Ocular Immunology & Inflammation, 2014; 22(6): 469–477 ! Informa Healthcare USA, Inc. ISSN: 0927-3948 print / 1744-5078 online DOI: 10.3109/09273948.2013.863944
ORIGINAL ARTICLE
Treatment of Chronic, Noninfectious, Nonnecrotizing Scleritis with Tumor Necrosis Factor Alpha Inhibitors Ashwinee Ragam, BS1, Anton M. Kolomeyer, MD, PhD1, Christina Fang, Yinfei Xu, MD1, and David S. Chu, MD1,2 1
1
BS
,
Institute of Ophthalmology and Visual Science, Rutgers New Jersey Medical School, Newark, New Jersey, USA, and 2Metropolitan Eye Research and Surgery Institute, Palisades Park, New Jersey, USA
ABSTRACT Purpose: To evaluate the use of TNF-alpha inhibitors for non-infectious, non-necrotizing scleritis. Methods: We conducted a retrospective chart review of patients with non-infectious, non-necrotizing scleritis treated at our institutions from 2002 to 2012. Results: Seventeen patients (26 eyes) were included. Ten patients were started on infliximab and seven on adalimumab; five patients were treated with both TNF-alpha inhibitors on separate occasions. All patients had an associated autoimmune disease. Control of active inflammation for at least 2 months was achieved in 15 (88%) of 17 patients. Seven out of eight patients successfully tapered concurrent corticosteroid use. Only one patient discontinued TNF-alpha inhibitor use due to an allergic reaction. Conclusions: TNF-alpha inhibitors appear to have a role in managing non-infectious, non-necrotizing scleritis refractory to initial therapy, mainly by reducing inflammation and decreasing concurrent CS use. Keywords: Inflammation, noninfectious scleritis, TNF-alpha inhibitors
Noninfectious scleritis is characterized by severe scleral redness, deep periocular pain, pinpoint tenderness, irritation, and photophobia, all of which may be so severe as to interfere with activities of daily living.1 Most cases of scleritis are either idiopathic or associated with systemic inflammatory diseases, such as rheumatoid arthritis (RA), granulomatosis, and polyangitis (Wegener granulomatosis), systemic vasculitis, and relapsing polychondritis, which have been reported to occur in up to 39–50% of patients.2–4 Scleritis necessitates prompt and appropriate treatment as complications of keratitis, uveitis, glaucoma, cataract, and exudative retinal or choroidal detachments can arise.3,4 Nonnecrotizing, noninfectious scleritis often responds to systemic nonsteroidal anti-inflammatory drugs (NSAIDs), which are typically first-line agents of treatment.3 Some of the most common side effects
of systemic NSAID use include GI toxicity (nausea, anorexia, vomiting, dyspepsia) and CNS effects (headache, dizziness, fatigue).5 Corticosteroids (CS), due to their rapid onset and potent anti-inflammatory effects, are also commonly used, especially in those patients refractory to NSAIDs. However, some cases of scleritis are refractory even to high-dose CS. Additionally, there is a dose-dependent risk of adverse effects from long-term CS use. Local adverse effects include development or worsening of cataract and glaucoma. Systemic side effects may include Cushingoid changes, osteoporosis, infection, poor wound healing, insulin-dependent diabetes mellitus, myopathy, and psychosis.6 In approximately 26% of patients with scleritis, additional immunosuppression is required in order to taper the CS dose to less than or equal to 10 mg per day. This dose has been shown to provide the
Received 18 August 2013; revised 27 September 2013; accepted 5 November 2013; published online 18 December 2013 Correspondence: David S. Chu, MD, Metropolitan Eye Research and Surgery Institute, 540 Bergen Blvd, Suite D, Palisades Park, NJ 07650, USA. E-mail: [email protected]
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470 A. Ragam et al. largest benefit-to-harm ratio.7–12 Several studies have reported success in treating scleritis with immunosuppressive agents such as cyclosporine (CsA),6,13 mycophenolate mofetil (MMF),14–16 and methotrexate (MTX).17,18 Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine whose level is elevated in various autoimmune conditions.19 Agents that selectively inhibit the actions of TNF-alpha have arisen as alternative immunosuppressive therapies, proving efficacious in the treatment of systemic autoimmune conditions such as Crohn disease, RA, and psoriatic arthritis.20–22 The three most widely available TNF-alpha blocking agents are (1) infliximab, a chimeric human–murine monoclonal antibody against TNF-alpha; (2) adalimumab, a fully human monoclonal antibody against TNF-alpha; and (3) etanercept, a fusion protein of the extracellular ligand-binding portion of human TNF receptor p75 and the fragment crystallizable (Fc) region of IgG1, effectively functioning as a decoy receptor for TNF-alpha.21 Other TNF-alpha inhibitors include certolizumab pegol, a PEGylated humanized antigen-binding fragment (Fab’) of the monoclonal antibody against TNF-alpha,23 and golimumab, another human monoclonal antibody against TNFalpha.24 TNF-alpha inhibitors have been used for several years in managing different forms of ocular inflammation. Studies focusing on the efficacy of TNF-alpha inhibitors for the treatment of scleritis have, for the most part, been limited to small case series24–28 and/or focused only on infliximab.25–27,29 Very few have discussed the use of adalimumab30,31 in such regard. This report is of a larger case series of patients with noninfectious scleritis treated by two TNF-alpha inhibitor agents: infliximab and/or adalimumab. The goal of the study was to determine whether TNF-alpha inhibitors may be efficacious in treating noninfectious scleritis refractory to other therapies.
MATERIALS AND METHODS This study was approved by the Rutgers Biomedical and Health Sciences institutional review board. A list of patients seen at our institutions between 2002 and 2012 with diagnoses of scleritis was created by searching our billing database using International Classification of Diseases 9 codes 379.00-09. Two hundred ninety-five charts were reviewed and only patients treated with TNF-alpha inhibitors for greater than or equal to 2 months were eligible. At the time of initiating TNF-alpha inhibitor therapy, patients must have had active inflammation. Seventeen patients fit the criteria to be included. All patients were treated with at least one course
of a TNF-alpha inhibitor. A database was created listing gender, age at onset of TNF-alpha inhibitor therapy, affected eye(s), associated systemic autoimmune condition(s), date first seen for scleritis, and prior systemic medications for the treatment of scleritis. The specific TNF-alpha inhibitor(s), maximum dosing, and duration of use were recorded for each patient. Initial dosing and schedule for infliximab and adalimumab were determined by the rheumatologist managing each patient’s associated autoimmune condition, based on the specific condition, symptom severity, and clinical parameters. Appropriate dosing adjustments throughout the duration of treatment were made based on response to therapy and discussion between the ophthalmologist (DSC) and rheumatologist. Infliximab was delivered as intravenous infusions dosed in mg/kg at various weekly frequencies, while adalimumab was administered subcutaneously with prefilled syringes of 40 mg weekly or biweekly. Other measures documented included inflammation grade, visual acuity, and dosing of CS and/or other immunomodulatory therapy (IMT), including NSAIDs, used throughout the duration of TNF-alpha inhibitor treatment. We often initiate IMT with infliximab as per manufacturer recommendations to prevent anti-chimeric antibodies from forming; therefore, the concurrent use of IMT is not necessarily to assist in treating inflammation. Adverse effects and abnormal labs while receiving TNF-alpha inhibitors were also recorded. Snellen visual acuity was converted into logMAR, and is reported as such in the paper. Inflammation grade ranged from 0 to 4, as outlined in the grading scheme proposed by Sen et al.,32 and was determined by a single physician (DSC) at every visit. Trace inflammation was recorded as a grading of 0.5. Inflammation quiescence was defined as inflammation grading of 0 on slit-lamp examination and lack of symptomatic complaints such as photophobia, pruritus, and ocular irritation. Inflammation control was defined as inflammation quiescence for at least 2 months duration. Successful CS sparing was defined as a final CS dosage of 10 mg per day or less in patients that were taking greater than 10 mg per day at the time of TNF-alpha inhibitor initiation, as outlined by the Standardization of Uveitis Nomenclature criteria.33 Paired t-tests were used to compare changes in inflammation grading and visual acuity before and after treatment with TNF-alpha inhibitors. Unpaired t-tests were used to compare outcomes between patients receiving infliximab and those receiving adalimumab. These tests were performed using JMP version 9 statistical software (SAS, Cary, NC) and statistical significance was accepted at p50.05. Ocular Immunology & Inflammation
