first infusion. Patients who had received a fluocinolone acetonide intravitreal implant (Retisert; Bausch & Lomb, Inc., Rochester, NY), who were infused offsite, or who had incomplete data or a follow-up period <5 months were excluded from the study. Baseline data collected included sex, diagnosis, location of uveitis, presence of vasculitis, prior local or systemic corticosteroid treatment, and prior systemic immunomodulatory treatment. Categorization of uveitis location was based on that defined by the Standardization of Uveitis Nomenclature Working Group,42 except that optic nerve head or retinal vessel inflammation was included as sufficient to satisfy the posterior components of panuveitis. Local corticosteroid use included topical, subtenon, transseptal, intracameral, and intravitreal routes of administration. At each visit, all patients underwent a detailed ophthalmic evaluation and systemic review. This included visual acuity, intraocular pressure, and slit-lamp biomicroscopy. During each follow-up visit, ocular inflammation was assessed by the primary investigator (C.S.F.) and graded according to the Standardization of Uveitis Nomenclature criteria.41 Remission was a clinical decision made by the principal investigator (C.S.F.) that was based on corticosteroid-free resolution of aqueous or vitreous cell (<0.5þ), vitreous haze, and fluorescein leakage on angiography (e.g., optic disc, macula, retinal vessels, chorioretinal lesions). All patients exhibiting a posterior component to their uveitis were required to demonstrate an absence of optic disc staining, active macular edema, and vasculitis on fluorescein angiography. Clinical remission was defined as no disease activity while taking infliximab, and durable remission was defined as no disease activity after successful treatment and discontinuation of infliximab. Relapse was defined as increased
2
anterior/posterior segment cell (<0.5þ) or evidence of inflammation on fluorescein angiogram as previously outlined. Therapeutic failure was defined as insufficient control of inflammation within 6 months of starting treatment with infliximab or 3 relapses while on infliximab. Infliximab was discontinued immediately in patients who failed therapy or had significant side effects. Patients were allowed a bridging period of 180 days from the beginning of their treatment with infliximab to be weaned off concomitant immunomodulatory medications. If patients continued on any additional immunomodulatory medication past 180 days, they were included in the category of patients who required infliximab þ additional therapy. At every infusion visit, the patient was assessed for treatment response and side effects. The starting dose and the maximum dose during each treatment period were recorded. All patients included in this study adhered to the tenants of the Declaration of Helsinki. Informed consent was obtained from all study subjects, and institutional review board approval was in place before commencement of the study.
Infliximab Protocol The protocol used in this study included a loading dose of infliximab administered at 0, 2, and 6 weeks, and then every 4 weeks until clinical remission was achieved. All patients were started on an initial dose of 4 to 6 mg/kg. Before starting treatment and during each follow-up visit, routine blood monitoring was performed to check for blood dyscrasia and liver toxicity. This included a complete blood count including differential and aspartate aminotransferase and alanine aminotransferase. Additional testing included tuberculosis screening with intradermal purified protein derivative and assessment for the development of drug-induced lupus with clinical assessment and antinuclear antibody testing before starting infliximab and every 6 months while on infusion therapy. The infusion interval and dose were adjusted according to patient response and side effects. After achieving clinical remission, the infusion interval was slowly prolonged at 2-week increments. We typically maintained any given infusion frequency for a minimum of 4 infusions before attempting to stretch the interval further. If the patient remained in remission after 4 infusions at an interval of 10 to 12 weeks, the drug was discontinued. The decision of when to complete treatment was individualized and based on prior response and total length of treatment time.
