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Uveitis in Patients with Multiple Sclerosis in Clinical Trials of Fingolimod
Uveitis in Patients with Multiple Sclerosis in Clinical Trials of Fingolimod Incidence, Prevalence, and Impact on Disease Course Lyndell L. Lim, DMedSci, FRANZCO,1,2,3,* Diego G. Silva, MD, PhD,4,* Tiffany C. Lo, MBBS,1,5 Ronald S. Pimentel, PhD,4 Helmut Butzkueven, MBBS, PhD,6,7 Anthony J. Hall, MD, FRANZCO3,5 Purpose: To determine the incidence and prevalence of uveitis and its effect on multiple sclerosis (MS) disease activity and outcomes in patients with MS who participated in the fingolimod clinical trial program. Design: Analysis of pooled data (N ¼ 27 528) from patients enrolled in fingolimod clinical studies and their extensions. Patients were stratified into 4 cohorts based on the history of uveitis at baseline and uveitis events during the observation period: no history and no uveitis events (“no uveitis”); history and no uveitis events (“history”); no history and uveitis events (“first event”); history and uveitis events (“recurrent event”). Participants: Adult patients diagnosed with relapsing or primary progressive MS. Intervention: Patients received fingolimod (0.5, 1.25, or 5 mg/day), placebo, or intramuscular interferon beta1a (IFNb-1a IM) during the core studies; patients receiving placebo or IFNb-1a IM were switched to fingolimod 0.5 mg therapy for study extensions. Main Outcome Measures: Incidence and prevalence of uveitis, and MS outcome measures, including annualized relapse rate (ARR), time to first relapse, change in Expanded Disability Status Scale (EDSS) score from baseline, and proportion of patients with 6-month confirmed disability progression. Results: A total of 189 patients in the analysis population had uveitis. Of these, 162 patients had a history of uveitis (prevalence, 0.59%). Uveitis occurred as a first event in 27 patients (incidence, 0.1 per 100 patient-years) and as a recurrent event in 10 of 162 patients (prevalence, 6.17%). Patients with uveitis had a significantly shorter time to first relapse (mean, 2.11 vs. 8.12 years; P ¼ 0.047) and a significantly higher ARR (0.31 vs. 0.21; P ¼ 0.025) than those without uveitis. Mean increase in EDSS score at month 120 and the proportions of patients with 6-month confirmed disability progression, and with EDSS score 4 during follow-up, were similar in patients with uveitis compared with those without uveitis. Conclusions: This pooled analysis involving a large patient cohort showed that patients with MS and uveitis had increased MS relapse activity compared with those without uveitis. Ophthalmology 2018;-:1e7 ª 2018 by the American Academy of Ophthalmology Supplemental material available at www.aaojournal.org.
The association between multiple sclerosis (MS) and uveitis is well recognized, although data for the prevalence of MS-associated uveitis are limited.1 Reported prevalence of MS-associated uveitis varies widely across studies (0.4%e 28.6%).1-9 This variation in prevalence may reflect differences in patient characteristics, diagnostic criteria, examination modalities, and length of follow-up across studies.1 It has been suggested that uveitis occurs more frequently in individuals with MS than in those without MS.2,10 A case-control study reported that patients with MS were more likely to have uveitis than matched controls,6 and an increased prevalence of uveitis was reported among patients attending an MS outpatient clinic compared with the general population.11 Likewise, there is an increased prevalence of MS in patients with some forms of uveitis, especially intermediate uveitis.1 In one retrospective ª 2018 by the American Academy of Ophthalmology Published by Elsevier Inc.
study of patients with uveitis, 8% of those with intermediate uveitis had MS,12 and, in some case series, rates of development of MS as high as 47.6% have been observed.13 Interestingly, there are similarities between animal models of MS (experimental autoimmune encephalomyelitis) and uveitis (experimental anterior uveitis), which are characterized by T-celledriven responses to central nervous system and retinal proteins, respectively.14 Fingolimod 0.5 mg (Gilenya, Novartis, Basel, Switzerland) is a once-daily oral therapy approved for the treatment of patients with relapsing MS (RMS). The efficacy and safety of fingolimod have been demonstrated in a large program of clinical trials across a range of patients.15-20 Because of the recognized risk of macular edema after fingolimod initiation, patients enrolled in these trials https://doi.org/10.1016/j.ophtha.2018.10.013 ISSN 0161-6420/18
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Ophthalmology Volume -, Number -, Month 2018 underwent standardized protocol-mandated repeated ophthalmic examination as part of their safety and tolerability assessments.21 These studies present a large data set in which the association between MS and uveitis may be investigated in a large cohort of patients. The aim of this pooled analysis was to determine the long-term incidence and prevalence of uveitis and its association with MS disease activity and outcomes in patients with MS enrolled in the fingolimod clinical trial program.
Methods Patient Population This pooled analysis included data from patients enrolled in fingolimod clinical trials and their extensions for RMS or primary progressive MS (PPMS). Details of these trials are shown in Table S1 (available at www.aaojournal.org). The cutoff date for data included in the analysis was February 28, 2017. All fingolimod trials were conducted in accordance with the International Conference on Harmonisation Guidelines for Good Clinical Practice and the Declaration of Helsinki. Institutional Review Board/Ethics Committee approval was obtained for each study, and patients gave written informed consent before the start of any study-related procedures. The analysis included patients with RMS and PPMS from phase 2, 3, and 4 fingolimod studies, as shown in Table S1 (available at www.aaojournal.org).15-18 For phase 2 and 3 studies, after the initial treatment periods of 6 to 24 months, patients could continue into study extension phases, so that the total observed time could exceed 60 months. In the extension period, patients initially randomized to placebo or intramuscular interferon beta-1a (IFNb-1a) were switched to fingolimod therapy. Fingolimod 0.5 mg is the approved dose; patients who received fingolimod 1.25 mg during the registration studies (n ¼ 1514) were switched to fingolimod 0.5 mg during the trial extensions.16 Inclusion and exclusion criteria varied in phase 2 and 3 studies; in general, these studies included patients aged 18 to 55 years diagnosed with RMS and with 1 or more documented relapses in the previous year, or 2 or more in the previous 2 years, and a score of 0 to 5.5 on the Expanded Disability Status Scale (EDSS).16-18 Phase 4 studies included patients with RMS in accordance with the local approved indication. Patients with PPMS were included from a single randomized, double-blind, phase 3 study comparing oral fingolimod with placebo over at least 36 months of treatment.22 The study enrolled patients aged 25 to 65 years with a clinical diagnosis of PPMS.22
Figure 1. Patient cohorts by history of uveitis/uveitis events.
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Pooled Analysis Cohorts and Assessment Measures Patients who received at least 1 dose of fingolimod during the clinical trials or their extension phases were included in this pooled analysis; patients were excluded from this analysis if they had been excluded from any of the trials because of protocol deviation. For the analysis, patients were stratified into 4 cohorts based on their history of uveitis at baseline and uveitis events during the observation period. Patients with no history of uveitis and no on-study uveitis events were included in the “no uveitis” cohort; patients with uveitis history or an on-study uveitis event were included in 1 of 3 uveitis cohorts: history, first event, or recurrent event (Fig 1). A history of uveitis at enrollment was established from patient reporting at screening or baseline for the core study. Medical history data were collected and reviewed by the principal investigator according to the protocols for each of the studies included in this analysis. In the phase 2 and 3 trials, self-reported uveitis history details were confirmed for accuracy against medical records (e.g., to exclude the possibility of other forms of ocular inflammation), with ophthalmological assessments or confirmation of uveitis performed routinely by a specialist ophthalmologist. On-study uveitis events were identified from adverse events recorded for each study using the Medical Dictionary for Regulatory Activities Preferred Term “uveitis.” The prevalence of uveitis was determined using patients with a history of uveitis; the incidence of uveitis per 100 patient-years was determined separately for patients with no history of uveitis and for patients with a history of uveitis. Time to first uveitis event was taken as the time from the first dose of any study drug to the reporting of any new uveitis event. The analysis also investigated whether patients with uveitis differed from those without uveitis for baseline demographics, MS disease characteristics, and MS disease outcomes. Baseline demographics and MS disease characteristics were summarized using data collected at screening/baseline from the patient’s core study; MS outcome measures were evaluated from data collected at each study visit. The MS outcome measures included number of relapses, annualized relapse rate (ARR), time to first MS relapse (calculated from first dose of study drug), and change in EDSS score from baseline to the end of the study, up to month 120 for some patients. The numbers of patients with EDSS score of 4 or above and 6 or above at any time after first dose of study drug were calculated for patients with a baseline EDSS score below 4 and below 6, respectively. The number of patients with 6-month confirmed disability progression (defined as an increase in EDSS score of at least 0.5, at least 1.0, or at least 1.5 points for patients with an EDSS score at baseline of 0, 1e5, or at least 5.5, respectively) during follow-up was also determined. In addition,
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Impact of Uveitis on the Course of MS
brain magnetic resonance imaging (MRI) outcomes (number of new/enlarged T2 lesions and percentage change in brain volume) and EDSS scores were assessed over 48 and 120 months of treatment, respectively.