TNF-a Inhibitors and Scleritis
RESULTS Seventeen patients (26 eyes) were included in the study. There were 14 (82%) females and 3 (18%) males. Eight (47%) patients were Caucasian, 4 (24%) patients were Hispanic, 4 (24%) patients were African-American, and 1 (6%) patient was Asian. Mean standard deviation (SD) age at start of treatment with TNF-alpha inhibitors was 58.8 12.6 years (range, 32–76 years). The mean SD duration of follow-up for scleritis at our institutions before starting the first trial of TNF-alpha inhibitor therapy was 12.8 19.8 months (range, 0–64.4 months). The mean SD duration of TNF-alpha inhibitor therapy was 25.8 23.5 months (range, 3.0–89.5 months). This excluded patient 11’s trial of infliximab, which consisted of a single infusion and subsequent development of an allergic reaction (Table 1). All 17 patients were found to have an associated autoimmune disease (Table 1). Eleven (65%) patients failed previous IMT, with 8 (47%) failing combination regimens. For these patients, the previous IMT was either ineffective at controlling inflammation or resulted in the development of unremitting side effects, most commonly seen with MTX. Four (36%) of these 11 patients were unable to control inflammation with NSAIDs, which are considered first-line therapy. One (6%) patient was on etanercept prior to being seen at our institution; however, dose, duration of treatment, and response to the therapy are unknown. Once seen at our institution, the patient was started on infliximab instead. Ten (59%) patients were started on infliximab and 7 (41%) patients were started on adalimumab. Five (29%) patients ended up switching from one TNF-alpha inhibitor to another because of treatment ineffectiveness (n = 3 [67%]), side effect (n = 1 [17%]), and decision by rheumatologist (n = 1 [17%]). The maximum dosing of TNF-alpha inhibitor therapy that each patient received is listed in Table 1. Figure 1 illustrates the outcomes of TNF-alpha inhibitor use in our 17 patients. Twelve patients (71%) achieved inflammation control of active scleritis after a mean SD of 5.0 3.9 months (range, 0.9– 14.9 months). Of these 12 patients, 7 (58%) showed no further recurrence of inflammation throughout the duration of use with the same TNF-alpha inhibitor (mean SD of 33.8 33.9 months). Patient 5 achieved inflammation control after 2.4 months of infliximab use and maintained quiescent scleritis for 33.8 months. She was then switched to adalimumab by the rheumatologist and continued to maintain control of inflammation for the remaining 1.3 months of follow-up. Three patients (11, 16, 17) achieving initial control of their active scleritis experienced recurrences of inflammation while on infliximab (Table 1). Six patients (1, 7, 9, 10, 14, 15) did not achieve inflammation control on their first course of !
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TNF-alpha inhibitor. Three patients (1, 10, 14) failed adalimumab after a mean SD 7.6 4.8 months (range, 3.0–12.6 months) and were switched to infliximab, achieving inflammation control after a mean SD of 1.0 0.5 months (range, 0.5–1.4 months). Patient 7 failed to respond to infliximab after 7.0 months of use, switched to other IMTs (MMF, rofecoxib, valdecoxib, cyclophosphamide, cyclosporine, and rituximab), and finally achieved and maintained inflammation control on celecoxib for 31.5 months. Patient 9 had an allergic reaction to a single infusion of infliximab, was switched to adalimumab, achieved inflammation control after 1.1 months, and maintained quiescence for 25.9 months without adverse effects. Patient 15 achieved inflammation quiescence for 1.6 months after 4.5 months of infliximab therapy, but was subsequently lost to follow-up. As the criteria set in this study required at least 2 months of inflammation quiescence, this patient was not considered to have successfully achieved inflammation control. The mean SD initial inflammation grade of scleritis at the start of TNF-alpha inhibitor therapy was 1.53 0.68 (range, 0.5–3; median, 1.0). This was significantly (p50.001) reduced to a mean SD final inflammation grade of 0.63 1.0 (range, 0–3; median, 0). These data exclude patient 6’s trial of adalimumab as she was switched from infliximab by her rheumatologist despite inflammation control; therefore, her initial and final inflammation grade for her course of adalimumab are 0. Control of active scleritis with TNF-alpha inhibitors was ultimately achieved in 15 (88%) of the 17 patients, including those patients requiring two trials of TNF-alpha inhibitor therapy. Table 2 compares the demographics and outcomes of scleritis patients in our study based on the type of TNF-alpha inhibitor they were treated with. The overall likelihood of achieving inflammation control on infliximab and adalimumab was 10/13 (77%) and 6/9 (66%), respectively. These results included both the initial failed course and subsequent successful course for patients who switched from adalimumab to infliximab. Patients who achieved quiescence of active inflammation for at least 2 months, despite subsequent flare-ups, were counted as successes in these data. Patient 5, who was controlled on infliximab but switched to adalimumab by the rheumatologist, was counted as a success for both TNF-alpha inhibitors. There was no significant difference between the rates of inflammation control with infliximab or adalimumab use (p = 0.63). There was also no significant difference in the duration of treatment (p = 0.30) or the time until inflammation control was achieved (p = 0.24) between infliximab and adalimumab therapies. There was an overall change in visual acuity (VA) by a mean SD logMAR of 0.008 0.400
Eye(s)
OU
OU OU OU
OU
OS OU
OS
OS
OS
OS
Age/ gender
46/F
57/F 62/F 48/F
63/F
71/M 52/F
48/F
74/F
32/F
72/F
Case
1
2 3 4
5
6 7
8
9
10
11
RA
RA
RA, CD
RA
RA RA
RA, GD
RA, CD Reactive arthritis RA
GD
Autoimmune syndrome(s)
Failed MTX þ CS (1 wk)
Failed MTX þ CS (3 mo)
Adalimumab 40 mg/wk
Failed NSAID þ MTX þ CS (4 mo) None
#1: Adalimumab 40 mg/wk #2: Infliximab 6 mg/kg/7 wk Infliximab 6 mg/kg/4 wk
#1: Infliximab – one dose givena #2: Adalimumab 40 mg/wk
Infliximab 6 mg/kg/6 wk Infliximab 10 mg/kg/4 wk
#1: Infliximab 3 mg/kg/wk #2: Adalimumab 40 mg/2 wk
#1: Adalimumab 40 mg/wk #2: Infliximab 10 mg/kg/7 wk Infliximab 6 mg/kg/5 wk Infliximab 6.5 mg/kg/6 wk Adalimumab 40 mg/wk
TNF-alpha inhibitor, maximum dosing
Failed CS (5 yr) Failed NSAID (2 mo)
Failed NSAID (3 mo) MTX þ CS (18 mo)
None Failed MTX þ CS (7 mo) Failed MTX (5 yr)
None
Systemic therapy for scleritis before TNF-alpha inhibitor (duration of use)
TABLE 1. Patient data and clinical outcomes of TNF-alpha inhibitors for the treatment of scleritis.
Never 20.8 12.3, 21.3
Never 18.4
9.1
5.6 Never
33.8 1.3
Never 60.8 39.4 87.3 16.6
12.6 22.2 56.8
1 inj. 27.0
65.2
5.6 7.0
36.2 1.3
7.1 62.0 40.3 89.5 20.4
MTX MTX NSAID
None None
MTX
None MTX
MTX MTX
MTX MTX MTX MTX MTX
Comments
None used Patient had an allergic None used reaction to a single infusion of infliximab. She developed a transaminitis while receiving adalimumab. None used None used 50 ! 0 After inflammation control for 12.3 months, her infliximab dosing was reduced, resulting in a flare-up over 1.9 months. She was able to regain control of her scleritis for another 42.6 months once the dosing was increased, despite subsequent decreases in infliximab dosing.