Data Analysis Statistical analysis was performed using the Stata software program, version 12 (StataCorp LP, College Station, TX). Percentages of categoric variables were computed, and means and standard deviations of quantitative variables were used as summary measures. Cox proportional hazards regression (survival) analysis was used to identify factors that were associated with the occurrence of clinical remission. The following variables were included in the Cox regression analysis: sex; vasculitis; location of inflammation; duration of uveitis before treatment; presence or absence of a diagnosis (birdshot chorioretinopathy, idiopathic, JIA, HLAB27); prior corticosteroid use (topical, transseptal triamcinolone [Kenalog; Ranbaxy Laboratories Inc., Haryana, India], subtenon, intracameral, intravitreal), prior systemic medications (corticosteroid, methotrexate [MTX], cyclophosphamide, mycophenolate, azathioprine, cyclosporine A [CSA], adalimumab, nonsteroidal anti-inflammatory drugs [NSAIDs], daclizumab, etanercept, sirolimus, chlorambucil); continued medications while taking infliximab (MTX, mycophenolate, azathioprine, CSA, NSAIDs, local corticosteroid); presence or absence of a side effect; starting dose; and highest dose. Some variables were not included because of small cell frequency. A backward elimination process was used
Kruh et al
Infliximab for Refractory Uveitis
Table 1. Patient Characteristics, Diagnosis, and Location of Uveitis
Table 2. Prior and Continued Medications While on Infliximab Variable
Variable Sex Female Male Race Caucasian African American Hispanic Asian Diagnosis Idiopathic JIA Birdshot chorioretinopathy HLA-B27 Sarcoidosis Behçet’s disease Presence of vasculitis Present Absent Location of inflammation Anterior Panuveitis Posterior Intermediate
No. (n [ 88)
%
68 20
77.3 22.7
75 8 4 1
85.2 9.0 4.5 1.1
34 16 13 6 6 3
38.6 18.2 14.8 6.8 6.8 3.4
46 42
52.9 47.1
36 28 17 7
40.9 31.8 19.3 8.0
HLA ¼ human leukocyte antigen; JIA ¼ juvenile idiopathic arthritis.
where variables that were not significant were dropped or removed from the regression model one at a time, starting with the least significant variable. Dropping of variables stopped when the regression model contained variables that were all significantly related to the outcome. A P value of <0.05 was considered statistically significant.
Results Descriptive Analysis Eighty-eight patients were included in the study, of whom 68 (77.3%) were female and 20 (22.7%) were male. The largest number had anterior uveitis and a diagnosis of idiopathic cause. Table 1 shows a detailed description of the location of uveitis, presence of vasculitis, and most frequent diagnoses. The mean follow-up of those who achieved remission was 28.75 months (range, 5e86.5 months). Table 2 details the medications used before and during infliximab treatment. The most commonly prescribed medications before infliximab treatment were topical corticosteroids (78.4%) and MTX (65.95%). The average number of failed treatments per patient in our study was 3 (Table 2).
Efficacy and Safety Seventy-two of the 88 patients (81.8%) achieved complete clinical remission while being treated with intravenous infliximab. Thirtythree patients (37.5%) were able to discontinue all additional topical or oral corticosteroids and other IMT within 180 days of beginning infusion therapy. Of the 55 patients (62.5%) who required additional medications, the most commonly continued drugs were MTX (26.1%) and topical corticosteroids (20.5%). From a total of 15 013 person-days at risk among all patients, the incidence density of the remission rate was 47 per 10 000 person-days, with a median
No. (n [ 88)
%
69 26 13 2 1
78.4 29.5 14.8 2.3 1.1
58 47 40 38 24 12 8 6 4 4 3
65.9 53.4 45.5 43.2 27.3 13.6 9.1 6.8 4.5 4.5 3.4
55 12 23 18 10 8 5 4
62.5 13.6 26.1 20.5 11.4 9.1 5.7 4.5
Prior corticosteroid use Topical Transseptal Intravitreal Subtenon Intracameral Prior systemic medication Methotrexate Mycophenolate Corticosteroid Cyclosporine NSAIDs Azathioprine Chlorambucil Adalimumab Cyclophosphamide Etanercept Sirolimus Continued systemic medication Continued other medicines Mycophenolate Methotrexate Local corticosteroid Systemic corticosteroid Cyclosporine NSAIDs Azathioprine NSAID ¼ nonsteroidal anti-inflammatory drug.
time of disease remission of 127 days. At 7 and 44.7 weeks, 25% and 75% of patients, respectively, achieved clinical remission (Fig 1). After achieving clinical remission, the rate of continued remission without a relapse while on therapy was 84.7% and 75.6% at 6 months and 12 months, respectively (Table 3). Patients who relapsed typically did so when the interval between infusions was increased. A relapse then triggered a return to the previous shortened infusion interval. Some 45% of patients had a history of systemic corticosteroid use (intravenous methylprednisolone or oral prednisone). On induction of infliximab therapy, 6 patients were receiving intravenous infusions of methylprednisolone (1000 mg) and 16 patients were receiving oral prednisone (mean, 13 mg/day; range, 2e40 mg/day). At 6 months on treatment, no patient required intravenous methylprednisolone and only 6 of 16 patients required oral prednisone. The mean dose of prednisone for patients continuing to take oral prednisone at 6 months was 4.6 mg/day (range, 1e7 mg), a reduction of 64.2%. At 9 months, of the 6 patients who required oral prednisone at 6 months, 2 were discontinued from the study, deemed failures, and 3 patients continued on daily oral prednisone, 4.3 mg/day (range, 1e7 mg/day). There was no change in the data at 12 months. A corticosteroid-sparing effect was achieved in all patients who responded to infliximab therapy. Side effects induced from infliximab were closely monitored during each patient visit. Most patients (63.6%) did not experience any side effects. The most common adverse effects experienced were rash and fatigue, noted in 8 patients (9.1%) and 7 patients (8%), respectively. Of the 32 patients who experienced any side effects, the effects were considered transitory or mild in 15 and the patients wanted to continue therapy. The remaining 17 patients discontinued treatment secondary to side effects, which were as follows in order of decreasing incidence: rash (n¼4), transitory
3
Ophthalmology Volume -, Number -, Month 2013
Figure 1. KaplaneMeier curve of time to clinical remission.
