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Clinical science
Combined therapy of cyclosporine A and mycophenolate mofetil for the treatment of birdshot retinochoroidopathy: a 12-month follow-up
  1. Rene Antonio Cervantes-Castañeda1,2,
  2. Luis Alonso Gonzalez-Gonzalez1,3,
  3. Miguel Cordero-Coma1,4,
  4. Taygan Yilmaz1,5,
  5. C Stephen Foster1,3,6
  1. 1Massachusetts Eye Research and Surgery Institution, Cambridge, Massachusetts, USA
  2. 2CODET Vision Institute, Ocular Inflammatory Disease Department, Tijuana, Mexico
  3. 3Ocular Immunology and Uveitis Foundation, Cambridge, Massachusetts, USA
  4. 4Uveitis Unit, Department of Ophthalmology, Hospital de Leon, León, Spain
  5. 5Stony Brook Medical Center, New York, New York, USA
  6. 6Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
  1. Correspondence to Dr C Stephen Foster, Massachusetts Eye Research and Surgery Institution, 5 Cambridge Center, 8th Floor, Cambridge, MA 02142, USA; fosters{at}uveitis.org

Abstract

Purpose To retrospectively report a 12-month follow up for combined therapy with systemic cyclosporine A (CSA) and mycophenolate mofetil (MM) in treatment of patients with birdshot retinochoroidopathy (BSRC).

Participants Ninety-eight eyes of patients who received CSA and MM for the treatment of BSRC were included in the study.

Methods All patients were followed for at least five visits during the study, or until treatment failure, or loss of follow-up. Clinical data were analysed using a Student paired t-test, Wilcoxon signed-rank test, McNemar's test, and Kaplan -Meier survival curve. Side effects related to therapy were also recorded. Main outcome measures included best-corrected logarithm of the minimum angle of resolution visual acuity, vitreous inflammation, fluorescein angiography pathologic features, and electroretinogram recordings.

Results Vitreous inflammation scores at baseline and at 1 year were statistically significantly reduced in both eyes (p<0.001; p=0.001). The presence of angiographic leakage at the 1-year follow-up was significantly reduced (p=0.004). However, the presence of cystoid macular oedema (p=0.32) and comparison of electroretinogram 30-Hz amplitude revealed no significant reduction between baseline and 1-year values for either eye (p=0.61, p=0.87); nonetheless, 30-Hz implicit times were statistically significantly shorter at the end of follow-up for both eyes (p<0.001, p=0.035). Thirty-one patients (67.4%) achieved inflammation control at the 1-year endpoint. Side effects were transient, and resolved after lowering or withholding IMT for a few weeks in the majority of patients.

Conclusions These results suggest that combined IMT with CSA and MM for BSRC is well tolerated and associated with long-term control of inflammation.

  • Immunology
  • Inflammation
  • Pharmacology

https://doi.org/10.1136/bjophthalmol-2012-302123

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    Introduction

    Birdshot retinochoroidopathy (BSRC) is a bilateral, chronic idiopathic posterior uveitis characterised by vitritis and multiple hypopigmented lesions at the level of the choroid and retinal pigment epithelium in the postequatorial fundus. These lesions evoke impacts from shotgun pellets; thus the term birdshot, which was first coined in 1980.1 The natural history of BSRC is characterised by multiple inflammatory exacerbations with some periods of remission. Untreated patients eventually progress to blindness, usually due to chronic cystoid macular oedema (CME) or to diffuse retinal dysfunction.2 ,3

    Corticosteroid monotherapy has proved to be ineffective in preventing progression and blindness.4–10 Several immunomodulatory therapy (IMT) regimens have been explored in efforts aimed at induction of durable remission without the risks associated with long-term corticosteroid therapy. The use of cyclosporine A (CSA) alone, mycophenolate mofetil (MM) alone and other IMT agents in treating patients with BSRC has been reported.2 ,6 ,11–17 However, there is no published consensus providing a guideline for BSRC treatment.