20 ! 40 40 ! 5 5!5 5!0 None used Patient developed a transaminitis, which resolved after MTX was discontinued. 10 ! 5 Rheumatologist switched 5!5 patient from infliximab to adalimumab even though patient was responding to infliximab therapy. None used 20 ! 5 Patient discontinued infliximab and MTX together. Switched between multiple therapies and finally controlled scleritis with celecoxib. 10 ! 0
Inflammation Duration of control treatment Concurrent CS sparing (months) (months) therapy (mg)
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OU
OU
OU
76/F
61/F
56/F
15
16
17
RA
RA
RA
RA RA RA
Adalimumab 40 mg/2 wk Adalimumab 40 mg/wk #1: Adalimumab 40 mg/2 wk #2: Infliximab 5 mg/kg/2 wk Infliximab 3 mg/kg/2 wk
None
#1: Infliximab 3 mg/kg/4 wk #2: Infliximab 3 mg/kg/6 wk
Failed etanercept,b NSAID Infliximab 8 mg/kg/6 wk (duration unknown)
Failed MTX þ CS (4 mo) None Failed NSAID (2 mo), MTX þ CS (6 mo) Failed MTX þ CS (2 mo)
2.6 12.6
3.9
3.3 6.3 Never 27.1 1.6
5.6 12.6
18.2
8.3 21.2 3.0 27.5 6.1
None used None used 15 ! 5 5!0 60 ! 0 After inflammation control for 1.6 months, patient had a flare-up and then was lost to follow-up. MTX, HCQ 40 ! 0 After inflammation control for 3.9 months, patient had a flare-up, which subsided after prednisone was started. Prednisone was discontinued due to undesired weight gain, and inflammation recurred. Patient then switched from infliximab to rituximab and regained control of her scleritis for 1.4 months. MTX 20 ! 5 Patient had recurrence of MTX 7.5 ! 5 inflammation after 5.6 months of use and was switched between several other therapies (celecoxib for 3 months, abatacept for 4 months, MTX with prednisone for 4 years). After another flare-up of inflammation, she was re-started on infliximab (5 years after her original course) with inflammation control for 12.6 months.
MTX None MTX MTX MTX
Note. F, female; M, male; OU, both eyes; OS, left eye; OD, right eye; GD, Graves disease; RA, rheumatoid arthritis; CD, Crohn disease; NSAID, nonsteroidal anti-inflammatory drug; MTX, methotrexate; HCQ, hydroxychloroquine; CS, corticosteroid; mo, month; yr, year; wk, week; inj, injection. a Exact dose of infusion is unavailable. b Failed prior treatment with etanercept was not considered as a failure of TNF-alpha inhibitor use in our study, as etanercept was not administered nor was progress monitored at our institution.
OD OD OS
68/M 65/M 41/F
12 13 14
TNF-a Inhibitors and Scleritis 473
474 A. Ragam et al.
FIGURE 1. Patient outcomes from TNF-alpha inhibitor trials. TNFaI = TNF-alpha inhibitor; MTX = methotrexate, CS = corticosteroid, MMF = mycophenolate mofetil.
TABLE 2. Demographics and outcomes of scleritis patients based on type of TNF-alpha inhibitor used.
No. (%) of patients No. of patients of each gender (F, M) No. of patients of each ethnicity (W, B, A, H) Mean duration of TNFaI therapy (range), months No. (%) of patients concurrently on IMT No. (%) of patients concurrently on CS No. of patients on first trial (% achieving inflammation control) No. of patients on second trial (% achieving inflammation control) Total rate of inflammation control (%)a Mean duration to inflammation control in those achieving it (range), monthsa No. (%) of patients who failed inflammation control with this TNFaI No. (%) of patients who switched to another TNFaI (%)
Infliximab
Adalimumab
13 12, 1 6, 3, 0, 4 30.2 (0–89.5)b 11 (85) 10 (77) 10 (70) 3 (100) 77 2.6 (0.5–6.3) 3 (23) 1 (8)
9 7, 2 4, 2, 1, 2 19.8 (3.0–65.2) 8 (89) 4 (44) 7 (57) 2 (100) 67 5.6 (0–14.9)c 3 (33) 3 (33)
F, female; M, male; W, White or Caucasian; B, Black or African-American; A, Asian; H, Hispanic; IMT, immunomodulatory therapy, including NSAIDs, other than TNF-alpha inhibitors; CS, corticosteroids; TNFaI, TNF-alpha inhibitor. a Includes first and second trial. b This calculation includes the patient who had an allergic reaction to infliximab and was considered to have duration of 0 months of infliximab use. c This calculation includes the patient who was switched from infliximab to adalimumab by the rheumatologist despite inflammation control; thus the time to achieve inflammation control is 0 months.
(from Snellen VA 20/44 to 20/43), which was not a statistically significant difference (p = 0.91). Considering only the courses of TNF-alpha inhibitor that resulted in inflammation control, mean SD logMAR VA was 0.391 0.441 (Snellen VA of 20/49) at the initiation of therapy and 0.403 0.469 (Snellen VA of 20/51) at the end of therapy. This was not a statistically significant change (p = 0.89). Due to the chronic, difficult to control nature of inflammation characteristic of our subject population, 15 (88%) patients were treated with other medications in addition to TNF-alpha inhibitors (Table 1). Most patients (n = 11 [65%]) were on a combination
of TNF-alpha inhibitors, IMT, and CS. Four (24%) patients were on TNF-alpha inhibitors and IMT and 2 (12%) were on TNF-alpha inhibitors alone. Eleven patients (65%) were treated with systemic CS therapy, which was initiated either before (n = 9 [82%]) (mean SD of 7.24 6.41 months) or during (n = 2 [18%]) TNF-alpha inhibitor therapy. The overall mean starting dose of CS of 20.8 mg per day (range, 5–60 mg per day) was decreased to a mean dose of 5.3 mg per day (range, 0–40 mg per day) (p = 0.014) over the duration of TNF-alpha inhibitor therapy. Eight patients were receiving greater than 10 mg daily of CS when TNF-alpha inhibitor treatment was Ocular Immunology & Inflammation
TNF-a Inhibitors and Scleritis initiated; 7 (88%) of these patients achieved successful CS sparing by our criteria. Six (55%) patients were able to completely discontinue their CS use. Two patients (4, 9) developed a transient transaminitis after a mean SD 3.4 2.9 months while on a maximum dose of adalimumab at 40 mg per week. In patient 4, the values normalized after discontinuation of concomitant MTX. Patient 9 was lost to followup before repeat blood work could be performed. At last follow-up, 13 (76%) patients were receiving TNF-alpha inhibitors for management of their scleritis, with 12 (92%) under inflammation control. Of the remaining 4 patients, 2 (1, 2) were on MTX alone at last follow-up. Patient 1 discontinued infliximab prior to undergoing bariatric surgery. Patient 2 discontinued infliximab after 40.3 months of use, of which inflammation was controlled for 39.4 months. Although inflammation was controlled at the time of discontinuation, the exact reason for stopping infliximab is unknown. Patient 7, who failed to respond to infliximab and several IMTs (Figure 1), was on celecoxib 200 mg twice a day at last follow-up. Patient 16 was switched to rituximab after a flare-up while on infliximab and MTX and has remained on that regimen. All of these 4 patients had quiet scleritis at last follow-up.
DISCUSSION TNF-alpha is a proinflammatory cytokine associated with pathogenesis of many chronic inflammatory diseases, such as RA, psoriasis and psoriatic arthritis, ankylosing spondylitis, and inflammatory bowel disease.20 The use of TNF-alpha inhibitors in treatment of such conditions has been well established, and in recent years there have even been an increasing number of publications attesting to the benefits of TNF-alpha inhibitors for uveitis.34–39 In contrast, there are few studies supporting the use of TNF-alpha inhibitors for the treatment of scleritis. Doctor et al. showed that of 10 patients treated with infliximab for refractory scleritis between 2003 and 2007, 9 (90%) showed a decrease in inflammation (after a mean duration of 13.2 weeks) and 6 (60%) were able to cease all other forms of immunosuppression.25 Sobrin et al. examined 27 patients seen from 2001 to 2006 with several different forms of ocular inflammation. All 10 (100%) patients with scleritis achieved inflammation control with infliximab infusions and 6 (60%) of them reduced or discontinued their concurrent IMT, including azathioprine, MMF, MTX, and/or CS.26 Smith et al. examined 16 total patients seen between 1999 and 2000, of which only 7 (44%) had scleritis. All 7 scleritis patients also had RA. Of these scleritis patients, 6 (86%) were treated with etanercept and 1 (14%) with infliximab. Although all 7 patients showed articular benefit from TNF-alpha inhibitor use, !
