Purpose
To evaluate the success of single-agent immunosuppression for patients with the posterior uveitides, birdshot chorioretinitis, multifocal choroiditis with panuveitis, and punctate inner choroiditis.
Design
Retrospective case series.
Methods
setting : Tertiary care uveitis practices. population : Patients initiated on immunomodulatory therapy. intervention : Patients were treated with prednisone 1 mg/kg and mycophenolate 2 g daily. Prednisone was tapered after 1 month. Immunosuppression was escalated to mycophenolate 3 g daily, with addition of a second agent, as needed, to achieve treatment success. outcome measure : Treatment success, defined as no disease activity with prednisone dose ≤10 mg daily, at 6, 12, and 24 months.
Results
Twenty-seven patients were followed. Mean presentation and 2-year follow-up acuities were 20/41 and 20/42, respectively. For birdshot chorioretinitis, mean (±standard deviation) quantitative Goldmann visual field scores improved from 761 ± 69 degrees (IV/4 isopter) and 496 ± 115 degrees (I/4 isopter) at presentation to 784 ± 57 degrees and 564 ± 125 degrees, respectively. Prednisone was successfully tapered in 95% of patients; mean prednisone doses at 1 and 2 years were 5.3 ± 4.1 and 5.7 ± 4.8 mg/day, respectively. At 2 years, prednisone was discontinued in 11% of patients. Treatment success was achieved in 74% of patients on 1 immunosuppressant, and in an additional 21% of patients on 2 agents, for an overall 95% success rate at 2 years.
Conclusions
Posterior uveitides can be treated with 1 agent in most patients, but the data suggest a need to escalate therapy to higher mycophenolate doses, and in one fifth of cases to add a second agent to maintain disease suppression with acceptably low prednisone doses.
The multifocal choroidopathies are a collection of several diseases characterized by multiple choroidal spots and include, among others, birdshot chorioretinitis, multifocal choroiditis with panuveitis, and punctate inner choroidopathy. Birdshot chorioretinitis and multifocal choroiditis with panuveitis are chronic diseases with poor prognoses unless treated with immunosuppression. Although some investigators have advocated combination immunosuppression from the beginning, others have begun with a single agent and escalated treatment as needed to maintain control of the inflammation and successfully taper prednisone to a level compatible with long-term treatment without side effects. Though recent reports have suggested through multimodal imaging that punctate inner choroiditis and multifocal choroiditis with panuveitis target identical structures and thus may not be different entities, punctate inner choroiditis traditionally has been described as having distinct features (no vitreous cells, small punctate lesions) and a more variable course than multifocal choroiditis with panuveitis: some patients with punctate inner choroiditis may have a monophasic illness, followed by prolonged remission; others a recurrent but episodic course; and a few a chronic course necessitating immunosuppression, whereas multifocal choroiditis with panuveitis is a chronic disease with a poor outcome unless immunosuppression is used. When immunosuppression is indicated, the approach is similar for all of these entities; prednisone and immunosuppression are initiated, and the prednisone then is tapered to <10 mg/day and (it is hoped) discontinued, while maintaining “grade 0” inflammation. Our approach to immunosuppression has been a stepwise one, beginning with a single immunosuppressive agent and escalating the dose and number of agents as needed. However, our group’s clinical impression has been that escalation of immunosuppression often was needed in order to achieve the goals of tapering of the prednisone while maintaining “grade 0” inflammation. Therefore we initiated a review of our experience with managing these diseases.
Patients and Methods
Patients with birdshot chorioretinitis, multifocal choroiditis with panuveitis, or punctate inner choroiditis were identified from the billing database (ICD-9 code 363.10) for the period July 2007 (the beginning of the Uveitis Service) through July 2012. Approval of this study was granted by the Mount Sinai School of Medicine Institutional Review Board and the Program for the Protection of Human Subjects. All study procedures were fully HIPAA compliant. In order to analyze the outcomes of our treatment approach, those patients who were started on treatment at our institution and followed formed the primary group analyzed. Birdshot chorioretinitis, multifocal choroiditis with panuveitis, and punctate inner choroiditis all were identified by the characteristic clinical picture and exclusion of potential infectious (eg, syphilis, Lyme disease) or systemic (eg, sarcoid) diseases by appropriate laboratory testing. Birdshot chorioretinitis was diagnosed when there was a multifocal choroiditis with yellow-orange ovoid spots, accompanied by a mild vitritis. Multifocal choroiditis with panuveitis and punctate inner choroiditis were diagnosed according to the original clinical descriptors by the presence of multifocal choroidal lesions with punched-out, atrophic spots, typically (though not always) with a mild vitritis (in multifocal choroiditis with panuveitis), or a multifocal choroiditis with punctate spots without other signs of intraocular inflammation (in punctate inner choroiditis).