Statistical Analyses Incidence and prevalence data were analyzed for the overall population and by study treatment at initial randomization (fingolimod, IFNb-1a IM, or placebo). Baseline characteristics and MS disease outcomes were analyzed for patients without uveitis and for all patients with uveitis combined, as well as for the individual uveitis subgroups (history, first event, recurrent event). KaplaneMeier estimates (with 95% confidence intervals) were made for time-tofirst uveitis event and time-to-first relapse, and an overall log-rank test was performed to assess significance between the uveitis and no uveitis groups. Comparisons between the uveitis and no uveitis groups for baseline measures and MS disease outcomes were analyzed using an overall log-rank test. Comparisons for uveitis incidence and prevalence by initial/randomized treatment groups were analyzed by Fisher exact test.
Results A total of 27 528 patients were included in the overall analysis population. The mean age was 39.7 years, and most patients were women (70.3%) and white (71.7%). Baseline demographics are detailed in Table S2 (available at www.aaojournal.org). Average time since MS diagnosis was 7.4 years, and the mean EDSS score at baseline was 2.8. A total of 189 patients in the analysis population had uveitis before enrollment or during the study period. A history of uveitis was reported in 162 patients (prevalence, 0.59%), and 44 uveitis events were reported in 37 patients during an overall mean observation period of 627 days (Table 1). Uveitis occurred as a first event in 27 patients, resulting in an incidence of 0.1 per 100 patient-years, and as a recurrent event in 10 of 162 patients. Uveitis on-study was mild or moderate in most patients, either as a first event (25 of 27 patients) or as a recurrent event (8 of 10 patients). In total, 18 patients required treatment, including 3 of the 4
patients with severe uveitis. The type of uveitis was anterior, n ¼ 2; intermediate, n ¼ 4; panuveitis, n ¼ 1; and not specified, n ¼ 30 (Table S3, available at www.aaojournal.org). In-depth clinical details of on-study uveitis events were available from 52 adverse event reports for 18 patients. Of these, 2 were cases of anterior uveitis, and there was 1 case each of intermediate uveitis, granulomatous uveitis, and panuveitis. Five cases of uveitis were described as unilateral. Two cases of uveitis were complicated by macular edema. One case of uveitis required topical glaucoma therapy. One patient was listed as having acute anterior uveitis, with 3 further cases listed as chronic; however, this descriptor (acute, chronic, or persistent) was not given in other reports. Two cases required treatment with oral prednisone, with the remaining treated cases receiving topical steroid preparations. Nine cases required continuous treatment with corticosteroid for less than 3 months, and 4 cases required treatment for at least 3 months. No other details (e.g., visual acuity) were available. There was no significant difference in the prevalence of uveitis between patients with RMS (0.45; N ¼ 16 873) and patients with PPMS (0.40; N ¼ 970). Analysis of the time-to-first uveitis event after the first dose of study drug showed no association between MS disease duration and the onset of uveitis.
Multiple Sclerosis Outcomes in Patients with Uveitis Analysis of demographics and MS disease characteristics at baseline by uveitis status showed that, compared with patients in the no uveitis group, patients in the uveitis group were significantly older (41.9 vs. 39.7 years; P ¼ 0.003) and had significantly more T2 lesions (30.2 vs. 21.2; P ¼ 0.018) but had experienced significantly fewer relapses in the previous 2 years (1.7 vs. 2.0; P ¼ 0.022; Table 2). Similar findings were observed for the individual uveitis subgroups compared with the no uveitis group, although the small numbers of patients in the first event and recurrent event cohorts meant that differences did not reach statistical significance. Multiple sclerosis disease characteristics were generally similar across the uveitis subgroups, although patients in the recurrent event cohort had longer disease duration and fewer gadoliniumenhancing T1 lesions than those in the other 2 uveitis cohorts (Table 2).
Table 1. Incidence and Prevalence of Uveitis by Initial/Randomized Treatment Parameter Mean observation period, days Total patient-yrsy History of Uveitis Patients with history of uveitis Prevalence, % On-study Uveitis Patients with uveitis events, n (%) Total number of uveitis eventsk Patients with uveitis as a first event, n (%) Incidence/100 patient-yrs Patients with a recurrent uveitis event, n (%)
Fingolimod All Doses* (n [ 24 864)
Placebo (n [ 1531)
Interferon beta-1a (n [ 1133)
Overall Population (N [ 27 528)
633 43 116
668 2801
425 1318
627 47 235
139 0.56z
8 0.52
15 1.32x
162 0.59
28z (0.1) 33 23 (0.1) 0.1 5z (3.60)
4 (0.3) 4 3 (0.2) 0.1 1 (12.50)
5 (0.4) 7 1 (0.1) 0.1 4 (26.67)
37 (0.1) 44 27 (0.1) 0.1 10 (6.17)
Treatment groups were based on initial randomization; patients were switched to fingolimod 0.5 mg in the extension studies. *Patients initially randomized to receive fingolimod were given 0.5 mg, 1.25 mg, or 5 mg fingolimod. y Total patient-years are defined as the sum of the number of years under the initial/randomized treatment. z P < 0.05 compared with interferon beta-1a, estimated by Fisher exact test. x P < 0.05 compared with placebo, estimated by Fisher exact test. k Patients may have had >1 uveitis event during the observation period.
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Ophthalmology Volume -, Number -, Month 2018 Table 2. Baseline Characteristics of Patients with or without Uveitis in the Overall Population Uveitis Parameter
No Uveitis (N [ 27 339) All (N ¼ 189) History (n ¼ 152) First Event (n ¼ 27) Recurrent Event (n ¼ 10)
Women, n (%) Age, yrs Duration of MS since diagnosis, yrs No. of relapses in the preceding 2 yrs EDSS score No. of T2 lesions No. of Gdþ T1 lesions Normalized brain volume, ml
19 214 (70.3) 39.710.3 7.46.4 2.01.7 2.81.7 21.228.9 1.13.4 1513.585.3
132 (69.8) 41.99.7* 7.36.5 1.71.4y 2.81.5 30.238.6y 1.33.7 1509.774.8
101 (66.4) 42.29.9* 7.26.3 1.81.5 2.81.5 31.340.9y 1.64.4 1513.876.8
23 (85.2) 40.58.9 7.74.8 1.50.9 3.31.8 25.431.5 0.81.5 1497.660.6
8 (80.0) 41.89.8 8.612.0 1.60.5 2.81.8 35.644.4 0.20.4 1508.198.4
Data are presented as mean standard deviation unless stated otherwise. P values were determined using an overall log rank test. EDSS ¼ Expanded Disability Status Scale; Gdþ ¼ gadolinium-enhancing; MS ¼ multiple sclerosis; SD ¼ standard deviation. *P < 0.01. y P < 0.05 vs. patients without uveitis.
Analysis of MS disease activity by uveitis status showed that time-to-first relapse was significantly shorter in the uveitis group than in the no uveitis group (mean standard error, 2.110.06 vs. 8.120.03 years; P ¼ 0.047). The ARR was approximately 50% higher in patients with uveitis than in those without uveitis (0.31 vs. 0.21; P ¼ 0.025; Table 3). The EDSS change or confirmed disability progression rates were no different between groups (Table 3). Some potential differences in disease outcomes were observed across the uveitis subgroups, although these should be interpreted with caution given the small numbers of patients in the first and recurrent event cohorts. In particular, the first event subgroup had a numerically greater EDSS worsening at study end than the other groups, with higher rates of confirmed disability progression and higher proportions of patients with EDSS scores of 4 or above and 6 or above than the other uveitis subgroups or nonuveitis groups (Table 3). Evaluation of long-term changes in EDSS score showed that EDSS scores increased numerically from baseline to 120 months in both the uveitis and no uveitis groups and across all uveitis subgroups. At study end, mean EDSS scores were numerically higher in the uveitis subgroup than in the no uveitis group, as shown in
Table S4 (available at www.aaojournal.org). Long-term brain MRI assessments showed a numerically greater percentage reduction in brain volume at month 48 for patients with uveitis than without uveitis (1.70 vs. 1.55%). The mean number of new T2 lesions increased over time and was similar in the uveitis and no uveitis groups at month 48, as shown in Table S5 (available at www.aaojournal.org).