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only 3 (43%) had a measurable improvement of ocular inflammation.28 Finally, Sen et al. executed a prospective study on the effect of infliximab in 5 patients with active anterior scleritis in 2009. All 5 patients (100%) achieved inflammation quiescence, although 1 patient developed new-onset inflammation 14 weeks after therapy initiation and was removed from the study. Three patients (60%) were able to taper concurrent steroid use to less than 10 mg daily.29 Our study included 17 patients (26 affected eyes) with active scleritis started on either infliximab (10 [59%] patients), or adalimumab (7 [41%] patients). Despite the fact that 65% of our patients failed prior IMT, 88% of those with active inflammation ultimately achieved inflammation control while on TNF-alpha inhibitors. Seven (88%) of the 8 patients who began TNF-alpha inhibitor treatment with concurrent CS dosing of greater than 10 mg daily were successfully able to taper dosing to 10 mg daily or less. This CS dose is significant, as the literature has supported the use of adjunctive immunosuppressive therapy in patients relapsing on systemic steroid doses higher than 10 mg daily.11,12 Direct comparison between our study and those previously discussed is difficult due to heterogeneous patient populations, different approaches to treatment, treatment duration, degree of inflammation, etc. Our data were also collected over a longer duration of patient follow-up (2002–2012). However, our results echo the favorable results of inflammation control and CS-sparing in the treatment of scleritis with TNF-alpha inhibitors. Side effect profile is an important component to consider when evaluating the use of an immunosuppressive agent. For 1 of the 2 patients who developed transaminitis while on TNF-alpha inhibitor therapy, we were able to attribute this abnormal laboratory finding to concurrent MTX use. Unfortunately, the second patient was lost to follow-up before we could determine the final outcome of his abnormal lab results. One (5%) patient developed an allergic reaction, which was to infliximab after one infusion. In the study by Smith et al., 1 of 2 patients on infliximab reported GI disturbances but not severe enough to discontinue use.28 The study by Doctor et al. reported 1 (10%) patient with drug-induced systemic lupus erythematosus (SLE) while on infliximab.25 Sobrin et al. likewise reported 1 (4%) patient with drug-induced SLE on infliximab use, which was severe enough to warrant discontinuation.26 Sen et al. reported adverse reactions in 2 (40%) of their patients, which included ear infection, respiratory tract infections, urinary tract infections, gastrointestinal discomfort, mouth sores, and extremity numbness and tingling.29 While the side effects from our small cohort of patients were mild, findings from other studies support the notion that one must be cautious
476 A. Ragam et al. when prescribing TNF-alpha inhibitors due to their potential, serious adverse reactions. The results of this study must be interpreted with caution. Limitations include (1) its retrospective nature, meaning that all information obtained during analysis was not applied to the patients as they were being treated; (2) heterogeneous patient population in type of associated systemic autoimmune conditions and concurrent ocular inflammatory conditions; (3) small sample size, thereby making statistical analysis less effective; (4) lack of a control group to compare the effects of TNF-alpha inhibitors to those of other agents; and (5) large proportion of patients on concurrent immunosuppressive agents during TNF-alpha inhibitor use, making it difficult to parse out the true ability of TNF-alpha inhibitors as standalone agents to reduce and stabilize inflammation. All of our patients had systemic autoimmune or inflammatory conditions; consequently, this study may represent a select population of patients who respond to TNF-alpha inhibitor therapy in a specific way. The small number of patients on each TNF-alpha inhibitor limits us from drawing meaningful comparative conclusions between these agents; also, as patients receiving more than one type of TNF-alpha inhibitor had their results attributed to each agent, direct comparisons are difficult to ascertain (Table 2). Lastly, our study may be affected by selection bias since our institution is a tertiary referral center and some of these patients may have already been worked up, diagnosed, and treated by other ophthalmologists using more conventional means. In our opinion, future studies directed at eliminating many of the above-mentioned limitations and seeking to answer some of the questions raise above are warranted. At the conclusion of our study, we found that TNF-alpha inhibitors have a significant role in treating scleritis, and they may be considered as second-line agents for disease refractory to NSAIDs, CS, or other IMT. TNF-alpha inhibitors may also be considered in patients who develop side effects to the aforementioned agents. Agents in this class, with their respectable inflammation control and steroid-sparing capabilities, are excellent immunosuppressive agents. As is the recent trend in the rheumatologic literature,40,41 it may be worth considering TNF-alpha inhibitors as first-line treatment of noninfectious, nonnecrotizing scleritis in select situations. Prospective controlled studies are needed to confirm and expand on our current findings.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
REFERENCES 1. Albini TA, Rao NA, Smith RE. The diagnosis and management of anterior scleritis. Int Ophthalmol Clin. 2005;45:191–204. 2. McCluskey PJ, Watson PG, Lightman S, et al. Posterior scleritis: clinical features, systemic associations, and outcome in a large series of patients. Ophthalmology. 1999;106: 2380–2386. 3. Jabs DA, Mudun A, Dunn JP, Marsh MJ. Episcleritis and scleritis: clinical features and treatment results. Am J Ophthalmol. 2000;130:469–476. 4. Sainz de la Maza M, Foster CS, Jabbur NS. Scleritis associated with rheumatoid arthritis and with other systemic immune-mediated diseases. Ophthalmology. 1994;101: 1281–1288. 5. Kim SJ, Flach AJ, Jampol LM. Nonsteroidal anti-inflammatory drugs in ophthalmology. Surv Ophthalmol. 2010;55: 108–133. 6. Hakin KN, Ham J, Lightman SL. Use of cyclosporin in the management of steroid dependent non-necrotising scleritis. Br J Ophthalmol. 1991;75:340–341. 7. Reed MD, Chu DS. Immunomodulatory therapy for anterior segment ocular inflammation. Curr Opin Allergy Clin Immunol. 2002;2:429–433. 8. Lustig MJ, Cunningham ET. Use of immunosuppressive agents in uveitis. Curr Opin Ophthalmol. 2003;14:399–412. 9. Gaudio PA. A review of evidence guiding the use of corticosteroids in the treatment of intraocular inflammation. Ocul Immunol Inflamm. 2004;12:169–192. 10. Jabs DA, Rosenbaum JT, Foster CS, et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel. Am J Ophthalmol. 2000;130:492–513. 11. Okhravi N, Odufuwa B, McCluskey P, Lightman S. Scleritis. Surv Ophthalmol. 2005;50:351–363. 12. Jabs DA, Rosenbaum JT, Foster CS, et al. Guidelines for use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations from an expert panel. Am J Ophthalmol. 2000;130:492–513. 13. Wakefield D, McCluskey P. Cyclosporin therapy for severe scleritis. Br J Ophthalmol. 1989;73:743–746. 14. Larkin G, Lightman S. Mycophenolate mofetil. A useful immunosuppressive in inflammatory eye disease. Ophthalmology. 1999;106:370–374. 15. Sen HN, Suhler EB, Al-Khatib SQ, et al. Mycophenolate mofetil for the treatment of scleritis. Ophthalmology. 2003; 110:1750–1755. 16. Kolomeyer AM, Ragam A, Shah K, et al. Mycophenolate mofetil in the treatment of non-infectious, non-necrotizing scleritis. Ocul Immunol Inflamm. 2012;20:113–118. 17. Shah SS, Lowder CY, Schmitt MA, et al. Low-dose methotrexate therapy for ocular inflammatory disease. Ophthalmology. 1992;99:1419–1423. 18. Jachens AW, Chu DS. Retrospective review of methotrexate therapy in the treatment of chronic, non-infectious, nonnecrotizing scleritis. Am J Ophthalmol. 2008;145:487–492. 19. Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Annu Rev Immunol. 1996;14:397–440. 20. Onrust SV, Lamb HM. Infliximab: a review of its use in Crohn’s disease and rheumatoid arthritis. BioDrugs. 1998; 10:397–422. 21. Valesini G, Iannuccelli C, Marocchi E, et al. Biological and clinical effects of anti-TNFalpha treatment. Autoimmun Rev. 2007;7:35–41. 22. Mease P. Infliximab (Remicade) in the treatment of psoriatic arthritis. Ther Clin Risk Manag. 2006;2:389–400. 23. Goel N, Stephens S. Certolizumab pegol. MAbs. 2010;2: 137–147. Ocular Immunology & Inflammation
TNF-a Inhibitors and Scleritis 24. Kavanaugh A, McInnes I, Mease P, et al. Golimumab, a new human tumor necrosis alpha antibody, administered every four weeks as a subcutaneous injection in psoriatic arthritis: twenty-four-week efficacy and safety results of a randomized, placebo-controlled study. Arthritis Rheum. 2009;60:976–986. 25. Doctor P, Sultan A, Syed S, et al. Infliximab for the treatment of refractory scleritis. Br J Ophthalmol. 2010;94: 578–583. 26. Sobrin L, Kim EC, Christen W, et al. Infliximab therapy for the treatment of refractory ocular inflammatory disease. Arch Ophthalmol. 2007;125:895–900. 27. Murphy CC, Ayliffe WH, Booth A, et al. Tumor necrosis factor alpha blockade with infliximab for refractory scleritis. Ophthalmology. 2004;111:352–356. 28. Smith JR, Levinson RD, Holland GN, et al. Differential efficacy of tumor necrosis factor inhibition in the management of inflammatory eye disease and associated rheumatic disease. Arthritis Rheum. 2001;45:252–257. 29. Sen HN, Sangave A, Hammel K, et al. Infliximab for the treatment of active scleritis. Can J Ophthalmol. 2009;44: e9–e12. 30. Restrepo JP, Molina MP. Successful treatment of severe nodular scleritis with adalimumab. Clin Rheumatol. 2010; 29:559–561. 31. Bawazeer AM, Raffa LH. Adalimumab in the treatment of recurrent idiopathic bilateral nodular scleritis. Oman J Ophthalmol. 2011;4:139–141. 32. Sen HN, Sangaave AA, Goldstein DA, et al. A standardized grading system for scleritis. Ophthalmology. 2011;118: 768–771. 33. Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of Uveitis Nomenclature (SUN) Working Group.