Treatment Approach
The decision to initiate and/or escalate treatment in this group of patients was based on the presence or progression of structural complications such as macular edema, or diffuse retinal dysfunction as detected by quantitative Goldmann visual field testing with or without electroretinography in birdshot chorioretinitis patients; or by the presence or progression of inflammatory lesions (seen as sub–pigment epithelial deposits or outer retinal loss by optical coherence tomography [OCT]) or choroidal neovascularization in patients with punctate inner choroiditis and multifocal choroiditis with panuveitis. Grade 0 vitreous (cells and haze) also were targets for treatment when appropriate. Increased vitritis in the setting of antecedent structural complications in all patients was an indication for escalating treatment. Patients without structural complications related to their underlying diagnosis, or with end-stage disease with evidence of inactivity, were monitored closely at regular intervals without treatment. Patients with a monophasic episode of punctate inner choroiditis were observed with or without a brief course of corticosteroids, and immunosuppression was delayed until there was clinical evidence of recurrent disease. Patients requiring immunosuppression were treated initially with prednisone 1 mg/kg/day up to 60 mg/day and mycophenolate (CellCept; Roche Pharmaceuticals, Nutley, New Jersey, USA) 1 g twice daily. In 2 cases, immunosuppressive therapy was initiated with tacrolimus 2 mg daily (Prograf; Astellas Pharma US, Inc, Deerfield, Illinois, USA) for a patient with birdshot chorioretinitis, or azathioprine 150 mg daily (Imuran; GlaxoSmithKline USA, Philadelphia, Pennsylvania, USA) for a patient with multifocal choroiditis with panuveitis, rather than mycophenolate. After 1 month, prednisone was tapered at weekly intervals to 10 mg/day as previously described. If the disease remained inactive for 1–3 months, the prednisone was tapered further at a rate of 1–2.5 mg/day decrements every 1–4 weeks, depending on clinical response. If prednisone could not be tapered successfully to <10 mg/day owing to recurrent inflammation, the dose of mycophenolate was increased to 1.5 g twice daily. If the patient could not tolerate the higher mycophenolate dose, the dose was titrated down to 1.25 g twice daily. If the increased mycophenolate dose was inadequate to allow successful tapering of prednisone to <10 mg/day while maintaining complete control of the inflammation, a second agent was added, such as tacrolimus (Prograf; Astellas Pharma US, Inc, Northbrook, Illinois, USA), cyclosporine (Neoral; Novartis Pharmaceuticals Corp, East Hanover, New Jersey, USA), or adalimumab (Humira; Abbott Laboratories, North Chicago, Illinois, USA). In cases complicated by choroidal neovascularization, intravitreal injections of anti–vascular endothelial growth factor (anti-VEGF) agents were given at the discretion of the provider.
Outcome Measures
The main outcome measure was “treatment success,” defined as inactive inflammation (grade 0 cells/haze and no new choroidal lesions), control of structural complications (such as macular edema, neovascularization), and a dose of prednisone ≤10 mg/day. Although choroidal lesions in birdshot chorioretinitis often resolved with immunosuppression, because some patients presented with scarring, resolution of all spots was not required for the definition of inactive disease. Similarly, resolution of atrophic, “punched-out” lesions in multifocal choroiditis with panuveitis and punctate atrophic scars in punctate inner choroiditis was not expected or required for the definition of “inactive disease.” The secondary outcomes were the dose of mycophenolate needed to achieve treatment success and the use of a second immunosuppressive agent to achieve treatment success. The use of anti-VEGF agents to treat choroidal neovascularization was not considered a “treatment failure,” but the occurrence of new choroidal neovascularization (eg, in the second eye) was considered treatment failure. Outcomes were evaluated at 6, 12, and 24 months after initiating therapy.
