Multiple Sclerosis-Associated Uveitis Therapy: Is Modern Better than Old Reliable?

Abstract

Background: Uveitis, although a rare complication of multiple sclerosis (MS), poses a significant challenge in clinical management. Traditional treatments like corticosteroids, immunosuppressants, and surgical interventions often provide limited efficacy. Treatment for MS-associated uveitis involves a combination of traditional and emerging therapies, with a growing emphasis on monoclonal antibodies (mAbs). While there is an increasing use of disease-modifying therapies for MS such as interferon-beta (IFN-β), mAbs are gaining attention for their potential to address both neurological and ophthalmological symptoms. Methods: We conducted a systematic review of the existing literature and analyzed the clinical effect of IFN-β and mAb therapies in the context of MS-associated uveitis, assessing their efficacy in reducing inflammation, maintaining visual acuity (VA), and minimizing steroid dependency. Results: MS-associated uveitis had improved or maintained VA in 95% (35/37) of eyes (21 patients) after an average of 34.7 months (range of 7.9 to 78.7 months) of IFN-β treatment. One hundred percent (10/10) of patients (19/19 eyes) had improved or maintained VA after a mean of 25 months (range 8 to 43 months) of mAb treatment. We also found that IFN-β effect on MS-associated uveitis is comparable to mAbs. Conclusions: We outline the need for further research through human data to strengthen current findings and guide evidence-based clinical practice.

1. Introduction

Multiple sclerosis (MS) is a chronic, episodic autoimmune demyelinating disorder of the central nervous system [1]. It is the most common chronic disease of the neurological system in young adults with continual increase in prevalence, affecting 2.5 million people worldwide [2]. MS primarily affects the brain, spinal cord, and optic nerves, which are part of the central nervous system (CNS). This immune-mediated process results in neurological deficits and varying degrees of disability. Four primary types of MS are recognized: Relapsing-remitting MS (RRMS), primary progressive MS (PPMS), secondary progressive MS (SPMS), and progressive relapsing MS (PRMS) [3,4]. Each type of MS has a unique pattern of symptoms and disease progression.

MS is commonly associated with ophthalmological manifestations, most commonly optic neuritis, but also other conditions such as internuclear ophthalmoplegia, demyelination of the medial longitudinal fasciculus, and nystagmus [5]. Ocular involvement due to MS causes significant disability and visual impairment for patients.

Uveitis is an inflammation of the uveal tract. This layer of the eye includes the iris, ciliary body, and choroid [6]. It is a serious condition that threatens visual impairment and blindness. Uveitis is linked to several CNS diseases, with MS being a primary example. Other related CNS diseases can include Behcet’s disease, sarcoidosis, and neurosyphilis, and a thorough ophthalmological and neurological evaluation is crucial for proper diagnosis and management [5]. Uveitis can occur in approximately 1–3% of MS patients, which is 10 times higher than in the general population, while MS accounts for 1% of all uveitis cases [7]. The association can involve uveitis preceding the diagnosis of MS, with intermediate uveitis and retinal vasculitis being common findings in MS patients. Although a rare complication of MS, uveitis can also precede the onset of other neurological symptoms and may serve as a leading indicator of MS disease progression, indicating a bidirectional association between MS and uveitis [8]. Moreover, both MS and uveitis overlap [9], with many cases being triggered by infectious agents when individuals have a genetic susceptibility. HLA-DR15 and HLA-DR-51 genes are an overlapping risk factor for both MS and uveitis [7,10].

Uveitis is further classified as anterior, intermediate, posterior, or pan uveitis depending on the structures involved [11]. MS-associated uveitis (MS-AU) is primarily classified as intermediate uveitis (IU) and presents with ocular inflammation, floaters, blurred vision, pain, and photophobia, substantially impacting quality of life [9,12]. Patients with IU have an estimated 8–12% risk of being diagnosed with MS [13], highlighting the need for an improved understanding of uveitis and demyelinating disease.

Uveitis and CNS diseases are often linked, with demyelination (damage to the myelin sheath of nerve cells) being a key factor in conditions like MS. While MS is a demyelinating disease that can cause both uveitis and other neurological symptoms, uveitis is not a direct result of demyelination itself. Instead, it is thought to be a co-occurring condition or a manifestation of the broader inflammatory process affecting the CNS [5].