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Standardization of uveitis nomenclature for reporting clinical data: results of the first international workshop. Am J Ophthalmol. 2005;140:509–516. Capella MJ, Foster CS. Long-term efficacy and safety of infliximab in the treatment of Behc¸et’s disease. Ocul Immunol Inflamm. 2012;20:198–202. Zannin ME, Birolo C, Gerloni VM, et al. Safety and efficacy of infliximab and adalimumab for refractory uveitis in juvenile idiopathic arthritis: 1-year follow-up data from the Italian registry. J Rheumatol. 2013;40:74–79. Matsuda J, Kaburaki T, Kobayashi S, Numaga J. Treatment of recurrent anterior uveitis with infliximab in patient with ankylosing spondlylitis. Jpn J Ophthalmol. 2013;57:104–107. Okada AA, Goto H, Ohno S, Mochizuki M. Multicenter study of infliximab for refractory uveoretinitis in Behc¸et disease. Arch Ophthalmol. 2012;130:592–598. Sugita S, Kawazoe Y, Imai A, et al. Inhibition of Th17 differentiation by anti-TNF-alpha therapy in uveitis patients with Behc¸et’s disease. Arthritis Res Ther. 2012;14: R99. Martel JN, Esterberg E, Nagpal A, Acharya NR. Infliximab and adalimumab for uveitis. Ocul Immunol Inflamm. 2012; 20:18–26. Barrera P, van der Maas A, van Ede AE, et al. Drug survival, efficacy, and toxicity of monotherapy with a fully human anti-tumour necrosis factor-alpha antibody compared with methotrexate in long-standing rheumatoid arthritis. Rheumatology. 2002;41:430–439. Peyrin-Biroulet L, Fiorino G, Buisson A, Danese S. First-line therapy in adult Crohn’s disease: who should receive anti-TNF agents? Nat Rev Gastroenterol Hepatol. doi:10.1038/nrgastro.2013.31. 2013-03-05.
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ORIGINAL ARTICLE
Treatment of Chronic, Noninfectious, Nonnecrotizing Scleritis with Tumor Necrosis Factor Alpha Inhibitors Ashwinee Ragam, BS1, Anton M. Kolomeyer, MD, PhD1, Christina Fang, Yinfei Xu, MD1, and David S. Chu, MD1,2 1
1
BS
,
Institute of Ophthalmology and Visual Science, Rutgers New Jersey Medical School, Newark, New Jersey, USA, and 2Metropolitan Eye Research and Surgery Institute, Palisades Park, New Jersey, USA
ABSTRACT Purpose: To evaluate the use of TNF-alpha inhibitors for non-infectious, non-necrotizing scleritis. Methods: We conducted a retrospective chart review of patients with non-infectious, non-necrotizing scleritis treated at our institutions from 2002 to 2012. Results: Seventeen patients (26 eyes) were included. Ten patients were started on infliximab and seven on adalimumab; five patients were treated with both TNF-alpha inhibitors on separate occasions. All patients had an associated autoimmune disease. Control of active inflammation for at least 2 months was achieved in 15 (88%) of 17 patients. Seven out of eight patients successfully tapered concurrent corticosteroid use. Only one patient discontinued TNF-alpha inhibitor use due to an allergic reaction. Conclusions: TNF-alpha inhibitors appear to have a role in managing non-infectious, non-necrotizing scleritis refractory to initial therapy, mainly by reducing inflammation and decreasing concurrent CS use. Keywords: Inflammation, noninfectious scleritis, TNF-alpha inhibitors
Noninfectious scleritis is characterized by severe scleral redness, deep periocular pain, pinpoint tenderness, irritation, and photophobia, all of which may be so severe as to interfere with activities of daily living.1 Most cases of scleritis are either idiopathic or associated with systemic inflammatory diseases, such as rheumatoid arthritis (RA), granulomatosis, and polyangitis (Wegener granulomatosis), systemic vasculitis, and relapsing polychondritis, which have been reported to occur in up to 39–50% of patients.2–4 Scleritis necessitates prompt and appropriate treatment as complications of keratitis, uveitis, glaucoma, cataract, and exudative retinal or choroidal detachments can arise.3,4 Nonnecrotizing, noninfectious scleritis often responds to systemic nonsteroidal anti-inflammatory drugs (NSAIDs), which are typically first-line agents of treatment.3 Some of the most common side effects
of systemic NSAID use include GI toxicity (nausea, anorexia, vomiting, dyspepsia) and CNS effects (headache, dizziness, fatigue).5 Corticosteroids (CS), due to their rapid onset and potent anti-inflammatory effects, are also commonly used, especially in those patients refractory to NSAIDs. However, some cases of scleritis are refractory even to high-dose CS. Additionally, there is a dose-dependent risk of adverse effects from long-term CS use. Local adverse effects include development or worsening of cataract and glaucoma. Systemic side effects may include Cushingoid changes, osteoporosis, infection, poor wound healing, insulin-dependent diabetes mellitus, myopathy, and psychosis.6 In approximately 26% of patients with scleritis, additional immunosuppression is required in order to taper the CS dose to less than or equal to 10 mg per day. This dose has been shown to provide the
Received 18 August 2013; revised 27 September 2013; accepted 5 November 2013; published online 18 December 2013 Correspondence: David S. Chu, MD, Metropolitan Eye Research and Surgery Institute, 540 Bergen Blvd, Suite D, Palisades Park, NJ 07650, USA. E-mail: [email protected]
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470 A. Ragam et al. largest benefit-to-harm ratio.7–12 Several studies have reported success in treating scleritis with immunosuppressive agents such as cyclosporine (CsA),6,13 mycophenolate mofetil (MMF),14–16 and methotrexate (MTX).17,18 Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine whose level is elevated in various autoimmune conditions.19 Agents that selectively inhibit the actions of TNF-alpha have arisen as alternative immunosuppressive therapies, proving efficacious in the treatment of systemic autoimmune conditions such as Crohn disease, RA, and psoriatic arthritis.20–22 The three most widely available TNF-alpha blocking agents are (1) infliximab, a chimeric human–murine monoclonal antibody against TNF-alpha; (2) adalimumab, a fully human monoclonal antibody against TNF-alpha; and (3) etanercept, a fusion protein of the extracellular ligand-binding portion of human TNF receptor p75 and the fragment crystallizable (Fc) region of IgG1, effectively functioning as a decoy receptor for TNF-alpha.21 Other TNF-alpha inhibitors include certolizumab pegol, a PEGylated humanized antigen-binding fragment (Fab’) of the monoclonal antibody against TNF-alpha,23 and golimumab, another human monoclonal antibody against TNFalpha.24 TNF-alpha inhibitors have been used for several years in managing different forms of ocular inflammation. Studies focusing on the efficacy of TNF-alpha inhibitors for the treatment of scleritis have, for the most part, been limited to small case series24–28 and/or focused only on infliximab.25–27,29 Very few have discussed the use of adalimumab30,31 in such regard. This report is of a larger case series of patients with noninfectious scleritis treated by two TNF-alpha inhibitor agents: infliximab and/or adalimumab. The goal of the study was to determine whether TNF-alpha inhibitors may be efficacious in treating noninfectious scleritis refractory to other therapies.