Discussion This is the largest assessment to date of the prevalence and incidence of uveitis in patients with MS and its relationship with disease outcomes. Our analysis showed, in a prospective cohort of more than 27 500 patients with MS who participated in the fingolimod clinical trial program, that patients with a history of uveitis or with uveitis during the study observation period had increased relapse activity compared with those without uveitis. No causative link can be inferred by this association, but identification of uveitis
Table 3. Multiple Sclerosis Disease Outcomes in Patients with or without Uveitis in the Overall Population Uveitis Outcome MS relapses Mean SD ARR Mean SD EDSS change from baseline at month 120 Mean SD 6-mo confirmed disability progression Proportion of patients, n (%) EDSS score 4 Proportion of patients, n (%) EDSS score 6 Proportion of patients, n (%)
No Uveitis (N [ 27 339) All (N ¼ 189) History (n ¼ 152) First Event (n ¼ 27) Recurrent Event (n ¼ 10) n ¼ 15 234 0.51.1 n ¼ 15 234 0.210.48 n ¼ 16 749 0.131.06 n ¼ 25 602 1996 (7.6) n ¼ 18 768 1935 (10.3) n ¼ 23 791 1215 (5.1)
n ¼ 106 0.71.3* n ¼ 106 0.310.64* n ¼ 134 0.201.06 n ¼ 181 17 (9.4) n ¼ 132 20 (15.2) n ¼ 170 9 (5.3)
n ¼ 76 0.81.4* n ¼ 76 0.340.71* n ¼ 101 0.110.96 n ¼ 145 10 (6.9) n ¼ 108 14 (13.0) n ¼ 138 6 (4.3)
n ¼ 23 0.61.2 n ¼ 23 0.180.32 n ¼ 24 0.501.42 n ¼ 26 5 (19.2) n ¼ 16 5 (31.3) n ¼ 23 3 (13.0)
n¼7 0.60.8 n¼7 0.390.61 n¼9 0.440.81 n ¼ 10 2 (20.0) n¼8 1 (12.5) n¼9 0 (0.0)
ARR ¼ annualized relapse rate; CDP ¼ confirmed disability progression; EDSS ¼ Expanded Disability Status Scale; MS ¼ multiple sclerosis; SD ¼ standard deviation. P values were determined using an overall log rank test. N ¼ number of patients assessed. *P < 0.05 versus patients without uveitis.
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Impact of Uveitis on the Course of MS
as a possible risk factor for more aggressive MS may be useful information for physicians when reviewing MS treatment options. The presence of uveitis in MS may be autoimmune related, although whether uveitis is an autoimmune disease in its own right remains unclear.23 The presence of nonautoimmune comorbidities in MS is generally associated with worse MS outcomes,24,25 but analyses of the MS disease course in patients with psoriasis26 or inflammatory bowel disease27 suggest that MS progresses more slowly in patients with MS and a second autoimmune disease than in control patients. Given the association between uveitis and autoinflammatory disease,23 copresentation of MS and uveitis may signal an exaggerated autoinflammatory response, with increased relapse and MRI lesion activity relative to controls. The overall incidence (0.1 per 100 patient-years) and prevalence (0.59%) of uveitis in this large MS cohort analysis were low compared with other analyses. Prevalence is at the lower end of the range reported in previous studies (0.4%e28.6%) but is consistent with the low prevalence observed in large database studies.1 For example, 2 retrospective database reviews, each involving more than 4000 patients with MS, reported a prevalence of approximately 0.7%,7,8 and a prevalence of 1.1% was seen in a review of more than 1000 consecutive patients at an MS clinic.2 The prevalence of uveitis in patients with MS is, however, much higher than in patients without MS, with a prevalence of approximately 0.04% reported for the general population in the United Kingdom and France.7,11 All data included in this analysis originated from clinical trials and are thus considered highly reliable. However, history of uveitis was determined by patient self-reporting, which could have introduced potential bias or inaccuracies. Over reporting may have occurred in patients who did not have uveitis but instead had other, more benign, ocularinflammatory conditions, whereas underreporting may have occurred in patients who had relatively asymptomatic or undiagnosed intermediate uveitis. Indeed, postmortem studies have revealed a surprisingly high incidence of undiagnosed uveitis in patients with MS.28 To reduce such errors, ophthalmological assessments or confirmation of uveitis was performed routinely by a specialist ophthalmologist in the phase 2 and 3 studies. However, these assessments were not necessarily carried out routinely in the phase 4 trials; thus, confirmation that patient history had been checked for accuracy against medical records did not exist in all cases. A further limitation of this study is possible selection bias due to exclusion from the randomized fingolimod trials of patients with a history of macular edema. Also, most of the patients considered in this analysis participated in phase 4, routine practice studies. Macular edema is listed under the warnings and precautions given in the fingolimod label, so patients predisposed to macular edema by ophthalmological conditions, including uveitis, may not have been prescribed fingolimod by their treating physician. Thus, these patients would have been excluded from the phase 4 studies. Therefore, the findings from our analysis likely represent the lower limit of the incidence and prevalence of uveitis in patients with MS. Despite this potential selection bias, we believe our findings can be generalized to other patients at a
similar stage and with a similar MS phenotype. Our analysis was based on a large cohort of more than 27 000 patients, of whom more than 95% had RMS. It also has the advantage over registry and retrospective studies of being based on prospective data, which are generally more robust than data from patient medical records. The current analysis showed that patients with uveitis were generally older with substantially more T2 lesions (particularly among patients with a history of uveitis) but overall had experienced fewer relapses in the previous 2 years than patients without uveitis. Previous studies comparing the characteristics of patients with MS with and without uveitis are limited. A retrospective database study reported a similar mean duration of MS for patients with and without uveitis (12.9 vs. 11.5 years; P ¼ 0.44) and no significant differences between the 2 groups for mean age at MS onset or sex ratio.7 Another retrospective study in patients with MS reported a trend toward higher mean age at onset of MS in patients with uveitis than in those without uveitis (31.1 vs. 27.9 years; P ¼ 0.09), although the mean duration of MS was similar (with uveitis, 10.6 years; no uveitis, 10.3 years).8 In a small case-comparison study, patients with MS and intermediate uveitis were significantly older at the time of first diagnosis of uveitis and more likely to be female than control individuals with idiopathic intermediate uveitis.29 Our analysis showed that ARR was significantly higher, and time to first relapse was significantly shorter in patients with uveitis than without uveitis, despite the higher MS relapse rate observed in the no uveitis group before baseline. Few previous studies have investigated the potential effect of uveitis on disease outcomes in patients with MS. In a retrospective, case-control study, 41 patients with MS and uveitis were compared with 100 unmatched, randomly selected patients with MS and no uveitis.8 Analysis showed significantly better disease outcomes, as assessed by EDSS score and progression index, in the uveitis group than in the no uveitis group. However, patient numbers in the study were small, and there was a marked difference in the types of MS (relapsing or progressive) seen in the 2 groups at baseline.8 A similar retrospective study in patients with MS compared disability outcomes in 28 patients with uveitis and 1553 patients without uveitis.7 This showed no significant difference between patients with uveitis and patients without uveitis in the median time to progression to an EDSS score of 4 (12 vs. 11.4 years; P ¼ 0.44) or an EDSS score of 6 (23.9 vs. 24.9 years; P ¼ 0.66). Multiple sclerosiseassociated uveitis is not well characterized, although there are suggested autoimmune and genetic aspects that may implicate an inflammatory response modulated by the human leukocyte antigen (HLA) system.1 An autoimmune association between MS and uveitis is supported by reports of autoantibodies against both brain and retinal arrestin in patients with MS.30,31 Increased T-cell proliferative responses to brain and retinal arrestin have been observed in patients with MS, which may suggest a mechanism of uveitis in MS.32 Furthermore, predisposition to MS is associated with the HLA-DR15 haplotype (a subtype of HLA-DR2) in HLA population studies in white individuals of Northern European
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Ophthalmology Volume -, Number -, Month 2018 descent.33 Intermediate uveitis has also been associated with the HLA-DR15 haplotype.34,35 A key strength of our analysis is the involvement of the prospective collection of clinical data and adverse outcomes (i.e., uveitis) in a large number of well-characterized patients with MS. However, there are a number of limitations associated with the study. Recruitment bias may have affected the prevalence and incidence of uveitis seen in this patient cohort. Macular edema is a known side effect of fingolimod and was an exclusion criterion for key fingolimod clinical trials.17,18 Given that macular edema is a recognized complication of uveitis, this likely would have led to under-enrollment of patients with uveitis. However, not all cases of uveitis are associated with macular edema, and a history of uveitis was not grounds for exclusion from the trials. The inclusion of noninterventional studies not designed to detect uveitis as an adverse event may have resulted in its under-reporting. Other limitations are that the anatomic subtype and severity of uveitis before enrollment, and, in most cases, the anatomic subtype of uveitis on study was not specified. The number of patients included in the uveitis group was small; numerically, it was less than 1% of the total group. Therefore, the statistical comparisons between the 2 groups should be interpreted with a degree of caution. Finally, fingolimod has been demonstrated to have a treatment effect on uveitis in animal studies; therefore, an effect of fingolimod on the incidence of uveitis cannot be excluded. Uveitis occurrence rates by treatment group at randomization (Table 1) were the same, but most patients included in this analysis were exposed to fingolimod, including those initially randomized to a comparator group. Also, no difference in occurrence rates was seen between groups randomized to different doses of fingolimod; however, as noted in the study methodology, most of these patients would have switched to the 0.5 mg dose. In conclusions, our pooled analysis involving a large cohort of patients from the fingolimod clinical trial program showed that patients with MS and uveitis had increased MS disease activity compared with those without uveitis. Therefore, uveitis should be considered a risk factor for greater disease activity in MS. Acknowledgments Writing assistance was provided by Dr. Alex Gavin of Oxford PharmaGenesis Ltd. A manuscript draft was prepared for the named authors to edit. Writing assistance was funded by Novartis Pharma AG.