Traditionally, MS-related IU is managed very similarly to non-infectious uveitis, utilizing systemic corticosteroids as first-line therapy, especially in acute settings of relapses [1]. It could also be treated with local steroids, such as topical eyedrops, steroid injections, or steroid implants into the vitreous, without the associated side effects of systemic steroids [14]. The departure of steroids for long-term management of MS and IU has been crucial as steroids caused their own complications of cataracts, glaucoma, and chorioretinopathy. Further treatment of both conditions may include a spectrum of immunosuppressants, cryotherapy, laser photocoagulation, and vitrectomy, though these interventions often yield limited effectiveness.

Emergence of newer disease-modifying therapies for MS, such as interferon-beta (IFN-β) and monoclonal antibodies (mAbs), presents opportunities to target both neurological and ophthalmological attributes of the disease. In the context of MS-related uveitis, evidence suggests that IFN-β may maintain or improve visual acuity (VA), reduce inflammation, and facilitate possible discontinuation of the traditional corticosteroid therapy [15,16]. Monoclonal antibodies are used to treat MS and uveitis, and there is an increasing focus on their use for MS-associated uveitis. Treatments for MS, such as natalizumab and ocrelizumab, can help reduce inflammation that may affect the eyes, while other monoclonal antibodies, like infliximab and adalimumab, are used to treat non-MS-related uveitis. While the exact link between MS and uveitis is complex, these therapies aim to control the autoimmune response that causes both conditions. Few studies, however, have specifically examined the impact of IFN-β or mAbs on MS-related uveitis despite its established use in MS management.

In this study, we have conducted a comprehensive and systematic review and an analysis of the effectiveness of IFN-β and mAbs in the treatment of MS-AU. We have examined the existing literature on the subject to provide a definitive answer and elaborate on the mechanistic model associated with the use of these therapies for this condition [17].

2. Methods

2.1. IFN-Βeta Literature Search Strategy

A systematic review was done according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [18] (Supplementary Files S1 and S2), and registered in PROSPERO (CRD42025639078). Electronic searches were performed in the PubMed, EMBASE, and Cochrane Library databases, from all available years until December 2024. The first search looked for studies following humans diagnosed with MS-AU who received IFN-β treatment. The following search strategy, using pertinent terms, was used for the PubMed and Cochrane Library databases and adapted for the EMBASE database using EMBASE-specific search syntaxes: (“Interferon” OR “Beta” OR “INF” OR “IFN” OR “type 1 interferon” OR “type one interferon” OR “IFN-Β” OR “IFN B” OR “IFN β” OR “IFN-β” OR “INF β” OR “INF-β” OR “IFN-Βeta” OR “IFN Beta”) AND (“Multiple Sclerosis” OR “MS”) AND (“uveitis” OR “Multiple Sclerosis-related Uveitis” OR “Multiple Sclerosis-Associated Uveitis” OR “MS-Associated Uveitis” OR “MS-related Uveitis” OR “choroiditis” OR “iritis” OR “iridocyclitis”). Studies were excluded from the review if they did not measure VA before and after IFN-β treatment in human patients with MS-AU. Variations in MS type (e.g., Relapsing-remitting, Primary progressive, Secondary progressive, and Progressive relapsing) were not considered during study selection and were not part of the exclusion criteria. Inclusion criteria were used of IFN-β to treat MS-AU in human patients.

2.2. Monoclonal Antibodies Literature Search Strategy

The systematic review was also done according to the PRISMA guidelines (Supplementary Files S1 and S3) and registered in PROSPERO (CRD420251021213). A search strategy utilizing pertinent terms was conducted in PubMed, EMBASE, and the Cochrane Library. From all available years until December 2024. The initial search strategy utilized the following keywords: (“Monoclonal” OR “Antibody” OR “Monoclonal Antibody” OR “mab” OR “Natalizumab” OR “Tocilizumab” OR “Bevacizumab” OR “Alemtuzumab” OR “Ocrelizumab” OR “mAB” OR “Monoclonal-Antibody” OR “MAB” OR “MoAB” OR “Antibody-based therapy”) AND (“Multiple Sclerosis” OR “MS”) AND (“Uveitis” OR “Multiple Sclerosis-related Uveitis” OR “Multiple Sclerosis-Associated Uveitis” OR “MS-Related Uveitis” OR “MS-Associated Uveitis” OR “Choroiditis” OR “Iritis” OR “Iridocyclitis”).