MATERIALS AND METHODS This study was approved by the Rutgers Biomedical and Health Sciences institutional review board. A list of patients seen at our institutions between 2002 and 2012 with diagnoses of scleritis was created by searching our billing database using International Classification of Diseases 9 codes 379.00-09. Two hundred ninety-five charts were reviewed and only patients treated with TNF-alpha inhibitors for greater than or equal to 2 months were eligible. At the time of initiating TNF-alpha inhibitor therapy, patients must have had active inflammation. Seventeen patients fit the criteria to be included. All patients were treated with at least one course
of a TNF-alpha inhibitor. A database was created listing gender, age at onset of TNF-alpha inhibitor therapy, affected eye(s), associated systemic autoimmune condition(s), date first seen for scleritis, and prior systemic medications for the treatment of scleritis. The specific TNF-alpha inhibitor(s), maximum dosing, and duration of use were recorded for each patient. Initial dosing and schedule for infliximab and adalimumab were determined by the rheumatologist managing each patient’s associated autoimmune condition, based on the specific condition, symptom severity, and clinical parameters. Appropriate dosing adjustments throughout the duration of treatment were made based on response to therapy and discussion between the ophthalmologist (DSC) and rheumatologist. Infliximab was delivered as intravenous infusions dosed in mg/kg at various weekly frequencies, while adalimumab was administered subcutaneously with prefilled syringes of 40 mg weekly or biweekly. Other measures documented included inflammation grade, visual acuity, and dosing of CS and/or other immunomodulatory therapy (IMT), including NSAIDs, used throughout the duration of TNF-alpha inhibitor treatment. We often initiate IMT with infliximab as per manufacturer recommendations to prevent anti-chimeric antibodies from forming; therefore, the concurrent use of IMT is not necessarily to assist in treating inflammation. Adverse effects and abnormal labs while receiving TNF-alpha inhibitors were also recorded. Snellen visual acuity was converted into logMAR, and is reported as such in the paper. Inflammation grade ranged from 0 to 4, as outlined in the grading scheme proposed by Sen et al.,32 and was determined by a single physician (DSC) at every visit. Trace inflammation was recorded as a grading of 0.5. Inflammation quiescence was defined as inflammation grading of 0 on slit-lamp examination and lack of symptomatic complaints such as photophobia, pruritus, and ocular irritation. Inflammation control was defined as inflammation quiescence for at least 2 months duration. Successful CS sparing was defined as a final CS dosage of 10 mg per day or less in patients that were taking greater than 10 mg per day at the time of TNF-alpha inhibitor initiation, as outlined by the Standardization of Uveitis Nomenclature criteria.33 Paired t-tests were used to compare changes in inflammation grading and visual acuity before and after treatment with TNF-alpha inhibitors. Unpaired t-tests were used to compare outcomes between patients receiving infliximab and those receiving adalimumab. These tests were performed using JMP version 9 statistical software (SAS, Cary, NC) and statistical significance was accepted at p50.05. Ocular Immunology & Inflammation
TNF-a Inhibitors and Scleritis
RESULTS Seventeen patients (26 eyes) were included in the study. There were 14 (82%) females and 3 (18%) males. Eight (47%) patients were Caucasian, 4 (24%) patients were Hispanic, 4 (24%) patients were African-American, and 1 (6%) patient was Asian. Mean standard deviation (SD) age at start of treatment with TNF-alpha inhibitors was 58.8 12.6 years (range, 32–76 years). The mean SD duration of follow-up for scleritis at our institutions before starting the first trial of TNF-alpha inhibitor therapy was 12.8 19.8 months (range, 0–64.4 months). The mean SD duration of TNF-alpha inhibitor therapy was 25.8 23.5 months (range, 3.0–89.5 months). This excluded patient 11’s trial of infliximab, which consisted of a single infusion and subsequent development of an allergic reaction (Table 1). All 17 patients were found to have an associated autoimmune disease (Table 1). Eleven (65%) patients failed previous IMT, with 8 (47%) failing combination regimens. For these patients, the previous IMT was either ineffective at controlling inflammation or resulted in the development of unremitting side effects, most commonly seen with MTX. Four (36%) of these 11 patients were unable to control inflammation with NSAIDs, which are considered first-line therapy. One (6%) patient was on etanercept prior to being seen at our institution; however, dose, duration of treatment, and response to the therapy are unknown. Once seen at our institution, the patient was started on infliximab instead. Ten (59%) patients were started on infliximab and 7 (41%) patients were started on adalimumab. Five (29%) patients ended up switching from one TNF-alpha inhibitor to another because of treatment ineffectiveness (n = 3 [67%]), side effect (n = 1 [17%]), and decision by rheumatologist (n = 1 [17%]). The maximum dosing of TNF-alpha inhibitor therapy that each patient received is listed in Table 1. Figure 1 illustrates the outcomes of TNF-alpha inhibitor use in our 17 patients. Twelve patients (71%) achieved inflammation control of active scleritis after a mean SD of 5.0 3.9 months (range, 0.9– 14.9 months). Of these 12 patients, 7 (58%) showed no further recurrence of inflammation throughout the duration of use with the same TNF-alpha inhibitor (mean SD of 33.8 33.9 months). Patient 5 achieved inflammation control after 2.4 months of infliximab use and maintained quiescent scleritis for 33.8 months. She was then switched to adalimumab by the rheumatologist and continued to maintain control of inflammation for the remaining 1.3 months of follow-up. Three patients (11, 16, 17) achieving initial control of their active scleritis experienced recurrences of inflammation while on infliximab (Table 1). Six patients (1, 7, 9, 10, 14, 15) did not achieve inflammation control on their first course of !