increased liver function test (LFT) results (n¼2), autoimmune hepatitis (n¼1), infusion-related reaction (n¼3), fatigue (n¼2), chronic infection (n¼2), nausea (n¼1), myalgia (n¼1), and druginduced lupus (n¼1) (Table 4, available at http://aaojournal.org). The mean time to the development of a side effect that necessitated discontinuation was 39.2 weeks (range, 2e113 weeks).
Factors Affecting Remission The incidence density of the remission rate was higher among male subjects (52.9/10 000 person-days), subjects without vasculitis (53.7/10 000 person-days), subjects with birdshot chorioretinopathy (55.2/10 000 person-days), subjects without idiopathic uveitis (52.2/10 000 person-days), subjects with JIA (48.6/10 000 persondays), and subjects without HLA-B27 (48.1/10 000 person-days). Remission incidence also was highest among those with anterior uveitis and a 4- to 6-year history of uveitis (Table 5). Incidence density of remission was higher among those with prior topical (51.1 cases per 10 000 person-days) and subtenon corticosteroid use. The relapse rate was higher among those with prior topical, intravitreal, and intracameral use. Lower percentages of relapse were observed in those who had transseptal triamcinolone (Kenalog) and subtenon injection. Patients who used prior systemic medications overall had a lower incidence rate of clinical remission compared with those who had not. Of those patients, patients taking mycophenolate, azathioprine, and CSA had a higher incidence rate of remission than those who were not taking these medications (Table 6, available at http://aaojournal.org). The percentage of incidence of relapse was higher among patients with prior use of MTX and daclizumab but lower with prior use of corticosteroid, mycophenolate, azathioprine, CSA, and NSAIDs. For patients who required additional immunomodulatory treatment while taking infliximab, those with the highest incidence rate of remission were as follows, in order of most effective: mycophenolate (74.5 cases per 10 000 person-days), azathioprine Table 3. Remission Rate While on Therapy Remission Remission Remission Remission
at at at at
6 mos (n ¼ 72 (95% CI) 12 mos (n ¼ 56 (95% CI) 18 mos (n ¼ 32 (95% CI) 24 mos (n ¼ 24 (95% CI)
CI ¼ confidence interval. n ¼ patients at risk for relapse.
4
61 32 24 16
(84.7%) (75.6%) (56.4%) (53.4%)
(61.8 cases per 10 000 person-days), CSA (56.9 cases per 10 000 person-days), and MTX (49.7 cases per 10 000 person-days) (Table 7, available at http://aaojournal.org). The lowest incidence rates of relapse were in patients receiving CSA (14.3 cases per 10 000 person-days) and mycophenolate (27.3 cases per 10 000 person-days). Incidence density of the remission rate also was higher among patients without side effects (52.1 cases per 10 000 person-days). The analysis of factors associated with a higher rate of first clinical remission showed the absence of idiopathic diagnosis (hazard ratio [HR], 3.15), standard and higher starting dose of infliximab (HR, 5.24 and 2.58, respectively), absence of vasculitis (HR, 6.8), and panuveitis or intermediate uveitis (HR, 5.37). Absence of some systemic medications before infliximab was also associated with clinical remission, in particular, no treatment with adalimumab (HR, 15.21), MTX (HR, 4.23), corticosteroid (HR, 3.54), or sirolimus (HR, 13.57). Use of local corticosteroids during infliximab treatment greatly increased the risk of not achieving clinical remission. Those not using a local corticosteroid were 61.44 times more likely to achieve clinical remission than those using a local corticosteroid while taking infliximab (Table 8).