Inclusion criteria included: use of an mAb to treat MS-AU in a human patient, VA measurements taken both before and after treatment, and a clinical diagnosis of uveitis and MS present. Relevant clinical variables were extracted and arranged to provide a view of the effect of mAbs in MS-AU. Uveitis and MS subtypes were not considered during study selection.

2.3. Data Retrieval

The following variables were extracted from the studies that fulfilled the inclusion criteria: treatment, dose (in international units, IU), sex, age at start of study, MS history (years), eye laterality, VA baseline, VA after treatment, presence of peripheral retinal vasculitis, presence of vitritis, presence of macular edema, and time on treatment (months). Some studies did not provide all of the variables.

2.4. Variables and Statistical Analysis

Relevant clinical variables were extracted and arranged to provide a view of the effect of IFN-β and/or mAbs in MS-AU. These included VA measurements taken both before and after treatment, and a clinical diagnosis of uveitis and MS. Time-stratified data was categorized, and ANOVA and regression analysis were run to assess the categorical effects of measurement on treatment outcome. Standardized effect sizes (Cohen’s d) were calculated for each type of treatment used across studies.

VA measurements were converted from Snellen decimal values to logarithm of the minimum angle of resolution (LogMAR) units to linearize the data for analysis. The conversion was performed using the formula: LogMAR = −log₁₀ (Snellen decimal). For eyes with VA measured as blind, values were standardized to 1.3 LogMAR to maintain consistency across calculations [19].

Data preprocessing and analysis were performed using Python (version 3.12). The pandas library was used for data wrangling and cleaning, including variable formatting, missing data handling, and derivation of summary variables. Descriptive statistics and univariate analyses were conducted using the tableone package to generate table-style summaries stratified by change in uveitis severity. No multivariate modeling was performed due to insufficient data. All scripts used for data analysis are available upon request. Grouped data were analyzed using GraphPad Prism 10.3.

3. Results

3.1. IFN-Βeta Effect on MS-Uveitis

The initial search for IFN-β and MS-uveitis yielded 150 papers (Figure 1). After screening and applying exclusion criteria, 10 papers were sought for retrieval. Of the nine reports retrieved, five reports were excluded because they did not include VA measurements before and after IFN-β treatment. No studies were removed because of quality. The four included studies measured VA in patients with a clinical diagnosis of MS and uveitis before and after IFN-β treatment. All four studies measured VA using Snellen charts. Studies included for review were published between the years 2005 and 2016. One of the papers was a case study [20]. The other three papers were retrospective observational studies in which all confirmed MS diagnoses in these patients were made by consulting their respective neurology departments [21,22,23]. The 2005 study by Becker et al. [22] included data from five healthcare centers and did not standardize the drug types, treatment protocols, study design, eligibility criteria, or follow-up schedules.

Data on VA was combined and compared before and after IFN-β treatment. With a p-value of 0.00094, we found that 95% (35/37) of eyes diagnosed with MS-AU in 21 patients had improved or maintained VA after an average of 34.7 months (range of 7.9 to 78.7 months) of IFN-β treatment (Figure 2). It is important to note that the authors attributed the decrease in VA in the remaining two eyes to cataract development. The average improvement in VA was 0.12 LogMAR. Two eyes were excluded from this graph due to a lack of specific VA measurements after treatment. It is important to note that VA decreased in these two eyes. 36/37 patients were diagnosed with IU, and the remaining one presented with anterior uveitis. Six of the patients were male, 15 were female, and the mean age at the time of treatment was 41.3 years old. One patient included in one of the retrospective studies was removed from analysis because they did not have a uveitis diagnosis, only retinal vasculitis.

Each of the four studies examined other aspects of MS progression, such as macular edema, optic neuritis, and vasculitis. Across three of the papers, 15 patients showed vasculitis, and nine showed a history of optic neuritis. Interestingly, one paper included seven people who presented with macular edema. Five of these patients experienced resolution of this edema following treatment.

3.2. Effect of mAbs on MS-Uveitis

Regarding the effect of mAbs on MS-uveitis, a total of 92 studies were screened, and 5 were compatible for data review (Figure 3). Studies included in the final review were published between 2008 and 2024.