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TNF-alpha inhibitor. Three patients (1, 10, 14) failed adalimumab after a mean SD 7.6 4.8 months (range, 3.0–12.6 months) and were switched to infliximab, achieving inflammation control after a mean SD of 1.0 0.5 months (range, 0.5–1.4 months). Patient 7 failed to respond to infliximab after 7.0 months of use, switched to other IMTs (MMF, rofecoxib, valdecoxib, cyclophosphamide, cyclosporine, and rituximab), and finally achieved and maintained inflammation control on celecoxib for 31.5 months. Patient 9 had an allergic reaction to a single infusion of infliximab, was switched to adalimumab, achieved inflammation control after 1.1 months, and maintained quiescence for 25.9 months without adverse effects. Patient 15 achieved inflammation quiescence for 1.6 months after 4.5 months of infliximab therapy, but was subsequently lost to follow-up. As the criteria set in this study required at least 2 months of inflammation quiescence, this patient was not considered to have successfully achieved inflammation control. The mean SD initial inflammation grade of scleritis at the start of TNF-alpha inhibitor therapy was 1.53 0.68 (range, 0.5–3; median, 1.0). This was significantly (p50.001) reduced to a mean SD final inflammation grade of 0.63 1.0 (range, 0–3; median, 0). These data exclude patient 6’s trial of adalimumab as she was switched from infliximab by her rheumatologist despite inflammation control; therefore, her initial and final inflammation grade for her course of adalimumab are 0. Control of active scleritis with TNF-alpha inhibitors was ultimately achieved in 15 (88%) of the 17 patients, including those patients requiring two trials of TNF-alpha inhibitor therapy. Table 2 compares the demographics and outcomes of scleritis patients in our study based on the type of TNF-alpha inhibitor they were treated with. The overall likelihood of achieving inflammation control on infliximab and adalimumab was 10/13 (77%) and 6/9 (66%), respectively. These results included both the initial failed course and subsequent successful course for patients who switched from adalimumab to infliximab. Patients who achieved quiescence of active inflammation for at least 2 months, despite subsequent flare-ups, were counted as successes in these data. Patient 5, who was controlled on infliximab but switched to adalimumab by the rheumatologist, was counted as a success for both TNF-alpha inhibitors. There was no significant difference between the rates of inflammation control with infliximab or adalimumab use (p = 0.63). There was also no significant difference in the duration of treatment (p = 0.30) or the time until inflammation control was achieved (p = 0.24) between infliximab and adalimumab therapies. There was an overall change in visual acuity (VA) by a mean SD logMAR of 0.008 0.400
Eye(s)
OU
OU OU OU
OU
OS OU
OS
OS
OS
OS
Age/ gender
46/F
57/F 62/F 48/F
63/F
71/M 52/F
48/F
74/F
32/F
72/F
Case
1
2 3 4
5
6 7
8
9
10
11
RA
RA
RA, CD
RA
RA RA
RA, GD
RA, CD Reactive arthritis RA
GD
Autoimmune syndrome(s)
Failed MTX þ CS (1 wk)
Failed MTX þ CS (3 mo)
Adalimumab 40 mg/wk
Failed NSAID þ MTX þ CS (4 mo) None
#1: Adalimumab 40 mg/wk #2: Infliximab 6 mg/kg/7 wk Infliximab 6 mg/kg/4 wk
#1: Infliximab – one dose givena #2: Adalimumab 40 mg/wk
Infliximab 6 mg/kg/6 wk Infliximab 10 mg/kg/4 wk
#1: Infliximab 3 mg/kg/wk #2: Adalimumab 40 mg/2 wk
#1: Adalimumab 40 mg/wk #2: Infliximab 10 mg/kg/7 wk Infliximab 6 mg/kg/5 wk Infliximab 6.5 mg/kg/6 wk Adalimumab 40 mg/wk
TNF-alpha inhibitor, maximum dosing
Failed CS (5 yr) Failed NSAID (2 mo)
Failed NSAID (3 mo) MTX þ CS (18 mo)
None Failed MTX þ CS (7 mo) Failed MTX (5 yr)
None
Systemic therapy for scleritis before TNF-alpha inhibitor (duration of use)
TABLE 1. Patient data and clinical outcomes of TNF-alpha inhibitors for the treatment of scleritis.
Never 20.8 12.3, 21.3
Never 18.4
9.1
5.6 Never
33.8 1.3
Never 60.8 39.4 87.3 16.6
12.6 22.2 56.8
1 inj. 27.0
65.2
5.6 7.0
36.2 1.3
7.1 62.0 40.3 89.5 20.4
MTX MTX NSAID
None None
MTX
None MTX
MTX MTX
MTX MTX MTX MTX MTX
Comments
None used Patient had an allergic None used reaction to a single infusion of infliximab. She developed a transaminitis while receiving adalimumab. None used None used 50 ! 0 After inflammation control for 12.3 months, her infliximab dosing was reduced, resulting in a flare-up over 1.9 months. She was able to regain control of her scleritis for another 42.6 months once the dosing was increased, despite subsequent decreases in infliximab dosing.
20 ! 40 40 ! 5 5!5 5!0 None used Patient developed a transaminitis, which resolved after MTX was discontinued. 10 ! 5 Rheumatologist switched 5!5 patient from infliximab to adalimumab even though patient was responding to infliximab therapy. None used 20 ! 5 Patient discontinued infliximab and MTX together. Switched between multiple therapies and finally controlled scleritis with celecoxib. 10 ! 0
Inflammation Duration of control treatment Concurrent CS sparing (months) (months) therapy (mg)
472 A. Ragam et al.
Ocular Immunology & Inflammation
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OU
OU
OU
76/F
61/F
56/F
15
16
17
RA
RA
RA
RA RA RA
Adalimumab 40 mg/2 wk Adalimumab 40 mg/wk #1: Adalimumab 40 mg/2 wk #2: Infliximab 5 mg/kg/2 wk Infliximab 3 mg/kg/2 wk
None
#1: Infliximab 3 mg/kg/4 wk #2: Infliximab 3 mg/kg/6 wk
Failed etanercept,b NSAID Infliximab 8 mg/kg/6 wk (duration unknown)
Failed MTX þ CS (4 mo) None Failed NSAID (2 mo), MTX þ CS (6 mo) Failed MTX þ CS (2 mo)
2.6 12.6
3.9
3.3 6.3 Never 27.1 1.6
5.6 12.6
18.2
8.3 21.2 3.0 27.5 6.1
None used None used 15 ! 5 5!0 60 ! 0 After inflammation control for 1.6 months, patient had a flare-up and then was lost to follow-up. MTX, HCQ 40 ! 0 After inflammation control for 3.9 months, patient had a flare-up, which subsided after prednisone was started. Prednisone was discontinued due to undesired weight gain, and inflammation recurred. Patient then switched from infliximab to rituximab and regained control of her scleritis for 1.4 months. MTX 20 ! 5 Patient had recurrence of MTX 7.5 ! 5 inflammation after 5.6 months of use and was switched between several other therapies (celecoxib for 3 months, abatacept for 4 months, MTX with prednisone for 4 years). After another flare-up of inflammation, she was re-started on infliximab (5 years after her original course) with inflammation control for 12.6 months.
MTX None MTX MTX MTX
Note. F, female; M, male; OU, both eyes; OS, left eye; OD, right eye; GD, Graves disease; RA, rheumatoid arthritis; CD, Crohn disease; NSAID, nonsteroidal anti-inflammatory drug; MTX, methotrexate; HCQ, hydroxychloroquine; CS, corticosteroid; mo, month; yr, year; wk, week; inj, injection. a Exact dose of infusion is unavailable. b Failed prior treatment with etanercept was not considered as a failure of TNF-alpha inhibitor use in our study, as etanercept was not administered nor was progress monitored at our institution.
OD OD OS
68/M 65/M 41/F
12 13 14
TNF-a Inhibitors and Scleritis 473
474 A. Ragam et al.
FIGURE 1. Patient outcomes from TNF-alpha inhibitor trials. TNFaI = TNF-alpha inhibitor; MTX = methotrexate, CS = corticosteroid, MMF = mycophenolate mofetil.
TABLE 2. Demographics and outcomes of scleritis patients based on type of TNF-alpha inhibitor used.
No. (%) of patients No. of patients of each gender (F, M) No. of patients of each ethnicity (W, B, A, H) Mean duration of TNFaI therapy (range), months No. (%) of patients concurrently on IMT No. (%) of patients concurrently on CS No. of patients on first trial (% achieving inflammation control) No. of patients on second trial (% achieving inflammation control) Total rate of inflammation control (%)a Mean duration to inflammation control in those achieving it (range), monthsa No. (%) of patients who failed inflammation control with this TNFaI No. (%) of patients who switched to another TNFaI (%)
Infliximab
Adalimumab
13 12, 1 6, 3, 0, 4 30.2 (0–89.5)b 11 (85) 10 (77) 10 (70) 3 (100) 77 2.6 (0.5–6.3) 3 (23) 1 (8)
9 7, 2 4, 2, 1, 2 19.8 (3.0–65.2) 8 (89) 4 (44) 7 (57) 2 (100) 67 5.6 (0–14.9)c 3 (33) 3 (33)
F, female; M, male; W, White or Caucasian; B, Black or African-American; A, Asian; H, Hispanic; IMT, immunomodulatory therapy, including NSAIDs, other than TNF-alpha inhibitors; CS, corticosteroids; TNFaI, TNF-alpha inhibitor. a Includes first and second trial. b This calculation includes the patient who had an allergic reaction to infliximab and was considered to have duration of 0 months of infliximab use. c This calculation includes the patient who was switched from infliximab to adalimumab by the rheumatologist despite inflammation control; thus the time to achieve inflammation control is 0 months.