Visual Outcomes
Visual outcomes were evaluated as well, in order to ensure that visual function was maintained or improved by treatment. Visual acuity was measured using Snellen charts, converted to logMAR for analysis, and converted back to Snellen equivalents for presentation purposes. Visual acuities below standard thresholds also were evaluated: 20/50 or worse and 20/200 or worse. For patients with birdshot chorioretinitis, serial visual fields also were evaluated using quantitative Goldmann fields as previously described. The normal visual field scores are IV/4 isopter 800 degrees of field and I/4 isopter 600 degrees of field. Abnormal scores are IV/4 isopter <700 degrees of field and I/4 isopter <560 degrees of field. In several cases, electroretinographic studies also were monitored, but Goldmann field scores were primarily used to measure peripheral retinal dysfunction, given that quantitative Goldmann testing comparably evaluates global retinal function and detects disease in birdshot chorioretinitis, and is easier to obtain with possibly less variability. Macular edema was evaluated with OCT. Early in the study, some eyes were evaluated with time-domain OCT (TD OCT); but later in the study, as technology was upgraded, eyes were evaluated with spectral-domain OCT (SD OCT). Abnormal values for central foveal subfield thickness were >250 μm for TD OCT and >315 μm for SD OCT.
Statistical Methods
Mixed analysis of variance (ANOVA) models, stratified by diagnosis (and overall), were used to compare mean Goldman I/4 and Goldman IV/4 values at baseline between treated and untreated groups. These models take into account the correlation between eyes in the same patient. Log-binomial regression models, stratified by diagnosis (and overall), were used to compare the binary outcomes between treated and untreated groups. The parameters of these models were estimated using generalized estimating equation methods, and like the mixed ANOVA models, this method accounts for the correlation between eyes within a patient. The χ 2 and Wilcoxon tests were used to compare patient characteristics on categorical and continuous variables, respectively, between treated and untreated groups. All statistical analyses were performed using SAS Version 9.2 (SAS Institute Inc, Cary, North Carolina, USA).
Results
Characteristics of the Study Population
Sixty-nine patients with birdshot chorioretinitis (n = 28), multifocal choroiditis with panuveitis (n = 19), or punctate inner choroiditis (n = 22) were identified during the study period. Of these, 22 were seen only once for consultation or had therapy initiated elsewhere (8 birdshot chorioretinitis, 8 multifocal choroiditis with panuveitis, and 6 punctate inner choroiditis); 20 were not treated (6 birdshot chorioretinitis, 4 multifocal choroiditis with panuveitis, and 10 punctate inner choroiditis) owing to absence of structural complications or disease activity; and 27 had therapy initiated with follow-up provided by our institution. Comparison of those included in the follow-up study (n = 27) and those not included (n = 42) is presented in Table 1 by disease diagnoses. In general, those patients included in the follow-up study appeared to be similar to those not included, and no significant differences were detected.