Data obtained from these studies showed that 100% (19/19) of eyes had improved or maintained VA after a mean of 25 months (range 8 to 43 months) of mAb treatment (p-value of 0.0014). The average improvement in VA was −0.16 LogMAR (Figure 4). Resolution of uveitis was reported in 10/10 patients and all 19/19 eyes, including both standalone and combination therapy.

Each of the 5 studies evaluated different aspects of disease progression, including vasculitis, macular edema, and other inflammatory markers such as chamber flare, synechiae, and granulomatous keratic precipitates. Notably, following treatment, macular edema was absent or reduced in the 6 patients with evidenced macular edema at baseline. Vitreous haze also resolved or was reduced in 6 patients who presented with presence of vitreous haze at baseline.

Out of 10 patients, 7 presented with IU, and the remaining 3 presented with panuveitis, with one of these patients’ disease states reduced from panuveitis to intermediate through the course of treatment. The majority of patients (8/10) were female, and the mean age at the time of treatment was 50 years old.

3.3. IFN-β Effect on MS-Associated Uveitis Is Comparable to mAbs

We then compared the effect of both treatments on VA (Figure 5). We divided mAbs into those targeting B cell marker CD20 (anti-CD20) and the rest of mAbs, which were directed towards IL-6R, CD52, and VEGF. No statistically significant difference between the treatments was found (p-value = 0.665, one-way ANOVA) as noted in Figure 5B.

4. Discussion

4.1. Evaluation of the Effect of IFN-β and mAb Treatment of MS-AU

Treatment for MS-AU typically involves corticosteroids as a first-line therapy to reduce inflammation, often administered as eye drops or oral/intravenous medication. If inflammation is persistent, other treatments may include systemic immunosuppressants, monoclonal antibodies, or surgical procedures like laser photocoagulation, cryotherapy, or vitrectomy for more severe cases [7]. Few studies regarding the optimal treatment of MS-AU are available. This systematic review suggests that there is no significant difference in VA maintenance or improvement between IFN-β and mAb treatment of MS-AU.

IFN-β was the first disease-modifying therapy, approved in the U.S. in 1993, particularly effective for RRMS and, in some cases, SPMS. It works by modulating the immune response, reducing pro-inflammatory cytokine activity, and decreasing T-cell infiltration in the central nervous system (CNS) [24]. IFN-β has particularly demonstrated reduced rates of MS relapse and a delay in disability progression. IFN-β has not only been shown to have beneficial effects in patients with MS but also on optical neuritis [22]. Treatment of MS-AU with IFN-β appears to have beneficial effects on VA, intraocular inflammation activity, and the presence of cystoid macular edema [22]. Proven success of other interferons like interferon alpha for treating uveitis in other inflammatory conditions like Behçet disease proposes further investigation of Type I IFNs and ophthalmological outcomes.

IFN-β has been shown to perform well in treating IU, regardless of MS diagnosis. In a randomized controlled clinical trial [25], IFN-β outperformed methotrexate in treating patients with either primary or MS-associated IU and macular edema. Not only did IFN-β improve VA, but it also reduced macular edema and lowered intraocular inflammation. Although the study included both primary and MS-associated IU, the findings are particularly relevant for MS patients, given IFN-β’s dual role as a disease-modifying treatment for MS and an effective agent against uveitic inflammation. The trial was terminated early due to clear treatment benefit in the IFN-β group, despite a small sample size, underscoring the clinical potential of this therapeutic agent.

Certain mAbs, such as natalizumab and ocrelizumab, have emerged as preferred treatment in patients with MS due to their targeted immune modulation and have proven to reduce relapses and inflammatory processes. This treatment class works by blocking specific immune cell activation, pro-inflammatory cytokines, thereby decreasing CNS inflammation and relapse rates. With the prevalence of mAb treatment increasing in the context of MS [26,27], its specific effect on MS-uveitis and its potential ophthalmological benefits have been called into question.

The reviewed mAb studies involved immunomodulatory and disease-modifying therapies targeting CD20, IL-6, CD52, and VEGF. The majority of eyes evaluated were being treated with concomitant steroids, with the addition of a mAb leading to resolution of disease severity and tapering or discontinuation of steroid usage. Each study’s variance in evaluation methods prevented comparison of relative eye inflammation between papers, but reduction in inflammatory markers was evident in 19/19 eyes.