    The use of combined IMT agents at low dose is particularly effective in the treatment of other immune-mediated posterior uveitides. Combination therapy not only addresses different therapeutic pathways but also decreases the incidence of side effects, directly proportional to the dose.6 ,18 We imagined (based upon our early experience with CSA therapy for patients with BSRC) that IMT would become the standard of care for patients with this disease;6 but while CSA monotherapy was highly effective at induction of remission, it required years of treatment rather than durable remission or cure after 2 years of therapy.

    To the extent of our knowledge, the use of combination IMT agents in the treatment of patients with BSRC has not been reported. We herein report the results of the use of combination therapy in 49 patients with BSRC (98 eyes) treated with a similar therapeutic regimen consisting of CSA (Sandimune, Neoral, Sandoz, East Hanover, New Jersey, USA) and MM (CellCept, Roche Laboratories, Nutley, New Jersey, USA) during a period of 12 months. This treatment protocol was chosen in the quest for durable remission on medication and possible cure during a finite period of time after drug discontinuation.

    Methods

    Retrospective chart review of patients with BSRC treated with a combination therapy of CSA and MM at the Massachusetts Eye Research and Surgery Institution (MERSI, Cambridge, Massachusetts, USA). An electronic health records search resulted in 79 patients with the keywords ‘birdshot’, ‘MM’ and ‘CSA’ (NextGen Healthcare Information System, Horsham, Pennsylvania, USA) at MERSI.

    Of these, 49 patients met the criteria to be included in the study. Patients were included if (1) they had the diagnosis of BSRC and (2) were treated with MM and CSA combination therapy between 1998 and 2010. We first analysed all patients who initiated combined therapy accounting for those patients who stopped before the 12-month follow-up period due to loss of follow-up, addition of a new IMT drug or lack of corticosteroid-sparing effect. We further analysed the efficacy of treatment to control inflammation at 1 year of follow-up. The diagnosis of BSRC was based upon the criteria established by an international consensus panel.19

    Collected data included demographic characteristics at presentation, features of ocular inflammation, human leukocyte antigen (HLA) A29 serotype and presence of systemic involvement at the time of presentation. Initial drug dosage was calculated by 3 mg per kg/weight for CSA and 1 gram twice daily for MM. These doses were adjusted if the patient showed no improvement, or if adverse effects were present. If a patient showed side effects or drug toxicity, IMT was discontinued for at least 2 weeks until improvement of symptoms and/or laboratory abnormalities. These data also included the duration of ocular disease, total cumulative follow-up times, previous use of corticosteroids by any route (oral, periocular, intravitreal, intravenous or topical), history of previous IMT, control of inflammation, electroretinogram (ERG) testing, presence of retinal angiographic leakage by fluorescein angiography (FA), best-corrected visual acuity and side-effects while on treatment with MM and CSA. Snellen visual acuities were converted to logarithm of the minimum angle of resolution (logMAR) scores for statistical analysis.

    Clinical evaluation included a thorough ophthalmologic exam (Snellen VA, Goldmann-tonometer intraocular pressure measurement, slit lamp examination and dilated fundus exam). Anterior chamber was graded according to the classification established by the Standardisation of Uveitis Nomenclature; whereas the National Eye Institute system was adopted for grading vitreous inflammation.20 ,21 FA was performed routinely before and after starting treatment to determine the presence or absence of retinal angiographic leakage. FA was reviewed for presence or absence of vasculitis, papillitis and CME. Treatment success was defined as grade 0 cells in anterior chamber and vitreous with absence of retinal and/or vascular leakage on FA. Full-field ERG outcomes were assessed by comparing the 30-hertz (Hz) amplitude and implicit times during the follow-up time. ERG was performed following the protocol established by the International Society for Clinical Electrophysiology of Vision. Treatment-related side effects were assessed on each visit with a thorough review of systems and complete blood-cell counts, blood urea nitrogen (BUN) level, creatinine level, and liver function test parameters obtained on a 6-week basis. Patients underwent blood pressure monitoring at every visit. Glomerular filtration rates were performed if renal damage was suspected. Failure to comply with blood monitoring was considered sufficient to terminate IMT.