Discussion To the best of our knowledge, to date, this is the largest single-center case study evaluating the safety and efficacy of infliximab for the treatment of varying types of uveitis that have failed other IMT. In this 6.5-year study of a cohort of 88 patients with recalcitrant uveitis treated with infliximab, the rate of clinical remission was 81.8%, and most patients tolerated the treatment well. This was comparable to a 2-year prospective trial of infliximab for refractory uveitis, which reported a success rate of 77% (24/31 patients).43 However, of the 65 patients in our cohort who were able to continue receiving long-term treatment with infliximab without serious side effects, only 5 were successfully tapered off infliximab after receiving a prolonged course, averaging 97.5 weeks. Of these 5 patients, 3 remained in durable remission off all IMT and corticosteroids for an average follow-up time of 89.4 weeks after completion of infliximab therapy. The remaining 2 patients both had anterior uveitis (idiopathic and HLA-B27 associated) and relapsed 58 weeks after completing their course of infliximab. This leads to the question of whether a TNF inhibitorfree remission is a feasible treatment goal. Likewise, this is a subject of much debate in the field of rheumatology. A recent study evaluated patients with recalcitrant rheumatoid arthritis who achieved remission on a combination of infliximab and MTX. After discontinuation of infliximab, 67% of patients achieved infliximab-free remission at 12 months while continuing on MTX monotherapy.44 Previous studies have suggested that a higher dose of infliximab is typically necessary to induce remission in patients with refractory uveitis compared with other autoimmune diseases.37 This study also supports this idea because dosing patients at 5 mg/kg was shown to be statistically significant for the induction of clinical remission. In addition, the dosing regimen used in our study is more aggressive than most rheumatology protocols, with loading doses at 0, 2, and 6 weeks, followed by maintenance doses every 4 weeks.
Kruh et al
Infliximab for Refractory Uveitis
Table 5. Percentage of Remission and Relapse by Sex, Location of Inflammation, and Diagnosis Remission Variable Sex Female Male Vasculitis Absent Present Location of inflammation Anterior Posterior Intermediate Panuveitis Duration of uveitis Before infliximab 1e3 yrs 4e6 yrs >6 yrs Diagnosis Birdshot chorioretinopathy Absent Present Idiopathic Absent Present JIA Absent Present HLA-B27 Absent Present
Relapse
No.
%
Time at Risk (Days)
Incidence Rate (per 10,000 Person Days)
No.
%
55 17
80.9 85.0
11 991 3022
45.9 52.9
23 6
41.8 35.3
39 33
95.1 71.7
7077 7762
53.7 42.5
16 13
41.0 39.4
33 14 5 20
91.7 82.4 71.4 71.4
6171 3509 1346 3987
51.9 39.9 37.1 50.2
12 3 3 11
36.4 21.4 60.0 55.0
33 16 23
91.7 72.7 79.3
7673 2881 4298
43.0 55.5 51.2
14 7 8
42.4 43.8 34.8
60 12
80.0 92.3
12 840 2173
46.0 55.2
27 2
45.0 16.7
48 24
88.9 70.6
8999 6014
52.2 39.9
18 11
37.5 45.8
57 15
79.2 93.8
12 134 2879
47.0 48.6
24 5
42.1 33.3
66 6
80.5 100.0
13 525 1488
48.1 40.3
26 3
39.4 50.0
HLA ¼ human leukocyte antigen; JIA ¼ juvenile idiopathic arthritis.