(from Snellen VA 20/44 to 20/43), which was not a statistically significant difference (p = 0.91). Considering only the courses of TNF-alpha inhibitor that resulted in inflammation control, mean SD logMAR VA was 0.391 0.441 (Snellen VA of 20/49) at the initiation of therapy and 0.403 0.469 (Snellen VA of 20/51) at the end of therapy. This was not a statistically significant change (p = 0.89). Due to the chronic, difficult to control nature of inflammation characteristic of our subject population, 15 (88%) patients were treated with other medications in addition to TNF-alpha inhibitors (Table 1). Most patients (n = 11 [65%]) were on a combination
of TNF-alpha inhibitors, IMT, and CS. Four (24%) patients were on TNF-alpha inhibitors and IMT and 2 (12%) were on TNF-alpha inhibitors alone. Eleven patients (65%) were treated with systemic CS therapy, which was initiated either before (n = 9 [82%]) (mean SD of 7.24 6.41 months) or during (n = 2 [18%]) TNF-alpha inhibitor therapy. The overall mean starting dose of CS of 20.8 mg per day (range, 5–60 mg per day) was decreased to a mean dose of 5.3 mg per day (range, 0–40 mg per day) (p = 0.014) over the duration of TNF-alpha inhibitor therapy. Eight patients were receiving greater than 10 mg daily of CS when TNF-alpha inhibitor treatment was Ocular Immunology & Inflammation
TNF-a Inhibitors and Scleritis initiated; 7 (88%) of these patients achieved successful CS sparing by our criteria. Six (55%) patients were able to completely discontinue their CS use. Two patients (4, 9) developed a transient transaminitis after a mean SD 3.4 2.9 months while on a maximum dose of adalimumab at 40 mg per week. In patient 4, the values normalized after discontinuation of concomitant MTX. Patient 9 was lost to followup before repeat blood work could be performed. At last follow-up, 13 (76%) patients were receiving TNF-alpha inhibitors for management of their scleritis, with 12 (92%) under inflammation control. Of the remaining 4 patients, 2 (1, 2) were on MTX alone at last follow-up. Patient 1 discontinued infliximab prior to undergoing bariatric surgery. Patient 2 discontinued infliximab after 40.3 months of use, of which inflammation was controlled for 39.4 months. Although inflammation was controlled at the time of discontinuation, the exact reason for stopping infliximab is unknown. Patient 7, who failed to respond to infliximab and several IMTs (Figure 1), was on celecoxib 200 mg twice a day at last follow-up. Patient 16 was switched to rituximab after a flare-up while on infliximab and MTX and has remained on that regimen. All of these 4 patients had quiet scleritis at last follow-up.
DISCUSSION TNF-alpha is a proinflammatory cytokine associated with pathogenesis of many chronic inflammatory diseases, such as RA, psoriasis and psoriatic arthritis, ankylosing spondylitis, and inflammatory bowel disease.20 The use of TNF-alpha inhibitors in treatment of such conditions has been well established, and in recent years there have even been an increasing number of publications attesting to the benefits of TNF-alpha inhibitors for uveitis.34–39 In contrast, there are few studies supporting the use of TNF-alpha inhibitors for the treatment of scleritis. Doctor et al. showed that of 10 patients treated with infliximab for refractory scleritis between 2003 and 2007, 9 (90%) showed a decrease in inflammation (after a mean duration of 13.2 weeks) and 6 (60%) were able to cease all other forms of immunosuppression.25 Sobrin et al. examined 27 patients seen from 2001 to 2006 with several different forms of ocular inflammation. All 10 (100%) patients with scleritis achieved inflammation control with infliximab infusions and 6 (60%) of them reduced or discontinued their concurrent IMT, including azathioprine, MMF, MTX, and/or CS.26 Smith et al. examined 16 total patients seen between 1999 and 2000, of which only 7 (44%) had scleritis. All 7 scleritis patients also had RA. Of these scleritis patients, 6 (86%) were treated with etanercept and 1 (14%) with infliximab. Although all 7 patients showed articular benefit from TNF-alpha inhibitor use, !
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only 3 (43%) had a measurable improvement of ocular inflammation.28 Finally, Sen et al. executed a prospective study on the effect of infliximab in 5 patients with active anterior scleritis in 2009. All 5 patients (100%) achieved inflammation quiescence, although 1 patient developed new-onset inflammation 14 weeks after therapy initiation and was removed from the study. Three patients (60%) were able to taper concurrent steroid use to less than 10 mg daily.29 Our study included 17 patients (26 affected eyes) with active scleritis started on either infliximab (10 [59%] patients), or adalimumab (7 [41%] patients). Despite the fact that 65% of our patients failed prior IMT, 88% of those with active inflammation ultimately achieved inflammation control while on TNF-alpha inhibitors. Seven (88%) of the 8 patients who began TNF-alpha inhibitor treatment with concurrent CS dosing of greater than 10 mg daily were successfully able to taper dosing to 10 mg daily or less. This CS dose is significant, as the literature has supported the use of adjunctive immunosuppressive therapy in patients relapsing on systemic steroid doses higher than 10 mg daily.11,12 Direct comparison between our study and those previously discussed is difficult due to heterogeneous patient populations, different approaches to treatment, treatment duration, degree of inflammation, etc. Our data were also collected over a longer duration of patient follow-up (2002–2012). However, our results echo the favorable results of inflammation control and CS-sparing in the treatment of scleritis with TNF-alpha inhibitors. Side effect profile is an important component to consider when evaluating the use of an immunosuppressive agent. For 1 of the 2 patients who developed transaminitis while on TNF-alpha inhibitor therapy, we were able to attribute this abnormal laboratory finding to concurrent MTX use. Unfortunately, the second patient was lost to follow-up before we could determine the final outcome of his abnormal lab results. One (5%) patient developed an allergic reaction, which was to infliximab after one infusion. In the study by Smith et al., 1 of 2 patients on infliximab reported GI disturbances but not severe enough to discontinue use.28 The study by Doctor et al. reported 1 (10%) patient with drug-induced systemic lupus erythematosus (SLE) while on infliximab.25 Sobrin et al. likewise reported 1 (4%) patient with drug-induced SLE on infliximab use, which was severe enough to warrant discontinuation.26 Sen et al. reported adverse reactions in 2 (40%) of their patients, which included ear infection, respiratory tract infections, urinary tract infections, gastrointestinal discomfort, mouth sores, and extremity numbness and tingling.29 While the side effects from our small cohort of patients were mild, findings from other studies support the notion that one must be cautious
476 A. Ragam et al. when prescribing TNF-alpha inhibitors due to their potential, serious adverse reactions. The results of this study must be interpreted with caution. Limitations include (1) its retrospective nature, meaning that all information obtained during analysis was not applied to the patients as they were being treated; (2) heterogeneous patient population in type of associated systemic autoimmune conditions and concurrent ocular inflammatory conditions; (3) small sample size, thereby making statistical analysis less effective; (4) lack of a control group to compare the effects of TNF-alpha inhibitors to those of other agents; and (5) large proportion of patients on concurrent immunosuppressive agents during TNF-alpha inhibitor use, making it difficult to parse out the true ability of TNF-alpha inhibitors as standalone agents to reduce and stabilize inflammation. All of our patients had systemic autoimmune or inflammatory conditions; consequently, this study may represent a select population of patients who respond to TNF-alpha inhibitor therapy in a specific way. The small number of patients on each TNF-alpha inhibitor limits us from drawing meaningful comparative conclusions between these agents; also, as patients receiving more than one type of TNF-alpha inhibitor had their results attributed to each agent, direct comparisons are difficult to ascertain (Table 2). Lastly, our study may be affected by selection bias since our institution is a tertiary referral center and some of these patients may have already been worked up, diagnosed, and treated by other ophthalmologists using more conventional means. In our opinion, future studies directed at eliminating many of the above-mentioned limitations and seeking to answer some of the questions raise above are warranted. At the conclusion of our study, we found that TNF-alpha inhibitors have a significant role in treating scleritis, and they may be considered as second-line agents for disease refractory to NSAIDs, CS, or other IMT. TNF-alpha inhibitors may also be considered in patients who develop side effects to the aforementioned agents. Agents in this class, with their respectable inflammation control and steroid-sparing capabilities, are excellent immunosuppressive agents. As is the recent trend in the rheumatologic literature,40,41 it may be worth considering TNF-alpha inhibitors as first-line treatment of noninfectious, nonnecrotizing scleritis in select situations. Prospective controlled studies are needed to confirm and expand on our current findings.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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