    Statistical analysis was performed using STATA software (StataCorp 2007. Stata Statistical Software: Release 10. College Station, Texas, USA: StataCorp LP). The statistical tests employed in the analysis included a Student paired t test, Wilcoxon signed-rank test, McNemar's test, and Kaplan–Meier survival curve.

    Informed consent was obtained from all the participants. All the proceedings followed the tenets of the Declaration of Helsinki.

    Results

    Demographics: table 1 lists demographic, diagnostic and previous treatments information for the 49 patients who form the basis of this report. All patients were Caucasian, and the ratio of men to women was 3 : 4. The median age at diagnosis of BSRC was 48.8 years (range 27.1–76.1). All cases had bilateral involvement at presentation. All included patients met diagnostic criteria for BSRC.19 HLA typing was not available for seven patients; however, they met the diagnostic criteria for BSRC with typical lesions in the fundus exam and FA.

    View this table:
    Table 1

    Summary of patient data

    The majority of patients had not had previous IMT (36 patients, 73.5%). Eight patients had received CSA monotherapy that failed to control ocular inflammation. Two patients were started on CSA-MM combination therapy, but discontinued shortly after unrelated side-effects or failure. Both resumed therapy after 6 months. The remaining patients had been treated with methotrexate (MTX), azathioprine in combination or alone without success. Twenty-seven patients had received corticosteroid therapy by several routes prior to starting combined therapy; systemic corticosteroids were used in 23 patients; prednisone given orally was the most frequent route of administration (21 patients), followed by periocular and/or intraocular triamcinolone (8 patients).

    IMT and side effects are shown in table 2. The median dose of combined IMT was 200 mg daily (range 100 mg–300 mg) for CSA and 2 grams daily (range 1 g–3 g) for MM during the 12-month follow-up period.

    View this table:
    Table 2

    Dosage, side effects and treatment outcome within the first year

    Eleven patients did not reach the 12-month follow-up (±6 weeks). Of these, five patients (45.5%) experienced side-effects that prompted IMT termination, three patients (27.3%) required additional IMT due to persistent inflammation, and two patients (18.2%) failed to comply with monitoring. The remaining patient was still on combined therapy at the time of the study, but had not reached 12 months of follow-up.

    Forty-six patients were included in the cohort. Of these, 31 patients (67.4%) achieved complete control of inflammation. Fifteen patients were considered failures due to persistent ocular inflammation or significant side effects, and required different IMT. One patient resumed IMT 6 months after treatment for unrelated colon cancer, but failed to achieve control, and experienced significant side effects that prompted to switch to another IMT protocol. The rest of the patients who failed required additional therapy (eg, daclizumab, infliximab) due to persistent active inflammation while on IMT. None of the 21 patients who were using oral prednisone at baseline were still on it at the end of the 12-month follow-up endpoint.