In our report, there are a few important points to mention given the seemingly small number of patients who were able to achieve infliximab-free durable remission. First, the infliximab protocol in this study had a slow tapering scheme, so completing a course of therapy often can take 2 to 3 years. Thus, a longer follow-up period will be required to truly determine the rate of durable remission in this cohort. Second, of the 81.8% of patients who achieved clinical remission, 40.2% went on to have at least 1 relapse during their treatment. These relapses often occurred during the tapering protocol, suggesting that prolonged maintenance dosing for infliximab is perhaps necessary in many cases of recalcitrant uveitis. At the induction of infliximab therapy, 22 patients were actively receiving systemic corticosteroids. Of these, only 6 continued to require systemic corticosteroids at 6 months. After 6 months of treatment, the average decrease in oral prednisone was 64.2%. A 100% rate of corticosteroidsparing success was found in our study and in a prior study published by our group.32 This rate is superior to the rate published in the previous literature.44 The American College of Rheumatology guidelines advise the use of combination therapy in recalcitrant cases, mainly MTX with antieTNF-a or other biologics.45 Of note, patients who required combination IMT with
infliximab, mycophenolate, and CSA had the highest incidence rates of remission and the lowest incidence rates of relapse. This finding should be taken into consideration when deciding on a treatment protocol requiring infliximab therapy in combination with another immunomodulatory agent. As with all immunomodulatory medications, infliximab has potentially serious side effects that must be weighed against the possible benefits for each patient. In our study, 32 patients (36.4%) experienced at least 1 side effect while on infliximab therapy and 17 patients (19.3%) ultimately had to discontinue treatment secondary to serious side effects, which was similar to a prospective trial that reported a rate of 19.4% (6/31 patients).33,43 Despite the similar rate of infliximab-induced side effects in both studies, the rate of serious adverse events in our study was 2.3% versus 19.3% reported by Suhler et al.43 The most common side effects in our cohort were rash (9.1%), fatigue (8%), leukopenia (5.7%), chronic infection (4.5%), increased LFT results (4.5%), and infusion-related reactions (4.5%). No patients were diagnosed with lymphoma or leukemia throughout their treatment or follow-up period. Of the 8 patients who reported a rash while receiving treatment, 6 were discontinued from treatment secondary to their reported rash. The average time to discontinuation of
5
Ophthalmology Volume -, Number -, Month 2013 Table 8. Factors Associated with Clinical Remission P Value
Variable
HR
Other than idiopathic cause Starting dose* Standard (5 mg/kg) High (>5 mg/kg) No vasculitis Panuveitis/intermediate inflammation No prior TSK (Kenalog; Ranbaxy Laboratories Inc., Haryana, India) corticosteroid treatment No prior intake of the following systemic medications Adalimumab Methotrexate Corticosteroid Sirolimus No local corticosteroid while on infliximab
3.15
0.001
5.24 2.58 6.80 5.37 3.43
<0.001 0.011 <0.001 <0.001 0.006
2.4e11.6 1.2e5.3 3.3e13.9 2.2e13.1 1.4e8.3
15.21 4.23 3.54 13.57 61.44
<0.001 <0.001 <0.001 0.001 <0.001
3.8e60.6 2.1e8.6 1.8e6.9 2.7e67.7 18.0e210.3
95% CI 1.6e6.1
CI ¼ confidence interval; HR ¼ hazard ratio; TSK ¼ transseptal triamcinolone. *Reference category: low (<5 mg/kg).
infliximab secondary to the development of rash was 39.8 weeks. Of these patients, 3 developed a hypersensitivity reaction to infliximab that resulted in a papular rash, 2 developed psoriasis, and 1 had a malar rash that led to the diagnosis of drug-induced lupus. Of the 2 patients who were able to continue treatment despite having a rash, 1 had a mild intermittent papular rash secondary to a hypersensitivity reaction and 1 developed a mild case of psoriasis. Drug-related, lupus-like illness is a significant adverse reaction of anti-TNF agents that improves after discontinuation of the medication and has been reported with infliximab in the treatment of refractory uveitis.33,43 We report a lower rate of 1 in 88 patients (1.1%) compared with 3 in 31 patients (9.7%) in the 2-year prospective trial by Suhler et al.43 The average time to discontinuation of infliximab secondary to elevated LFT results was 54 weeks. One of the 3 patients who discontinued infliximab because of an increase in LFT results went on to develop biopsy-proven autoimmune hepatitis after 24.8 weeks of treatment with infliximab. Three patients in our study had an infusion-related reaction at an average of 35.2 weeks. Each case was accompanied by tightness in the chest and flushed appearance. In addition, 2 patients had pruritus and 1 patient had neck stiffness. All 3 patients recovered quickly once infusion therapy was withdrawn, and there were no long-term effects. In conclusion, although our study is limited by the follow-up period and the retrospective design without a control group, we have shown that our infliximab protocol is highly effective in inducing clinical remission in refractory uveitis, with a relatively low rate of treatment-ending adverse events. Few patients achieved durable remission off infliximab during our follow-up period, but extended maintenance therapy may well be a necessary component in the treatment of recalcitrant uveitis. Continued follow-up of our cohort will be required to fully determine the long-term effects of infliximab, and our results will need to be confirmed by a larger multicenter study.
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Footnotes and Financial Disclosures Originally received: January 28, 2013. Final revision: July 16, 2013. Accepted: July 16, 2013. Available online: ---.
3
Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.
Manuscript no. 2013-160.
1
Massachusetts Eye Research and Surgery Institution, Cambridge, Massachusetts.
2
Ocular Immunology Massachusetts.
and
Uveitis
Foundation,
Cambridge,
Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Correspondence: C. Stephen Foster, MD, FACS, 5 Cambridge Center, 8th Floor, Cambridge, MA 02142. E-mail: [email protected].
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