References 1. Vadboncoeur J, Biernacki K, Prat A, Jaworski L. Multiple sclerosis-associated uveitis. Exp Rev Ophthalmol. 2017;12: 57e67. 2. Biousse V, Trichet C, Bloch-Michel E, Roullet E. Multiple sclerosis associated with uveitis in two large clinic-based series. Neurology. 1999;52:179e181. 3. Breger BC, Leopold IH. The incidence of uveitis in multiple sclerosis. Am J Ophthalmol. 1966;62:540e545.
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4. Karara AM, Macky TA, Sharawy MH. Pattern of uveitis in an Egyptian population with multiple sclerosis: a hospital-based study. Ophthalmic Res. 2013;49:25e29. 5. Kaya D, Kaya M, Ozakbas S, Idiman E. Uveitis associated with multiple sclerosis: complications and visual prognosis. Int J Ophthalmol. 2014;7:1010e1013. 6. Langer-Gould A, Albers KB, Van Den Eeden SK, Nelson LM. Autoimmune diseases prior to the diagnosis of multiple sclerosis: a population-based case-control study. Mult Scler. 2010;16:855e861. 7. Le Scanff J, Seve P, Renoux C, et al. Uveitis associated with multiple sclerosis. Mult Scler. 2008;14:415e417. 8. Shugaiv E, Tuzun E, Kurtuncu M, et al. Uveitis as a prognostic factor in multiple sclerosis. Mult Scler. 2015;21:105e107. 9. Vidovic T, Cerovski B, Jukic T. The appearance of pars planitis in multiple sclerosis. Coll Antropol. 2005;29:203e206. 10. Graves J, Balcer LJ. Eye disorders in patients with multiple sclerosis: natural history and management. Clin Ophthalmol. 2010;4:1409e1422. 11. Edwards LJ, Constantinescu CS. A prospective study of conditions associated with multiple sclerosis in a cohort of 658 consecutive outpatients attending a multiple sclerosis clinic. Mult Scler. 2004;10:575e581. 12. Zein G, Berta A, Foster CS. Multiple sclerosis-associated uveitis. Ocul Immunol Inflamm. 2004;12:137e142. 13. Prieto JF, Dios E, Gutierrez JM, et al. Pars planitis: epidemiology, treatment, and association with multiple sclerosis. Ocul Immunol Inflamm. 2001;9:93e102. 14. Calder VL, Lightman SL. Experimental autoimmune uveoretinitis (EAU) versus experimental allergic encephalomyelitis (EAE): a comparison of T cell-mediated mechanisms. Clin Exp Immunol. 1992;89:165e169. 15. Kappos L, Antel J, Comi G, et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med. 2006;355: 1124e1140. 16. Kappos L, Radue EW, O’Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362:387e401. 17. Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362:402e415. 18. Calabresi PA, Radue EW, Goodin D, et al. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebocontrolled, phase 3 trial. Lancet Neurol. 2014;13:545e556. 19. Khatri BO. Fingolimod in the treatment of relapsingremitting multiple sclerosis: long-term experience and an update on the clinical evidence. Ther Adv Neurol Disord. 2016;9:130e147. 20. Kappos L, O’Connor P, Radue EW, et al. Long-term effects of fingolimod in multiple sclerosis: the randomized FREEDOMS extension trial. Neurology. 2015;84:1582e1591. 21. Zarbin MA, Jampol LM, Jager RD, et al. Ophthalmic evaluations in clinical studies of fingolimod (FTY720) in multiple sclerosis. Ophthalmology. 2013;120:1432e1439. 22. Lublin F, Miller DH, Freedman MS, et al. Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet. 2016;387:1075e1084. 23. Forrester JV, Kuffova L, Dick AD. Autoimmunity, autoinflammation and infection in uveitis. Am J Ophthalmol. 2018;189:77e85. 24. Conway DS, Thompson NR, Cohen JA. Influence of hypertension, diabetes, hyperlipidemia, and obstructive lung disease on multiple sclerosis disease course. Mult Scler. 2017;23: 277e285.
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25. Kowalec K, McKay KA, Patten SB, et al. Comorbidity increases the risk of relapse in multiple sclerosis: a prospective study. Neurology. 2017;89:2455e2461. 26. Miron G, Gurevich M, Baum S, et al. Psoriasis comorbidity affects multiple sclerosis neurological progression: a retrospective case-control analysis. J Eur Acad Dermatol Venereol. 2017;31:2055e2061. 27. Zephir H, Gower-Rousseau C, Salleron J, et al. Milder multiple sclerosis course in patients with concomitant inflammatory bowel disease. Mult Scler. 2014;20:1135e1139. 28. Kerrison JB, Flynn T, Green WR. Retinal pathologic changes in multiple sclerosis. Retina. 1994;14:445e451. 29. Messenger W, Hildebrandt L, Mackensen F, et al. Characterisation of uveitis in association with multiple sclerosis. Br J Ophthalmol. 2015;99:205e209. 30. McDowell JH, Smith WC, Miller RL, et al. Sulfhydryl reactivity demonstrates different conformational states for arrestin,
31. 32. 33. 34. 35.
arrestin activated by a synthetic phosphopeptide, and constitutively active arrestin. Biochemistry. 1999;38:6119e6125. Ohguro H, Chiba S, Igarashi Y, et al. Beta-arrestin and arrestin are recognized by autoantibodies in sera from multiple sclerosis patients. Proc Natl Acad Sci U S A. 1993;90:3241e3245. Forooghian F, Cheung RK, Smith WC, et al. Enolase and arrestin are novel nonmyelin autoantigens in multiple sclerosis. J Clin Immunol. 2007;27:388e396. Giordano M, D’Alfonso S, Momigliano-Richiardi P. Genetics of multiple sclerosis: linkage and association studies. Am J Pharmacogenomics. 2002;2:37e58. Raja SC, Jabs DA, Dunn JP, et al. Pars planitis: clinical features and class II HLA associations. Ophthalmology. 1999;106:594e599. Tang WM, Pulido JS, Eckels DD, et al. The association of HLA-DR15 and intermediate uveitis. Am J Ophthalmol. 1997;123:70e75.
Footnotes and Financial Disclosures Originally received: December 6, 2017. Final revision: September 27, 2018. Accepted: October 4, 2018. Available online: ---.
Manuscript no. 2017-2776.
1
Centre for Eye Research Australia, University of Melbourne, Parkville, VIC, Australia.
2
Royal Victorian Eye and Ear Hospital, Melbourne, VIC, Australia.
3
Eye Surgery Associates, East Melbourne, VIC, Australia.
4
Novartis Pharma AG, Basel, Switzerland.
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Department of Ophthalmology, Alfred Hospital, Melbourne, VIC, Australia. 6 MSNI, Department of Neuroscience, Central Clinical School, Alfred Campus, Monash University, VIC, Australia. 7
Writing support was provided by Oxford PharmaGenesis Ltd. (Oxford, UK) and funded by Novartis Pharma AG (Basel, Switzerland). Employees of Novartis Pharma AG are listed as authors of this manuscript and participated in the design and conduct of the study, collection, management, analysis, and interpretation of data, and preparation, review, and approval of the manuscript. HUMAN SUBJECTS: Human subjects were included in this study. Institutional Review Board/Ethics Committee approval noted in main manuscript methods section. All fingolimod trials were conducted in accordance with the International Conference on Harmonisation Guidelines for Good Clinical Practice and the Declaration of Helsinki. Institutional Review Board/Ethics Committee approval was obtained for each study, and patients gave written informed consent before the start of any study related procedures.
MS Unit, Department of Neurology, Eastern Health, Monash University, Clayton, VIC, Australia.
No animal subjects were used in this study.
Presented at: the Association for Research in Vision and Ophthalmology Annual meeting, May 7e11, 2017, Baltimore, Maryland; and The Royal Australian and New Zealand College of Ophthalmologists Annual Scientific Congress, Perth, Australia, October 28 to November 1, 2017.