    Of the 49 patients who initiated combined therapy, five experienced side effects significant enough to discontinue IMT before 12 months of follow-up. Severe fatigue (2), hypertension (1), neuropathy (1) and gastrointestinal (GI) upset (1) were the reported side effects among these patients. Of the 46 patients included in the analysis, 38 patients achieved a 12-month follow-up. Of these, 21 (55.3%) patients developed a side effect related to therapy. Ten patients developed transient mild side effects (eg, high blood pressure, fatigue, GI upset, flu-like symptoms) who did not require modification of dosage or additional medications. Seven patients (18.4%) did not experience side effects. We observed that hypertension was a common side effect. Of the 38 patients who had complete follow-up, 13 patients had previous history of hypertension (defined by the National Heart Lung and Blood Institute as a systolic pressure ≥140 mm hg and diastolic ≥90). Two (15.4%) of these patients developed uncontrolled blood pressure that required adjustment to their antihypertensive medication, additional antihypertensive medication or a decrease in the CSA dose. Three of these patients with known hypertension had a transient blood pressure elevation that did not require any modification to their current regimen. The remaining eight patients did not develop alterations in the blood pressure and continued with their antihypertensive regimen. Five patients who had normal blood pressure at baseline developed hypertension. Three of these patients experienced transitory elevation of blood pressure that did not require additional therapy. One patient required additional therapy to control blood pressure, and the remaining one responded to a decrease in the CSA dose. Blood monitoring disclosed slight transient abnormalities in the blood cell counts in seven (18.4%) patients of whom two required a reduction in the dose of MM. Additionally, we observed BUN and/or elevated creatinine levels in eight (21.1%) patients. Of these, only two patients required lowering the IMT. Other side effects related to medication are shown in table 3.

    View this table:
    Table 3

    Side effects

    The median of follow-up time since BSRC diagnosis for all included patients was 65.3 months (range 6.2–248.5); while the median time on MM/CSA therapy was 17.6 (range 0.77–78.4). Of the 31 patients who achieved control of inflammation in the first 12 months, 8 (25.8%) had a flare that responded to adjustment in the dose of CSA and/or MM. We also analysed the incidence of combined therapy failure during the period time from IMT initiation to loss of follow-up, failure or last visit in all patients (median=17.37, range 0.77–109.3). The incidence rate of failure was 17% per person-year.

    Mean logMAR visual acuities were not statistically significantly different after the 1-year endpoint in either the right or left eye (p=0.38; p=0.76). Median vitreous inflammation scores in both right and left eyes at the 12-month follow-up were less than that of baseline; this difference was statistically significant (right eye (OD), p<0.001; left eye (OS), p=0.001) (see online supplementary table). Additionally, we determined that the cumulative probabilities of having a vitreous inflammation score of zero at 3, 6, 9 and 12 months, were 42.1%, 50.0%, 68.4%, 81.6%, respectively (figure 1). The presence of angiographic leakage of any retinal vessel was significantly reduced (p=0.0039), but CME was not (p=0.32). Analysis of full-field ERG recordings revealed that the 30-Hz amplitudes were not statistically different between baseline and 1-year values for either eye (OD, p=0.61, OS, p=0.87). Nonetheless, 30-Hz implicit times were statistically significantly shorter at the end of follow-up in both eyes (p<0.001, p=0.035).

    Figure 1
    Figure 1

    Percentage of patients with active inflammation

    Discussion

    We report herein on the outcomes of patients with BSRC treated with a combination of CSA and MM. Since the use of systemic corticosteroid-sparing IMT is widely accepted for patients with BSRC, several IMT regimens have been explored in efforts aimed at induction of durable remission without the risk of long-term corticosteroid therapy.

    Several attempts to therapeutically manage patients using CSA alone, MTX alone or other different IMT have been reported.2 ,6 ,11–17 Nussenblatt and associates reported the success of high-dose CSA monotherapy (10 mg/kg/day) for treating birdshot retinochoroidopathy. Although efficacious to achieve inflammatory control, high-dose CSA was associated with multiple side effects.22 We reported the efficacy of low-dose cyclosporine (2.5–5 mg/kg/day) in treating patients with BSRC. Control and resolution of vitreous inflammation were achieved in 88.5% of the patients. However, some of these patients required the use of adjuvant azathioprine.6 Moreover, inflammation usually recurred after discontinuing CSA. Other authors have reported the success of intravenous immunoglobulin, daclizumab and other IMT agents in small series of patients with BSRC.14 ,23 These therapies are usually reserved for refractory cases.