| Characteristic | Birdshot Chorioretinitis | Multifocal Choroiditis | Punctate Inner Choroiditis | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Not Included | Included | P Value a | Not Included | Included | P Value a | Not Included | Included | P Value a | |
| Number of patients | 14 | 14 | 12 | 7 | 16 | 6 | |||
| Age (y) | .49 | .51 | .29 | ||||||
| Mean (SD) | 52 (14) | 56 (12) | 47 (16) | 42 (11) | 35 (7) | 31 (13) | |||
| Median(interquartile range) | 51 (47, 60) | 56 (45, 66) | 44 (38, 62) | 40 (35, 51) | 34 (28, 42) | 32 (18, 40) | |||
| Sex (%) | 1.00 | .51 | 1.00 | ||||||
| Female | 10 (71%) | 11 (79%) | 10 (83%) | 7 (100%) | 14 (88%) | 6 (100%) | |||
| Male | 4 (29%) | 3 (21%) | 2 (17%) | 0 (0%) | 2 (12%) | 0 (0%) | |||
| Race/ethnicity (%) | 1.00 | 1.00 | NE | ||||||
| White, non-Hispanic | 13 (93%) | 14 (100%) | 11 (92%) | 7 (100%) | 16 (100%) | 6 (100%) | |||
| Hispanic | 1 (7%) | 0 (0%) | |||||||
| Other | 1 (8%) | 0 (0%) | |||||||
| Bilateral disease (%) | 13 (93%) | 13 (93%) | 1.00 | 11 (92%) | 5 (71%) | .52 | 9 (56%) | 4 (67%) | 1.00 |
| Number of patients (%) | |||||||||
| Macular edema in either eye | 3 (25%) | 6 (43%) | .43 | ||||||
| Choroidal neovascularization in either eye | 1 (7%) | 0 (0%) | 1.00 | 8 (73%) | 6 (86%) | 1.00 | 12 (75%) | 5 (83%) | 1.00 |
| Abnormal Goldmann visual field b | 4 (36%) | 9 (75%) | 0.10 | ||||||
| VA 20/50 to 20/160 in better eye | 1 (7%) | 2 (14%) | 1.00 | 1 (8%) | 0 (0%) | 1.00 | 0 (0%) | 0 (0%) | 1.00 |
| VA 20/200 or worse in better eye | 0 (0%) | 0 (0%) | 1.00 | 1 (8%) | 0 (0%) | 1.00 | 1 (6%) | 1 (17%) | .48 |
| Number of involved eyes | 27 | 27 | 23 | 12 | 25 | 10 | |||
| Macular edema (% eyes) | 5 (22%) | 8 (30%) | .62 | ||||||
| Choroidal neovascularization (% eyes) | 1 (4%) | 0 (0%) | 1.00 | 13 (62%) | 7 (58%) | .92 | 13 (52%) | 6 (60%) | .65 |
| Abnormal visual field (% eyes) | 7 (33%) | 14 (56%) | .26 | ||||||
| Mean Goldmann IV/4 score (SD) | 722 (161) | 751 (64) | .56 | ||||||
| Mean Goldmann I/4 score (SD) | 532 (233) | 506 (130) | .75 | ||||||
| VA 20/50 to 20/160 (% eyes) | 2 (7%) | 5 (19%) | .25 | 2 (9%) | 3 (25%) | .19 | 1 (4%) | 1 (10%) | .51 |
| VA 20/200 or worse (% eyes) | 1 (4%) | 3 (11%) | .32 | 6 (26%) | 1 (8%) | .33 | 5 (20%) | 2 (20%) | .97 |
a P value is for comparing included vs not-included.
b Abnormal scores are IV/4 isopter <700 degrees of field and I/4 isopter <560 degrees of field.
Visual Outcomes
Visual outcomes of the 27 patients in the follow-up study are presented in Table 2 . Follow-up was available for 93% of patients for 1 year and for 70% of patients for 2 years. In general, good visual acuity was maintained throughout the 2 years with a mean acuity in involved eyes of 20/41 at presentation, 20/39 at 1 year of follow-up, and 20/42 at 2 years of follow-up. The proportion of eyes with visual impairment (20/50 or worse) declined slightly from 22% (11 of 49 eyes in 27 patients) at presentation to 17% (6 of 35 eyes in 19 patients) at 2 years, and the proportion “blind” (20/200 or worse) went from 10% at presentation (5 of 49 eyes in 27 patients) to 9% at 2 years (3 of 35 eyes in 19 patients). At the start of treatment, 36% of birdshot chorioretinitis patients had macular edema (9 of 25 imaged affected eyes in 13 patients); by 2 years, 16% had macular edema (3 of 19 imaged affected eyes in 10 patients), attributed in all 3 eyes to the presence of concurrent epiretinal membranes rather than to disease activity. Patients with birdshot chorioretinitis also develop visual field loss if left untreated or are treated intermittently. Among the birdshot chorioretinitis patients in the study, there appeared to be a progressive increase in the mean quantitative Goldmann visual field score for the IV/4 and the I/4 isopters from 761 ± 69 degrees and 496 ± 115 degrees, respectively, to 784 ± 57 degrees and 564 ± 125 degrees, respectively, at 2 years. These results demonstrate a significant increase in both isopters on treatment (I/4 slope for visual field score = 50.9 degrees/year, P ≤ .009, and IV/4 slope for visual field score = 18.6 degrees/year, P = .004, Figure ). As such, treatment appeared to result in successful preservation of vision. The success at preserving vision is evident from the fact that the only 3 “blind” eyes (20/200 or worse) at the 2 year follow-up visit were all blind at presentation from irreversible causes: macular atrophy in 2 birdshot chorioretinitis eyes and foveal scarring from choroidal neovascularization in 1 multifocal choroiditis with panuveitis eye. Of the 6 eyes that were “visually impaired” but not “blind” (visual acuity 20/50–20/160) at 2 years of follow-up, all similarly had irreversible structural damage at presentation (macular atrophy in 4 birdshot chorioretinitis eyes, and subretinal fibrosis from choroidal neovascularization in 1 each multifocal choroiditis with panuveitis and punctate inner choroiditis eyes).
