Purpose
To describe the outcomes of the use of rituximab in the treatment of refractory noninfectious scleritis.
Design
Retrospective case series.
Methods
Review of the medical charts of patients with noninfectious scleritis refractory to conventional immunomodulatory therapy who were seen at the Massachusetts Eye Research and Surgery Institution between 2005 and 2015. The primary outcome measure in this study was steroid-free remission. Secondary outcomes were favorable response (decrease in scleritis activity score) and decrease in steroid dependence.
Results
There were 15 patients, with a mean follow-up duration of 34 months. Fourteen patients (93.3%) showed a clinical improvement, with 13 (86.6%) achieving a scleritis activity score of zero at 6 months. To date, 2 patients continue to enjoy durable drug-free remission (28 and 32 months follow-up). There was only 1 adverse effect recorded (infusion hypotension) requiring cessation of rituximab.
Conclusion
Rituximab can be an effective treatment modality for recalcitrant noninfectious scleritis and, in some, can result in long-term durable drug-free remission.
Scleritis is an inflammatory process of the sclera and adjacent tissues with a wide spectrum of clinical presentation. It may be self-limited or may be an early sign of an underlying systemic disease, which could potentially be life threatening. Noninfectious scleritis is a potentially blinding ocular inflammatory disease whose pathogenesis is thought to stem from scleral vessel vasculitis. The association between scleritis and systemic disease has been reported to occur in approximately 40%–50% of patients. The most frequent systemic accompanying disease is rheumatoid arthritis (RA), which accounts for as high as 17%–33% of scleritis cases. The second most frequent underlying disease is proteinase-3 anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis or granulomatosis with polyangiitis (GPA). Other observed associations are microscopic polyangiitis, relapsing polychondritis, and lupus and inflammatory bowel disease. Moreover, strong association has been found between active scleritis and life-threatening systemic vasculitis. When recurrent scleritis fails nonsteroidal anti-inflammatory drugs (NSAIDs), is corticosteroid dependent, or is associated with systemic life-threatening illness, an aggressive approach with immunosuppressive therapy is warranted. Nevertheless, a selected number of cases prove refractory to conventional immunomodulatory agents and need a different approach to be put into remission.
Rituximab (Rituxan; Genentech, San Francisco, California, USA) is a chimeric mouse monoclonal antibody that directly targets the CD20 antigen expressed on the majority of B cells. It is currently approved by the United States Food and Drug Administration (FDA) for the treatment of non-Hodgkin lymphoma, chronic lymphocytic leukemia, RA-failing tumor necrosis factor antagonists, GPA, and microscopic polyangiitis. Additionally, there is increasing evidence that rituximab can be employed to successfully treat ocular inflammatory disease.
There are limited studies (primarily case reports) describing the use of rituximab in the treatment of scleritis. Suhler and associates reported a randomized unmasked trial of 12 patients who were treated with either 500 mg or 1000 mg of rituximab given at 1 and 15 days. Here we present a retrospective case series of 15 patients who were successfully treated with rituximab for intractable noninfectious scleritis, which sheds light on a new treatment option for these severely ill patients.
Methods
We reviewed the electronic health records of all patients with scleritis treated with rituximab who were seen at the Massachusetts Eye Research and Surgery Institution (MERSI) in Waltham, Massachusetts, during a 10-year period from 2005 to 2015. Approval for this study was obtained through the New England Institutional Review Board, which issued a waiver of informed consent based on standard operating procedures for retrospective chart reviews. This study was performed in conformity with all country, federal, and state laws, in adherence to the tenets of the Declaration of Helsinki, and is HIPAA compliant.
All patients were clinically diagnosed by the senior author (C.S.F.) with noninfectious scleritis (defined as edema and vessel injection present in both the episcleral and scleral tissues, pain, persistence of injection after application of topical 10% phenylephrine, and negative infectious serologies). The diagnosis and classification of scleritis has been previously described by Watson and Hayreh. Scleritis was classified as anterior (diffuse, sectoral, nodular, or necrotizing) or posterior scleritis on the basis of clinical exam and ultrasound imaging. Scleritis activity was graded using a modified McCluskey Grading Scale for Scleritis Activity, as has been published and used elsewhere ( Table 1 ). Given that this was a retrospective study, grading was derived from clinical notes and, when available, slit-lamp photography. Each patient underwent complete ophthalmologic and serologic evaluation, including slit-lamp examination, tonometry, and funduscopy. Slit-lamp photography was performed to document pertinent anterior segment findings. Laboratory evaluation included, but was not limited to, complete blood count, serum chemistry, fluorescent treponemal antibody absorption analysis, rheumatoid factor, human leukocyte antigen (HLA) B27 genotyping, angiotensin converting enzyme, lysozyme, ANCA, Lyme disease antibody titers, and urinalysis. Connective tissue disease and systemic vasculitic diseases were diagnosed with the assistance of rheumatology when present.