Conception and design: Lim, Silva, Pimentel, Hall
*L.L.L. and D.G.S. contributed equally toward this work. Financial Disclosure(s): The author(s) have made the following disclosure(s): L.L.L.: Advisory boards and consultant e AbbVie, Bayer, Allergan, and her institution has received research funding from AbbVie and Bayer. H.B.: Scientific advisory boards e Biogen, Novartis, Merck, Teva; Consultancy and lecture fees e Novartis, Biogen; Steering committees e trials and studies conducted by Biogen, Merck, Roche, Novartis; and his institutions have received research support from Novartis and Biogen. A.J.H.: Advisory board and consultant e AbbVie; Research support e Novartis.
Author Contributions: Data collection: Silva, Pimentel, Butzkueven, Hall Analysis and interpretation: Lim, Silva, Lo, Pimentel, Butzkueven, Hall Obtained funding: Lim, Silva, Pimentel, Butzkueven, Hall Overall responsibility: Lim, Silva, Lo, Pimentel, Butzkueven, Hall Abbreviations and Acronyms: ARR ¼ annualized relapse rate; EDSS ¼ Expanded Disability Status Scale; HLA ¼ human leukocyte antigen; IFNb-1a IM ¼ intramuscular interferon beta-1a; MRI ¼ magnetic resonance imaging; MS ¼ multiple sclerosis; PPMS ¼ primary progressive multiple sclerosis; RMS ¼ relapsing multiple sclerosis. Correspondence: Anthony J. Hall, MD, FRANZCO, Department of Ophthalmology, Alfred Hospital, Melbourne, VIC, Australia. E-mail: [email protected].
D.G.S. and R.S.P.: Employees e Novartis.
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The association between multiple sclerosis (MS) and uveitis is well recognized, although data for the prevalence of MS-associated uveitis are limited.1 Reported prevalence of MS-associated uveitis varies widely across studies (0.4%e 28.6%).1-9 This variation in prevalence may reflect differences in patient characteristics, diagnostic criteria, examination modalities, and length of follow-up across studies.1 It has been suggested that uveitis occurs more frequently in individuals with MS than in those without MS.2,10 A case-control study reported that patients with MS were more likely to have uveitis than matched controls,6 and an increased prevalence of uveitis was reported among patients attending an MS outpatient clinic compared with the general population.11 Likewise, there is an increased prevalence of MS in patients with some forms of uveitis, especially intermediate uveitis.1 In one retrospective ª 2018 by the American Academy of Ophthalmology Published by Elsevier Inc.
study of patients with uveitis, 8% of those with intermediate uveitis had MS,12 and, in some case series, rates of development of MS as high as 47.6% have been observed.13 Interestingly, there are similarities between animal models of MS (experimental autoimmune encephalomyelitis) and uveitis (experimental anterior uveitis), which are characterized by T-celledriven responses to central nervous system and retinal proteins, respectively.14 Fingolimod 0.5 mg (Gilenya, Novartis, Basel, Switzerland) is a once-daily oral therapy approved for the treatment of patients with relapsing MS (RMS). The efficacy and safety of fingolimod have been demonstrated in a large program of clinical trials across a range of patients.15-20 Because of the recognized risk of macular edema after fingolimod initiation, patients enrolled in these trials https://doi.org/10.1016/j.ophtha.2018.10.013 ISSN 0161-6420/18
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Ophthalmology Volume -, Number -, Month 2018 underwent standardized protocol-mandated repeated ophthalmic examination as part of their safety and tolerability assessments.21 These studies present a large data set in which the association between MS and uveitis may be investigated in a large cohort of patients. The aim of this pooled analysis was to determine the long-term incidence and prevalence of uveitis and its association with MS disease activity and outcomes in patients with MS enrolled in the fingolimod clinical trial program.
Methods Patient Population This pooled analysis included data from patients enrolled in fingolimod clinical trials and their extensions for RMS or primary progressive MS (PPMS). Details of these trials are shown in Table S1 (available at www.aaojournal.org). The cutoff date for data included in the analysis was February 28, 2017. All fingolimod trials were conducted in accordance with the International Conference on Harmonisation Guidelines for Good Clinical Practice and the Declaration of Helsinki. Institutional Review Board/Ethics Committee approval was obtained for each study, and patients gave written informed consent before the start of any study-related procedures. The analysis included patients with RMS and PPMS from phase 2, 3, and 4 fingolimod studies, as shown in Table S1 (available at www.aaojournal.org).15-18 For phase 2 and 3 studies, after the initial treatment periods of 6 to 24 months, patients could continue into study extension phases, so that the total observed time could exceed 60 months. In the extension period, patients initially randomized to placebo or intramuscular interferon beta-1a (IFNb-1a) were switched to fingolimod therapy. Fingolimod 0.5 mg is the approved dose; patients who received fingolimod 1.25 mg during the registration studies (n ¼ 1514) were switched to fingolimod 0.5 mg during the trial extensions.16 Inclusion and exclusion criteria varied in phase 2 and 3 studies; in general, these studies included patients aged 18 to 55 years diagnosed with RMS and with 1 or more documented relapses in the previous year, or 2 or more in the previous 2 years, and a score of 0 to 5.5 on the Expanded Disability Status Scale (EDSS).16-18 Phase 4 studies included patients with RMS in accordance with the local approved indication. Patients with PPMS were included from a single randomized, double-blind, phase 3 study comparing oral fingolimod with placebo over at least 36 months of treatment.22 The study enrolled patients aged 25 to 65 years with a clinical diagnosis of PPMS.22
Figure 1. Patient cohorts by history of uveitis/uveitis events.
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Pooled Analysis Cohorts and Assessment Measures Patients who received at least 1 dose of fingolimod during the clinical trials or their extension phases were included in this pooled analysis; patients were excluded from this analysis if they had been excluded from any of the trials because of protocol deviation. For the analysis, patients were stratified into 4 cohorts based on their history of uveitis at baseline and uveitis events during the observation period. Patients with no history of uveitis and no on-study uveitis events were included in the “no uveitis” cohort; patients with uveitis history or an on-study uveitis event were included in 1 of 3 uveitis cohorts: history, first event, or recurrent event (Fig 1). A history of uveitis at enrollment was established from patient reporting at screening or baseline for the core study. Medical history data were collected and reviewed by the principal investigator according to the protocols for each of the studies included in this analysis. In the phase 2 and 3 trials, self-reported uveitis history details were confirmed for accuracy against medical records (e.g., to exclude the possibility of other forms of ocular inflammation), with ophthalmological assessments or confirmation of uveitis performed routinely by a specialist ophthalmologist. On-study uveitis events were identified from adverse events recorded for each study using the Medical Dictionary for Regulatory Activities Preferred Term “uveitis.” The prevalence of uveitis was determined using patients with a history of uveitis; the incidence of uveitis per 100 patient-years was determined separately for patients with no history of uveitis and for patients with a history of uveitis. Time to first uveitis event was taken as the time from the first dose of any study drug to the reporting of any new uveitis event. The analysis also investigated whether patients with uveitis differed from those without uveitis for baseline demographics, MS disease characteristics, and MS disease outcomes. Baseline demographics and MS disease characteristics were summarized using data collected at screening/baseline from the patient’s core study; MS outcome measures were evaluated from data collected at each study visit. The MS outcome measures included number of relapses, annualized relapse rate (ARR), time to first MS relapse (calculated from first dose of study drug), and change in EDSS score from baseline to the end of the study, up to month 120 for some patients. The numbers of patients with EDSS score of 4 or above and 6 or above at any time after first dose of study drug were calculated for patients with a baseline EDSS score below 4 and below 6, respectively. The number of patients with 6-month confirmed disability progression (defined as an increase in EDSS score of at least 0.5, at least 1.0, or at least 1.5 points for patients with an EDSS score at baseline of 0, 1e5, or at least 5.5, respectively) during follow-up was also determined. In addition,
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brain magnetic resonance imaging (MRI) outcomes (number of new/enlarged T2 lesions and percentage change in brain volume) and EDSS scores were assessed over 48 and 120 months of treatment, respectively.
Statistical Analyses Incidence and prevalence data were analyzed for the overall population and by study treatment at initial randomization (fingolimod, IFNb-1a IM, or placebo). Baseline characteristics and MS disease outcomes were analyzed for patients without uveitis and for all patients with uveitis combined, as well as for the individual uveitis subgroups (history, first event, recurrent event). KaplaneMeier estimates (with 95% confidence intervals) were made for time-tofirst uveitis event and time-to-first relapse, and an overall log-rank test was performed to assess significance between the uveitis and no uveitis groups. Comparisons between the uveitis and no uveitis groups for baseline measures and MS disease outcomes were analyzed using an overall log-rank test. Comparisons for uveitis incidence and prevalence by initial/randomized treatment groups were analyzed by Fisher exact test.