    While the role of cyclosporine A for the treatment of uveitis is well established in the medical literature, MM is a relatively new drug and its role for the management of uveitides refractory to conventional treatment is being progressively supported by some recent publications.24–26 Some potential sight-threatening complications of uveitis have also been successfully treated by MM, such as choroidal neovascularisation and CME.27 ,28 Moreover, MM may carry some potential advantages on the safety profile of CSA monotherapy by lowering CSA nephrotoxicity.29

    Our results suggest a highly beneficial effect of this combination therapy on the control of the inflammatory signs and vision function degradation secondary to BSRC after 1 year of follow-up. Eighty-one percent of patients receiving combined therapy with CSA and MM achieved control of inflammation during the first year of treatment. All these patients were able to maintain inflammatory remission off any kind of corticosteroids after 1 year of follow-up. Clinically, vitreous inflammation scores at the 1-year endpoint dramatically declined compared with pre-IMT baseline scores, showing a statistically significant difference. Not only vitreous inflammation but also other frequent manifestations associated with active BSRC, such as retinal angiographic leakage were also significantly reduced.

    Visual acuity (VA) measurements during the 12-month time point were not statistically significantly different compared with baseline values; this must be carefully analysed to avoid erroneous interpretation. It has been documented that patients with BSRC may report progressive, debilitating vision symptoms even in the face of quantitatively preserved Snellen VA.30 A VA of 20/20 or better has been reported in up to 34% of patients with a median duration of the disease of 3.8 years.2 In patients with 20/20 vision at baseline, VA should not be considered a reliable parameter to assess the response to therapy and its potential clinical significance. Other parameters that evaluate visual function might contribute to a better understanding of the potential benefit of any intervention. We documented that some visual disturbances linked to vitritis, such as floaters, a common complaint of BSRC patients, were substantially alleviated and decreased after initiating combined therapy. However, as symptoms vary greatly from patient to patient, we believe that more objective parameters offer a better assessment of inflammatory activity and of retinal damage progression. Specifically, the ERG 30-Hz cone flicker implicit time is a reliable parameter to monitor patients with BSRC. The 30-Hz implicit time has been associated with worse vision and duration of symptoms, and it seems to remain stable in patients under IMT treatment.3 Comparisons of 30-Hz implicit times revealed statistically significant differences when comparing baseline results to those obtained 1 year after treatment. Although ERG assessment of rods and cones is abnormal in a great number of patients with a variable degree of impairment,3 the exact affectation of ERG in BSRC is not completely understood; therefore, there is no consensus on which parameters are the best indicators of disease progression. Moreover, some studies suggest that different parameters may be affected depending on the stage of the disease.3 Previous reports showing a potential beneficial therapy for birdshot retinochoroidopathy have pointed out the controversial worsening of ERG parameters in some patients.3 In our series, we favourably interpret the absence of a statistical significant difference in ERG 30 Hz amplitudes as a stabilisation of retinal function in most patients, and the significantly shorter 30 Hz implicit times as an indicator of less degree of retinal impairment.

    Our philosophy is one of zero tolerance even for low-grade inflammation, and of limited tolerance for corticosteroid use in patients with chronic vision-threatening ocular inflammatory disease, such as BSRC. Thus, we believe that the presence of intraocular inflammation rather than an arbitrary VA measurement should dictate the use of IMT.

    Conclusion

    These data suggest that combined therapy with CSA and MM was well tolerated and efficacious in controlling inflammation and stabilising vision for the majority of patients with BSRC in this study group. A prospective randomised trial may provide a more definitive potential benefit of this intervention and its safety profile.

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    Supplementary materials

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    Footnotes

    • Funding The authors have no proprietary or commercial interest in any of the materials discussed in this article. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

    • Contributors The corresponding author certifies that each author listed above contributed substantially to the concept, design, acquisition of data and data analysis, drafting and/or revision of the manuscript, and final approval of the submitted version, in a significant capacity.

    • Competing interests None.

    • Ethics approval New England IRB.

    • Provenance and peer review Not commissioned; externally peer reviewed.