| Factor | Points | Score at Presentation | Score at Final Visit |
|---|---|---|---|
| Number of quadrants inflamed | 0–4; 1 point per quadrant. 1 point for posterior scleritis | ||
| Tenderness | 0–4: none, mild, moderate, severe 2 = if pain was listed as “present” | ||
| Nodules | 0 = absent 1= present | ||
| Scleral necrosis | 0 = absent 1= present | ||
| Active corneal disease | 0 = absent/quiescent 2 = present 4 = progressive | ||
| Anterior chamber cell | 0 = none 2 = 1–20 cells 4 = >20 cells | ||
| Vitreous activity | 0 = absent 1 = 1–2+ Haze 2 = 3–4+ haze | ||
| Retinal detachment | 0 = absent 2= present | ||
| Total (out of 25) |
Demographic data including age, sex, additional systemic diagnoses, previous failed treatment, and rituximab dosage were recorded. Owing to lack of independence in cases of bilateral scleritis, the eye with the worse disease burden was chosen for analysis. Outcome variables collected included treatment response, inflammation recurrence, follow-up length, and adverse events.
Treatment with rituximab was FDA approved for cases of ANCA-associated scleritis. For all other cases, rituximab was infused on an off-label basis after failure of alternative immunosuppression. Infusion schedules varied depending on the clinic that ultimately gained insurance approval for drug administration. Rituximab infusions were given at 2 doses of 1000 mg separated by 14 days, cycled every 3–6 months based on the rheumatologic protocol, 375 mg/m 2 weekly ×4 based on the oncologic protocol, and 375 mg/m 2 weekly ×8 followed by monthly with extension as tolerated for ocular inflammatory disease. The latter protocol, first described by Ahmed and Foster, has been used most extensively in the treatment of ocular cicatricial pemphigoid. In 2 instances in which the patient had previously failed cyclophosphamide therapy as a single agent, rituximab was added to the treatment regimen instead of substitution in the pre-existing treatment regimen.
The treatment goal was steroid-free remission, defined as control of the disease with a scleritis score of “0” on the modified scleritis grading score while on rituximab (± additional immunomodulatory agents) and in the absence of corticosteroid use.
In patients who improved clinically but could not achieve steroid-free remission, additional and/or alternative therapies were sought. Relapse was defined as achievement of remission, followed by another flare of scleritis disease activity. Failure was defined as no response to rituximab treatment. Durable remission was defined as cessation of all immunomodulatory and steroid therapy with enjoyment of prolonged (>1 year) drug-free disease-free state.
The primary outcome measure in this study was steroid-free remission. Secondary outcomes were favorable response (decrease in scleritis activity score) and decrease in steroid dependence.
Data were collected from the electronic health records of all patients meeting inclusion criteria and analyzed using customized database software. We chose to report the results in terms of patients rather than eyes, given the lack of independence of the clinical course of each eye in the same patient. Statistical analysis was performed using the Student t test to compare means of categorical variables. A paired t test was used to compare pre- and posttreatment scleritis grading scores. Statistical significance was defined as P < .05.
Results
A total of 15 consecutive patients (24 eyes) with refractory noninfectious scleritis met inclusion criteria. Thirteen patients (87%) were female. The mean age at initiation for rituximab treatment was 48.3 ± 16.3 (range 21–78) years. The mean duration of follow-up after initiation of rituximab was 34.1 ± 24.8 (range 6–88) months. Eleven patients (73.3%) had scleritis associated with a systemic disease, while 4 (26.6%) had isolated idiopathic scleritis ( Table 2 ).