Results A total of 27 528 patients were included in the overall analysis population. The mean age was 39.7 years, and most patients were women (70.3%) and white (71.7%). Baseline demographics are detailed in Table S2 (available at www.aaojournal.org). Average time since MS diagnosis was 7.4 years, and the mean EDSS score at baseline was 2.8. A total of 189 patients in the analysis population had uveitis before enrollment or during the study period. A history of uveitis was reported in 162 patients (prevalence, 0.59%), and 44 uveitis events were reported in 37 patients during an overall mean observation period of 627 days (Table 1). Uveitis occurred as a first event in 27 patients, resulting in an incidence of 0.1 per 100 patient-years, and as a recurrent event in 10 of 162 patients. Uveitis on-study was mild or moderate in most patients, either as a first event (25 of 27 patients) or as a recurrent event (8 of 10 patients). In total, 18 patients required treatment, including 3 of the 4
patients with severe uveitis. The type of uveitis was anterior, n ¼ 2; intermediate, n ¼ 4; panuveitis, n ¼ 1; and not specified, n ¼ 30 (Table S3, available at www.aaojournal.org). In-depth clinical details of on-study uveitis events were available from 52 adverse event reports for 18 patients. Of these, 2 were cases of anterior uveitis, and there was 1 case each of intermediate uveitis, granulomatous uveitis, and panuveitis. Five cases of uveitis were described as unilateral. Two cases of uveitis were complicated by macular edema. One case of uveitis required topical glaucoma therapy. One patient was listed as having acute anterior uveitis, with 3 further cases listed as chronic; however, this descriptor (acute, chronic, or persistent) was not given in other reports. Two cases required treatment with oral prednisone, with the remaining treated cases receiving topical steroid preparations. Nine cases required continuous treatment with corticosteroid for less than 3 months, and 4 cases required treatment for at least 3 months. No other details (e.g., visual acuity) were available. There was no significant difference in the prevalence of uveitis between patients with RMS (0.45; N ¼ 16 873) and patients with PPMS (0.40; N ¼ 970). Analysis of the time-to-first uveitis event after the first dose of study drug showed no association between MS disease duration and the onset of uveitis.
Multiple Sclerosis Outcomes in Patients with Uveitis Analysis of demographics and MS disease characteristics at baseline by uveitis status showed that, compared with patients in the no uveitis group, patients in the uveitis group were significantly older (41.9 vs. 39.7 years; P ¼ 0.003) and had significantly more T2 lesions (30.2 vs. 21.2; P ¼ 0.018) but had experienced significantly fewer relapses in the previous 2 years (1.7 vs. 2.0; P ¼ 0.022; Table 2). Similar findings were observed for the individual uveitis subgroups compared with the no uveitis group, although the small numbers of patients in the first event and recurrent event cohorts meant that differences did not reach statistical significance. Multiple sclerosis disease characteristics were generally similar across the uveitis subgroups, although patients in the recurrent event cohort had longer disease duration and fewer gadoliniumenhancing T1 lesions than those in the other 2 uveitis cohorts (Table 2).
Table 1. Incidence and Prevalence of Uveitis by Initial/Randomized Treatment Parameter Mean observation period, days Total patient-yrsy History of Uveitis Patients with history of uveitis Prevalence, % On-study Uveitis Patients with uveitis events, n (%) Total number of uveitis eventsk Patients with uveitis as a first event, n (%) Incidence/100 patient-yrs Patients with a recurrent uveitis event, n (%)
Fingolimod All Doses* (n [ 24 864)
Placebo (n [ 1531)
Interferon beta-1a (n [ 1133)
Overall Population (N [ 27 528)
633 43 116
668 2801
425 1318
627 47 235
139 0.56z
8 0.52
15 1.32x
162 0.59
28z (0.1) 33 23 (0.1) 0.1 5z (3.60)
4 (0.3) 4 3 (0.2) 0.1 1 (12.50)
5 (0.4) 7 1 (0.1) 0.1 4 (26.67)
37 (0.1) 44 27 (0.1) 0.1 10 (6.17)
Treatment groups were based on initial randomization; patients were switched to fingolimod 0.5 mg in the extension studies. *Patients initially randomized to receive fingolimod were given 0.5 mg, 1.25 mg, or 5 mg fingolimod. y Total patient-years are defined as the sum of the number of years under the initial/randomized treatment. z P < 0.05 compared with interferon beta-1a, estimated by Fisher exact test. x P < 0.05 compared with placebo, estimated by Fisher exact test. k Patients may have had >1 uveitis event during the observation period.
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Ophthalmology Volume -, Number -, Month 2018 Table 2. Baseline Characteristics of Patients with or without Uveitis in the Overall Population Uveitis Parameter
No Uveitis (N [ 27 339) All (N ¼ 189) History (n ¼ 152) First Event (n ¼ 27) Recurrent Event (n ¼ 10)
Women, n (%) Age, yrs Duration of MS since diagnosis, yrs No. of relapses in the preceding 2 yrs EDSS score No. of T2 lesions No. of Gdþ T1 lesions Normalized brain volume, ml
19 214 (70.3) 39.710.3 7.46.4 2.01.7 2.81.7 21.228.9 1.13.4 1513.585.3
132 (69.8) 41.99.7* 7.36.5 1.71.4y 2.81.5 30.238.6y 1.33.7 1509.774.8
101 (66.4) 42.29.9* 7.26.3 1.81.5 2.81.5 31.340.9y 1.64.4 1513.876.8
23 (85.2) 40.58.9 7.74.8 1.50.9 3.31.8 25.431.5 0.81.5 1497.660.6
8 (80.0) 41.89.8 8.612.0 1.60.5 2.81.8 35.644.4 0.20.4 1508.198.4
Data are presented as mean standard deviation unless stated otherwise. P values were determined using an overall log rank test. EDSS ¼ Expanded Disability Status Scale; Gdþ ¼ gadolinium-enhancing; MS ¼ multiple sclerosis; SD ¼ standard deviation. *P < 0.01. y P < 0.05 vs. patients without uveitis.
Analysis of MS disease activity by uveitis status showed that time-to-first relapse was significantly shorter in the uveitis group than in the no uveitis group (mean standard error, 2.110.06 vs. 8.120.03 years; P ¼ 0.047). The ARR was approximately 50% higher in patients with uveitis than in those without uveitis (0.31 vs. 0.21; P ¼ 0.025; Table 3). The EDSS change or confirmed disability progression rates were no different between groups (Table 3). Some potential differences in disease outcomes were observed across the uveitis subgroups, although these should be interpreted with caution given the small numbers of patients in the first and recurrent event cohorts. In particular, the first event subgroup had a numerically greater EDSS worsening at study end than the other groups, with higher rates of confirmed disability progression and higher proportions of patients with EDSS scores of 4 or above and 6 or above than the other uveitis subgroups or nonuveitis groups (Table 3). Evaluation of long-term changes in EDSS score showed that EDSS scores increased numerically from baseline to 120 months in both the uveitis and no uveitis groups and across all uveitis subgroups. At study end, mean EDSS scores were numerically higher in the uveitis subgroup than in the no uveitis group, as shown in
Table S4 (available at www.aaojournal.org). Long-term brain MRI assessments showed a numerically greater percentage reduction in brain volume at month 48 for patients with uveitis than without uveitis (1.70 vs. 1.55%). The mean number of new T2 lesions increased over time and was similar in the uveitis and no uveitis groups at month 48, as shown in Table S5 (available at www.aaojournal.org).
Discussion This is the largest assessment to date of the prevalence and incidence of uveitis in patients with MS and its relationship with disease outcomes. Our analysis showed, in a prospective cohort of more than 27 500 patients with MS who participated in the fingolimod clinical trial program, that patients with a history of uveitis or with uveitis during the study observation period had increased relapse activity compared with those without uveitis. No causative link can be inferred by this association, but identification of uveitis
Table 3. Multiple Sclerosis Disease Outcomes in Patients with or without Uveitis in the Overall Population Uveitis Outcome MS relapses Mean SD ARR Mean SD EDSS change from baseline at month 120 Mean SD 6-mo confirmed disability progression Proportion of patients, n (%) EDSS score 4 Proportion of patients, n (%) EDSS score 6 Proportion of patients, n (%)
No Uveitis (N [ 27 339) All (N ¼ 189) History (n ¼ 152) First Event (n ¼ 27) Recurrent Event (n ¼ 10) n ¼ 15 234 0.51.1 n ¼ 15 234 0.210.48 n ¼ 16 749 0.131.06 n ¼ 25 602 1996 (7.6) n ¼ 18 768 1935 (10.3) n ¼ 23 791 1215 (5.1)
n ¼ 106 0.71.3* n ¼ 106 0.310.64* n ¼ 134 0.201.06 n ¼ 181 17 (9.4) n ¼ 132 20 (15.2) n ¼ 170 9 (5.3)
n ¼ 76 0.81.4* n ¼ 76 0.340.71* n ¼ 101 0.110.96 n ¼ 145 10 (6.9) n ¼ 108 14 (13.0) n ¼ 138 6 (4.3)
n ¼ 23 0.61.2 n ¼ 23 0.180.32 n ¼ 24 0.501.42 n ¼ 26 5 (19.2) n ¼ 16 5 (31.3) n ¼ 23 3 (13.0)
n¼7 0.60.8 n¼7 0.390.61 n¼9 0.440.81 n ¼ 10 2 (20.0) n¼8 1 (12.5) n¼9 0 (0.0)
ARR ¼ annualized relapse rate; CDP ¼ confirmed disability progression; EDSS ¼ Expanded Disability Status Scale; MS ¼ multiple sclerosis; SD ¼ standard deviation. P values were determined using an overall log rank test. N ¼ number of patients assessed. *P < 0.05 versus patients without uveitis.