| Outcome | Start Treatment | Follow-up (Months) | ||
|---|---|---|---|---|
| 6 | 12 | 24 | ||
| Entire population | ||||
| Number of patients | 27 | 26 a | 25 | 19 |
| Number of eyes | 49 | 47 | 47 | 35 |
| Mean acuity (SD) | 0.314 (0.27) | 0.289 (0.21) | 0.295 (0.27) | 0.324 (0.36) |
| Mean Snellen visual acuity | 20/41 | 20/39 | 20/39 | 20/42 |
| VA 20/50 to 20/160 (% eyes) | 11 (22%) | 8 (17%) | 4 (9%) | 6 (17%) |
| VA 20/200 or worse (% eyes) | 5 (10%) | 5 (11%) | 6 (13%) | 3 (9%) |
| Birdshot chorioretinitis | ||||
| Number of patients | 14 | 14 | 14 | 11 |
| Number of eyes | 27 | 27 | 27 | 21 |
| Macular edema (% eyes) | 9 (36%) | 6 (26%) | 4 (15%) | 3 (16%) |
| Abnormal Goldmann visual field (% eyes) | 17 (63%) | 8 (38%) | 10 (48%) | 7 (37%) |
| Mean Goldmann IV/4 score (SD) | 761 (69) | 782 (44) | 794 (54) | 784 (57) |
| Mean Goldmann I/4 score (SD) | 496 (115) | 564 (119) | 552 (124) | 564 (125) |
| Mean acuity (SD) | 0.326 (0.19) | 0.290 (0.19) | 0.329 (0.18) | 0.318 (0.25) |
| Mean Snellen visual acuity | 20/42 | 20/39 | 20/43 | 20/42 |
| VA 20/50 to 20/160 (% eyes) | 7 (26%) | 4 (15%) | 3 (11%) | 4 (19%) |
| VA 20/200 or worse (% eyes) | 2 (7%) | 3 (11%) | 4 (15%) | 2 (10%) |
| Multifocal choroiditis with panuveitis | ||||
| Number of patients | 7 | 7 | 7 | 6 |
| Number of eyes | 12 | 12 | 12 | 10 |
| Mean acuity (SD) | 0.369 (0.40) | 0.321 (0.38) | 0.409 (0.78) | 0.454 (0.85) |
| Snellen visual acuity | 20/47 | 20/42 | 20/52 | 20/57 |
| VA 20/50 to 20/160 (% eyes) | 3 (25%) | 3 (25%) | 1 (8%) | 1 (10%) |
| VA 20/200 or worse (% eyes) | 1 (8%) | 1 (8%) | 1 (8%) | 1 (10%) |
| Punctate inner choroiditis | ||||
| Number of patients | 6 | 5 | 4 | 2 |
| Number of eyes | 10 | 8 | 8 | 4 |
| Mean acuity (SD) | 0.254 (0.41) | 0.302 (0.32) | 0.137 (0.16) | 0.199 (0.18) |
| Snellen visual acuity | 20/36 | 20/40 | 20/27 | 20/32 |
| VA 20/50 to 20/160 (% eyes) | 1 (10%) | 1 (12%) | 0 (0%) | 1 (25%) |
| VA 20/200 or worse (% eyes) | 2 (20%) | 1 (12%) | 1 (12%) | 0 (0%) |
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