| Number | % | P Value | |
|---|---|---|---|
| Sex | |||
| Male | 2 | 13.3 | |
| Female | 13 | 86.7 | |
| Age at treatment (y) | |||
| <40 | 5 | 33.3 | |
| 40–60 | 6 | 40.0 | |
| >60 | 4 | 26.7 | |
| Race | |||
| White | 12 | 80.0 | |
| Hispanic | 1 | 6.7 | |
| Unknown | 2 | 13.3 | |
| Type of scleritis | |||
| Sectoral | 4 | 26.7 | |
| Diffuse | 5 | 33.3 | |
| Nodular | 1 | 6.7 | |
| Necrotizing | 4 | 26.7 | |
| Posterior | 1 | 6.7 | |
| Scleritis activity score | |||
| Before treatment | 6.2 | n/a | .0006 |
| After treatment | 1.0 | ||
| Systemic associations | |||
| Idiopathic | 4 | 26.7 | n/a |
| Granulomatosis with polyangiitis | 6 | 40.0 | |
| Rheumatoid arthritis | 4 | 26.7 | |
| Undifferentiated mixed connective tissue disorder | 1 | 6.7 |
Most patients (93%) presented with anterior scleritis: 4 (29%) sectoral, 5 (36%) diffuse, 1 (7%) nodular, 4 (29%) necrotizing. There was only 1 patient (7%) who presented with posterior scleritis. Scleritis was bilateral in 9 patients (60%). There were 6 patients with GPA, 4 with RA, 1 with undifferentiated mixed connective tissue disease with scleroderma-type features, and 4 patients with idiopathic scleritis ( Table 2 ).
Our cohort failed a mean of 3 other immunomodulatory agents prior to the institution of rituximab ( Table 3 ). There were 8 patients (53%) who received rituximab treatment using the rheumatology protocol, 4 patients (26%) who received rituximab treatment using the Foster ocular inflammatory disease protocol, and 3 patients (20%) who received rituximab treatment using the oncology protocol.
| Patient | Diagnosis | Previously Failed Medications | Rituximab Dose a | Response | Adverse Events | Relapse | Last Follow-up | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Response (Y/N) | Remission (Y/N) | Event (Y/N) | Lead to Cessation (Y/N) | Relapse (Y/N) | Time to Relapse (mo) | Current Regimen | Remission (Y/N) | ||||
| 1 | GPA | MTX, MM, AZA, CYC | Rheumatologic | Y | Y | N | – | Y | 20 | RTX + IVIG | N |
| 2 | RA | LEF, MTX, IFX, ADA, ETN, NSAIDs, Doxycycline, | Rheumatologic | Y | Y | N | – | N | – | RTX | Y |
| 3 | RA | NSAIDs, MM, AZA, IFX, ADA, Chlorambucil | Rheumatologic | Y | Y | Y | Y | – | – | ABT + IVIG | N |
| 4 | Idiopathic | NSAIDs, CYC | Rheumatologic | Y | Y | N | – | N | – | RTX | Y |
| 5 | Idiopathic | NSAIDs, HCQ, LEF, MTX, AZA, IFX, TCZ, CYC, Ara-C | Ocular inflammation | N | N | N | – | N | – | IVIG | Y |
| 6 | GPA | MTX, ADA | Oncologic | Y | Y | N | – | Y | 5 | IVIG | Y |
| 7 | RA | MTX, IFX, ETN, CYC | Rheumatologic | Y | Y | N | – | N | – | Drug-free | Y |
| 8 | Idiopathic | NSAIDs | Rheumatologic | Y | Y | N | – | N | – | Drug-free | Y |
| 9 | GPA | MTX, MM | Rheumatologic + CYC | Y | Y | N | – | N | – | RTX | Y |
| 10 | Idiopathic | NSAIDs, MM | Ocular inflammation | Y | N | N | – | Y | 5 | CYC | Y |
| 11 | GPA | AZA | Rheumatologic | Y | Y | N | – | N | – | RTX + IVIG | Y |
| 12 | MCTD, Scl | MTX | Ocular inflammation | Y | Y | N | – | N | – | MTX | Y |
| 13 | RA | CYC | Ocular inflammation | Y | Y | N | – | N | – | RTX + CYC | LTF |
| 14 | GPA | CYC | Rheumatologic | Y | Y | N | – | N | – | RTX + CYC | LTF |
| 15 | GPA | NSAIDs, CYC | Rheumatologic | Y | Y | N | – | N | – | RTX | Y |
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