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Impact of Uveitis on the Course of MS
as a possible risk factor for more aggressive MS may be useful information for physicians when reviewing MS treatment options. The presence of uveitis in MS may be autoimmune related, although whether uveitis is an autoimmune disease in its own right remains unclear.23 The presence of nonautoimmune comorbidities in MS is generally associated with worse MS outcomes,24,25 but analyses of the MS disease course in patients with psoriasis26 or inflammatory bowel disease27 suggest that MS progresses more slowly in patients with MS and a second autoimmune disease than in control patients. Given the association between uveitis and autoinflammatory disease,23 copresentation of MS and uveitis may signal an exaggerated autoinflammatory response, with increased relapse and MRI lesion activity relative to controls. The overall incidence (0.1 per 100 patient-years) and prevalence (0.59%) of uveitis in this large MS cohort analysis were low compared with other analyses. Prevalence is at the lower end of the range reported in previous studies (0.4%e28.6%) but is consistent with the low prevalence observed in large database studies.1 For example, 2 retrospective database reviews, each involving more than 4000 patients with MS, reported a prevalence of approximately 0.7%,7,8 and a prevalence of 1.1% was seen in a review of more than 1000 consecutive patients at an MS clinic.2 The prevalence of uveitis in patients with MS is, however, much higher than in patients without MS, with a prevalence of approximately 0.04% reported for the general population in the United Kingdom and France.7,11 All data included in this analysis originated from clinical trials and are thus considered highly reliable. However, history of uveitis was determined by patient self-reporting, which could have introduced potential bias or inaccuracies. Over reporting may have occurred in patients who did not have uveitis but instead had other, more benign, ocularinflammatory conditions, whereas underreporting may have occurred in patients who had relatively asymptomatic or undiagnosed intermediate uveitis. Indeed, postmortem studies have revealed a surprisingly high incidence of undiagnosed uveitis in patients with MS.28 To reduce such errors, ophthalmological assessments or confirmation of uveitis was performed routinely by a specialist ophthalmologist in the phase 2 and 3 studies. However, these assessments were not necessarily carried out routinely in the phase 4 trials; thus, confirmation that patient history had been checked for accuracy against medical records did not exist in all cases. A further limitation of this study is possible selection bias due to exclusion from the randomized fingolimod trials of patients with a history of macular edema. Also, most of the patients considered in this analysis participated in phase 4, routine practice studies. Macular edema is listed under the warnings and precautions given in the fingolimod label, so patients predisposed to macular edema by ophthalmological conditions, including uveitis, may not have been prescribed fingolimod by their treating physician. Thus, these patients would have been excluded from the phase 4 studies. Therefore, the findings from our analysis likely represent the lower limit of the incidence and prevalence of uveitis in patients with MS. Despite this potential selection bias, we believe our findings can be generalized to other patients at a
similar stage and with a similar MS phenotype. Our analysis was based on a large cohort of more than 27 000 patients, of whom more than 95% had RMS. It also has the advantage over registry and retrospective studies of being based on prospective data, which are generally more robust than data from patient medical records. The current analysis showed that patients with uveitis were generally older with substantially more T2 lesions (particularly among patients with a history of uveitis) but overall had experienced fewer relapses in the previous 2 years than patients without uveitis. Previous studies comparing the characteristics of patients with MS with and without uveitis are limited. A retrospective database study reported a similar mean duration of MS for patients with and without uveitis (12.9 vs. 11.5 years; P ¼ 0.44) and no significant differences between the 2 groups for mean age at MS onset or sex ratio.7 Another retrospective study in patients with MS reported a trend toward higher mean age at onset of MS in patients with uveitis than in those without uveitis (31.1 vs. 27.9 years; P ¼ 0.09), although the mean duration of MS was similar (with uveitis, 10.6 years; no uveitis, 10.3 years).8 In a small case-comparison study, patients with MS and intermediate uveitis were significantly older at the time of first diagnosis of uveitis and more likely to be female than control individuals with idiopathic intermediate uveitis.29 Our analysis showed that ARR was significantly higher, and time to first relapse was significantly shorter in patients with uveitis than without uveitis, despite the higher MS relapse rate observed in the no uveitis group before baseline. Few previous studies have investigated the potential effect of uveitis on disease outcomes in patients with MS. In a retrospective, case-control study, 41 patients with MS and uveitis were compared with 100 unmatched, randomly selected patients with MS and no uveitis.8 Analysis showed significantly better disease outcomes, as assessed by EDSS score and progression index, in the uveitis group than in the no uveitis group. However, patient numbers in the study were small, and there was a marked difference in the types of MS (relapsing or progressive) seen in the 2 groups at baseline.8 A similar retrospective study in patients with MS compared disability outcomes in 28 patients with uveitis and 1553 patients without uveitis.7 This showed no significant difference between patients with uveitis and patients without uveitis in the median time to progression to an EDSS score of 4 (12 vs. 11.4 years; P ¼ 0.44) or an EDSS score of 6 (23.9 vs. 24.9 years; P ¼ 0.66). Multiple sclerosiseassociated uveitis is not well characterized, although there are suggested autoimmune and genetic aspects that may implicate an inflammatory response modulated by the human leukocyte antigen (HLA) system.1 An autoimmune association between MS and uveitis is supported by reports of autoantibodies against both brain and retinal arrestin in patients with MS.30,31 Increased T-cell proliferative responses to brain and retinal arrestin have been observed in patients with MS, which may suggest a mechanism of uveitis in MS.32 Furthermore, predisposition to MS is associated with the HLA-DR15 haplotype (a subtype of HLA-DR2) in HLA population studies in white individuals of Northern European
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Ophthalmology Volume -, Number -, Month 2018 descent.33 Intermediate uveitis has also been associated with the HLA-DR15 haplotype.34,35 A key strength of our analysis is the involvement of the prospective collection of clinical data and adverse outcomes (i.e., uveitis) in a large number of well-characterized patients with MS. However, there are a number of limitations associated with the study. Recruitment bias may have affected the prevalence and incidence of uveitis seen in this patient cohort. Macular edema is a known side effect of fingolimod and was an exclusion criterion for key fingolimod clinical trials.17,18 Given that macular edema is a recognized complication of uveitis, this likely would have led to under-enrollment of patients with uveitis. However, not all cases of uveitis are associated with macular edema, and a history of uveitis was not grounds for exclusion from the trials. The inclusion of noninterventional studies not designed to detect uveitis as an adverse event may have resulted in its under-reporting. Other limitations are that the anatomic subtype and severity of uveitis before enrollment, and, in most cases, the anatomic subtype of uveitis on study was not specified. The number of patients included in the uveitis group was small; numerically, it was less than 1% of the total group. Therefore, the statistical comparisons between the 2 groups should be interpreted with a degree of caution. Finally, fingolimod has been demonstrated to have a treatment effect on uveitis in animal studies; therefore, an effect of fingolimod on the incidence of uveitis cannot be excluded. Uveitis occurrence rates by treatment group at randomization (Table 1) were the same, but most patients included in this analysis were exposed to fingolimod, including those initially randomized to a comparator group. Also, no difference in occurrence rates was seen between groups randomized to different doses of fingolimod; however, as noted in the study methodology, most of these patients would have switched to the 0.5 mg dose. In conclusions, our pooled analysis involving a large cohort of patients from the fingolimod clinical trial program showed that patients with MS and uveitis had increased MS disease activity compared with those without uveitis. Therefore, uveitis should be considered a risk factor for greater disease activity in MS. Acknowledgments Writing assistance was provided by Dr. Alex Gavin of Oxford PharmaGenesis Ltd. A manuscript draft was prepared for the named authors to edit. Writing assistance was funded by Novartis Pharma AG.
References 1. Vadboncoeur J, Biernacki K, Prat A, Jaworski L. Multiple sclerosis-associated uveitis. Exp Rev Ophthalmol. 2017;12: 57e67. 2. Biousse V, Trichet C, Bloch-Michel E, Roullet E. Multiple sclerosis associated with uveitis in two large clinic-based series. Neurology. 1999;52:179e181. 3. Breger BC, Leopold IH. The incidence of uveitis in multiple sclerosis. Am J Ophthalmol. 1966;62:540e545.