As new biological treatment options for MS are preferred by clinicians, it is important to evaluate their efficacy not only for neurological symptoms but also for ophthalmological complications and tissue inflammation [4]. In the limited number of cases analyzed in this review, both IFN-β and mAbs are potentially effective treatments for MS-AU, suggesting a possible role in the stabilization or improvement of VA, promotion of complete inflammation resolution, and enabling corticosteroid tapering or discontinuation. However, given the small sample size and reliance on case reports and case series, these preliminary findings should be interpreted with caution and warrant validation in larger, controlled studies. Preliminary studies had suggested that mAbs, much like IFN-β, could improve VA, reduce ocular inflammation, or attenuate corticosteroid use [28]. This treatment may be even justified in MS patients with severe or chronic uveitis, as this appeared associated (p < 0.05 and p = 0.06, respectively) with IFN-β treatment in a small comparative study [29]. Specifically, anti-CD20 therapy has shown to be associated with an improvement of vitreous haze, retinal vasculitis, central retinal thickness, VA, and decline in annual uveitis relapse rate [30]. A recent report of treatment of two patients with alpha-4 integrin blocking mAb natalizumab that led to their rapid and sustained resolution of uveitis supports the idea that mAbs may help discontinuation of other immunosuppressive therapies [31].

mAbs may offer several advantages over IFN-β or fingolimod, including relatively reduced relapse rates and more targeted immune modulation [32]. Studies have shown that certain mAbs offer the greatest anti-inflammatory effect in the eyes as well as tissue inflammation [33]. Such targeted reduction in inflammatory activity may make mAbs suitable for management of severe or treatment-resistant IU in MS patients.

Notably anti-TNF and anti-IL-6 treatment options may worsen demyelinating disease, and there is ongoing discourse surrounding their safety and efficacy [34]. One of the case reports [35] displayed the successful use of tocilizumab (anti-IL-6 mAb) in the context of refractory bilateral panuveitis in which the patient’s MS was well controlled and displayed no evidence of recurrence or worsening.

The relationship between MS and uveitis is complex; their underlying immunological mechanisms not only pose therapeutic obstacles [36] but diagnostic challenges as well. One important aspect of this condition is that, although a rare complication of MS (less than 2%) [7], uveitis can present 1–17 years prior to neurologic symptoms in a large proportion (44%) [37] (78%) [29] of MS patients. In fact, MS can be diagnosed in up to 3% of patients with uveitis [7]. Both were subsequently identified to have radiologically isolated MS in the absence of clinical demyelination. Treatment with natalizumab in isolation led to rapid and sustained resolution of uveitis, enabling discontinuation of other immunosuppression.

4.2. Limitations

A few limitations existed in our study. First, two studies only provided VA measurements in the form of a scatter plot, so the VA measurements were extracted using Plot Digitizer (plotdigitizer.com). Although the authors of one of these studies stated that 24 eyes were evaluated, only 22 data points were visible on the plot. Therefore, for consistency and transparency in data extraction, we used the 22 measurable values presented in the figure for our analysis. The second potential limitation consisted of one of the analyzed articles being written in Turkish. Google Translate was used to translate the paper to English, and data were extracted directly from the tables and figures. As the study’s quantitative data were clearly presented, inclusion was based on the availability and clarity of the reported outcomes rather than language.

5. Conclusions

Although MS-AU is a relatively rare complication of MS [7,36], it may present in MS patients as complaints of floaters or blurred vision, due to a reduction in VA. The rapidly evolving landscape of MS treatment offers promising avenues for managing associated uveitis. Due to the small sample size and reliance on case series, definitive conclusions remain limited. The known risks of opportunistic infection and exacerbation of demyelinating disease necessitate careful patient selection and interdisciplinary management. In such cases, larger prospective studies and controlled trials are needed to validate these findings, establish comparative efficacy across mAbs and IFN-β, and better define safety profiles in this unique population. A better understanding of how targeted immunotherapy can help preserve vision in this patient population is warranted.

IFN-β and mAbs demonstrate potential in addressing both neurological and ophthalmological symptoms, though further human data is essential to optimize treatment strategies. By determining the efficacy of these treatments in improving VA for MS-AU patients, we hope to contribute to the evidence-based treatment strategies for physicians managing this difficult comorbidity.