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4. Karara AM, Macky TA, Sharawy MH. Pattern of uveitis in an Egyptian population with multiple sclerosis: a hospital-based study. Ophthalmic Res. 2013;49:25e29. 5. Kaya D, Kaya M, Ozakbas S, Idiman E. Uveitis associated with multiple sclerosis: complications and visual prognosis. Int J Ophthalmol. 2014;7:1010e1013. 6. Langer-Gould A, Albers KB, Van Den Eeden SK, Nelson LM. Autoimmune diseases prior to the diagnosis of multiple sclerosis: a population-based case-control study. Mult Scler. 2010;16:855e861. 7. Le Scanff J, Seve P, Renoux C, et al. Uveitis associated with multiple sclerosis. Mult Scler. 2008;14:415e417. 8. Shugaiv E, Tuzun E, Kurtuncu M, et al. Uveitis as a prognostic factor in multiple sclerosis. Mult Scler. 2015;21:105e107. 9. Vidovic T, Cerovski B, Jukic T. The appearance of pars planitis in multiple sclerosis. Coll Antropol. 2005;29:203e206. 10. Graves J, Balcer LJ. Eye disorders in patients with multiple sclerosis: natural history and management. Clin Ophthalmol. 2010;4:1409e1422. 11. Edwards LJ, Constantinescu CS. A prospective study of conditions associated with multiple sclerosis in a cohort of 658 consecutive outpatients attending a multiple sclerosis clinic. Mult Scler. 2004;10:575e581. 12. Zein G, Berta A, Foster CS. Multiple sclerosis-associated uveitis. Ocul Immunol Inflamm. 2004;12:137e142. 13. Prieto JF, Dios E, Gutierrez JM, et al. Pars planitis: epidemiology, treatment, and association with multiple sclerosis. Ocul Immunol Inflamm. 2001;9:93e102. 14. Calder VL, Lightman SL. Experimental autoimmune uveoretinitis (EAU) versus experimental allergic encephalomyelitis (EAE): a comparison of T cell-mediated mechanisms. Clin Exp Immunol. 1992;89:165e169. 15. Kappos L, Antel J, Comi G, et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med. 2006;355: 1124e1140. 16. Kappos L, Radue EW, O’Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362:387e401. 17. Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362:402e415. 18. Calabresi PA, Radue EW, Goodin D, et al. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebocontrolled, phase 3 trial. Lancet Neurol. 2014;13:545e556. 19. Khatri BO. Fingolimod in the treatment of relapsingremitting multiple sclerosis: long-term experience and an update on the clinical evidence. Ther Adv Neurol Disord. 2016;9:130e147. 20. Kappos L, O’Connor P, Radue EW, et al. Long-term effects of fingolimod in multiple sclerosis: the randomized FREEDOMS extension trial. Neurology. 2015;84:1582e1591. 21. Zarbin MA, Jampol LM, Jager RD, et al. Ophthalmic evaluations in clinical studies of fingolimod (FTY720) in multiple sclerosis. Ophthalmology. 2013;120:1432e1439. 22. Lublin F, Miller DH, Freedman MS, et al. Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet. 2016;387:1075e1084. 23. Forrester JV, Kuffova L, Dick AD. Autoimmunity, autoinflammation and infection in uveitis. Am J Ophthalmol. 2018;189:77e85. 24. Conway DS, Thompson NR, Cohen JA. Influence of hypertension, diabetes, hyperlipidemia, and obstructive lung disease on multiple sclerosis disease course. Mult Scler. 2017;23: 277e285.
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25. Kowalec K, McKay KA, Patten SB, et al. Comorbidity increases the risk of relapse in multiple sclerosis: a prospective study. Neurology. 2017;89:2455e2461. 26. Miron G, Gurevich M, Baum S, et al. Psoriasis comorbidity affects multiple sclerosis neurological progression: a retrospective case-control analysis. J Eur Acad Dermatol Venereol. 2017;31:2055e2061. 27. Zephir H, Gower-Rousseau C, Salleron J, et al. Milder multiple sclerosis course in patients with concomitant inflammatory bowel disease. Mult Scler. 2014;20:1135e1139. 28. Kerrison JB, Flynn T, Green WR. Retinal pathologic changes in multiple sclerosis. Retina. 1994;14:445e451. 29. Messenger W, Hildebrandt L, Mackensen F, et al. Characterisation of uveitis in association with multiple sclerosis. Br J Ophthalmol. 2015;99:205e209. 30. McDowell JH, Smith WC, Miller RL, et al. Sulfhydryl reactivity demonstrates different conformational states for arrestin,
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arrestin activated by a synthetic phosphopeptide, and constitutively active arrestin. Biochemistry. 1999;38:6119e6125. Ohguro H, Chiba S, Igarashi Y, et al. Beta-arrestin and arrestin are recognized by autoantibodies in sera from multiple sclerosis patients. Proc Natl Acad Sci U S A. 1993;90:3241e3245. Forooghian F, Cheung RK, Smith WC, et al. Enolase and arrestin are novel nonmyelin autoantigens in multiple sclerosis. J Clin Immunol. 2007;27:388e396. Giordano M, D’Alfonso S, Momigliano-Richiardi P. Genetics of multiple sclerosis: linkage and association studies. Am J Pharmacogenomics. 2002;2:37e58. Raja SC, Jabs DA, Dunn JP, et al. Pars planitis: clinical features and class II HLA associations. Ophthalmology. 1999;106:594e599. Tang WM, Pulido JS, Eckels DD, et al. The association of HLA-DR15 and intermediate uveitis. Am J Ophthalmol. 1997;123:70e75.
Footnotes and Financial Disclosures Originally received: December 6, 2017. Final revision: September 27, 2018. Accepted: October 4, 2018. Available online: ---.
Manuscript no. 2017-2776.
1
Centre for Eye Research Australia, University of Melbourne, Parkville, VIC, Australia.
2
Royal Victorian Eye and Ear Hospital, Melbourne, VIC, Australia.
3
Eye Surgery Associates, East Melbourne, VIC, Australia.
4
Novartis Pharma AG, Basel, Switzerland.
5
Department of Ophthalmology, Alfred Hospital, Melbourne, VIC, Australia. 6 MSNI, Department of Neuroscience, Central Clinical School, Alfred Campus, Monash University, VIC, Australia. 7
Writing support was provided by Oxford PharmaGenesis Ltd. (Oxford, UK) and funded by Novartis Pharma AG (Basel, Switzerland). Employees of Novartis Pharma AG are listed as authors of this manuscript and participated in the design and conduct of the study, collection, management, analysis, and interpretation of data, and preparation, review, and approval of the manuscript. HUMAN SUBJECTS: Human subjects were included in this study. Institutional Review Board/Ethics Committee approval noted in main manuscript methods section. All fingolimod trials were conducted in accordance with the International Conference on Harmonisation Guidelines for Good Clinical Practice and the Declaration of Helsinki. Institutional Review Board/Ethics Committee approval was obtained for each study, and patients gave written informed consent before the start of any study related procedures.
MS Unit, Department of Neurology, Eastern Health, Monash University, Clayton, VIC, Australia.
No animal subjects were used in this study.
Presented at: the Association for Research in Vision and Ophthalmology Annual meeting, May 7e11, 2017, Baltimore, Maryland; and The Royal Australian and New Zealand College of Ophthalmologists Annual Scientific Congress, Perth, Australia, October 28 to November 1, 2017.
Conception and design: Lim, Silva, Pimentel, Hall
*L.L.L. and D.G.S. contributed equally toward this work. Financial Disclosure(s): The author(s) have made the following disclosure(s): L.L.L.: Advisory boards and consultant e AbbVie, Bayer, Allergan, and her institution has received research funding from AbbVie and Bayer. H.B.: Scientific advisory boards e Biogen, Novartis, Merck, Teva; Consultancy and lecture fees e Novartis, Biogen; Steering committees e trials and studies conducted by Biogen, Merck, Roche, Novartis; and his institutions have received research support from Novartis and Biogen. A.J.H.: Advisory board and consultant e AbbVie; Research support e Novartis.
Author Contributions: Data collection: Silva, Pimentel, Butzkueven, Hall Analysis and interpretation: Lim, Silva, Lo, Pimentel, Butzkueven, Hall Obtained funding: Lim, Silva, Pimentel, Butzkueven, Hall Overall responsibility: Lim, Silva, Lo, Pimentel, Butzkueven, Hall Abbreviations and Acronyms: ARR ¼ annualized relapse rate; EDSS ¼ Expanded Disability Status Scale; HLA ¼ human leukocyte antigen; IFNb-1a IM ¼ intramuscular interferon beta-1a; MRI ¼ magnetic resonance imaging; MS ¼ multiple sclerosis; PPMS ¼ primary progressive multiple sclerosis; RMS ¼ relapsing multiple sclerosis. Correspondence: Anthony J. Hall, MD, FRANZCO, Department of Ophthalmology, Alfred Hospital, Melbourne, VIC, Australia. E-mail: [email protected].
D.G.S. and R.S.P.: Employees e Novartis.
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