Insights from a trial of narrowband UVB for early multiple sclerosis

Insights from a trial of narrowband UVB for early multiple sclerosis

Abstract

There is a greater prevalence of multiple sclerosis (MS), a neurological autoimmune condition, in populations living further from the equator, hypothesised to be due to reduced sunlight exposure. There exists a proven sunlight surrogate therapy for dermatological inflammatory conditions, in the form of narrowband (NB; 311–312 nm)-UVB phototherapy. Yet, there is a paucity of randomized trials of the therapeutic delivery of NB-UVB beyond dermatology for conditions with a systemic inflammatory component. To investigate the potential for use in MS, the PhoCIS trial (narrowband UVB phototherapy for Clinically Isolated Syndrome)(ACTRN 12614000185662), was established. Participants with Clinically Isolated Syndrome, the earliest symptomatic form of MS, were given NB-UVB (24 sessions over 8 weeks) and followed for 12 months. The published clinical, immunological, and quality of life results from the PhoCIS trial have uncovered new evidence of systemic immune stabilisation by NB-UVB. This perspective provides the first unified overview of these results to inspire future randomised trials of NB-UVB across other autoimmune diseases which share both prevalence that follows UVB exposure, and systemic immune dysregulation.

1 Narrowband UVB phototherapy

Delivery of narrowband (NB, 311–312 nm) UVB is a safe, mainstay treatment by dermatologists for patients with inflammatory skin conditions. The treatment regulates the inflammatory actions of keratinocytes and immune cells and the trafficking of antigen presenting cells to the draining lymph nodes (for review, [1,2,3]). Systemic consequences of NB-UVB have also been realised by effects of NB-UVB on psoriatic skin not directly irradiated [1]. The proapoptotic, immunomodulatory, antipruritic, antifibrotic and propigmentary effects of NB-UVB have improved the clinical outcomes for patients with psoriasis, atopic dermatitis, graft-versus-host disease, vitiligo, scleroderma and cutaneous T-cell lymphoma (for review, [1,2,3]). Decades of dermatological research have found NB-UVB optimised the risk benefit ratio as a treatment when compared to UVA, or broad band UVB [4]. One study reported that psoriasis patients receiving phototherapy had better health-related quality of life overall than did patients treated with adalimumab, an anti-TNF-α antibody, despite both treatments improving skin-related quality of life [5].

2 Risks associated with NB-UVB phototherapy

Over decades of use, the safety profile for NB-UVB use has been excellent; there have been very few reports of induction of skin cancers by NB-UVB despite dermatologists prescribing, delivering and surveilling their NB-UVB patients for skin cancers for decades [6]. The 2019 American Academy of Dermatology Guidelines for Phototherapy summarized the risks as follows: “No increased risk of melanoma and keratinocyte cancer was found with phototherapy. The most common complication is erythema, with resolution within 24–48 hours. The mitigation is titration of dose escalation. There was no reported increase in melanoma, the most clinically relevant skin cancer.” [4]. The 2022 Australasian guidelines are in agreement, with specific notes for patients with a history of melanoma, “Whilst NBUVB is not proven to increase risk of skin cancer, informed consent should be sought from patients with a history of melanoma and/or are at a high risk of developing melanoma, as the risk of developing primary melanoma is high even without UVB therapy.” [7].

The reality is that for many patients with psoriasis, vitiligo and eczema, NB-UVB phototherapy is of similar efficacy as biologics (advanced prescription drugs, generally large complex proteins made by living organisms), and significantly cheaper by 10–30 times [8]. Furthermore, NB-UVB phototherapy delivered by at-home units to patients with psoriasis are as effective and more convenient, with less commuting, for patients than phototherapy delivered in clinic rooms [9, 10].

3 Multiple sclerosis

Both genetic and environmental factors contribute to risk for multiple sclerosis (MS). Environmental ultraviolet radiation, as in sunlight, has been hypothesised to contribute in a major way to lowered disease risk. In support, a latitude gradient for MS prevalence [11,12,13] and disease severity [14] has been reported. Initially, it was proposed that the destruction of the myelin nerve sheets by inflammatory cells in patients with MS was due to reduced levels of the active molecules of the vitamin D cascade. However, as reviewed elsewhere [15,16,17], vitamin D supplementation for patients with MS has been disappointing with few studies of supplementation with physiological amounts of vitamin D suggesting significant benefit.

Serum vitamin D levels (measured as 25(OH) D3 with serum half-life of approximately 2–3 weeks) are generally a biomarker of recent sun exposure, and as consistently shown, associations of serum 25(OH)D3 levels with disease prevalence, including for MS, do not signal causation of disease (for review [18, 19]). Thus, after re-evaluation of associations between higher MS prevalence in patients with low serum 25(OH)D3 levels, it was proposed that other beneficial molecules (for example cis-urocanic acid, neuropeptides and multiple cytokines) produced in skin upon UV and sunlight exposure may control MS development (for review [18, 19]). With low levels of such molecules, MS and potentially other autoimmune conditions may progress. Rather than attempting to replicate the multifactorial benefits of sunlight exposure through selecting one or few molecules for supplementation, the delivery of narrowband UVB, a component of sunlight, was considered the most appropriate, safe and unbiased experimental tool for treatment of MS by the PhoCIS trial investigators (Phototherapy for CIS) (ACTRN 12614000185662) [20, 21]. Clinically Isolated Syndrome (CIS) is the first symptomatic form of MS, and a stage at which the disease course may be delayed or deviated away from a worsening trajectory. As for patients with inflammatory skin conditions, it was proposed that a study of the immunomodulating effects of NB-UVB would provide a model, albeit imperfect and incomplete, for studies of the effect of sunlight per se on MS development and provide some relevance to the observed latitude gradient for MS [20].

4 The PhoCIS trial

In the PhoCIS trial [20, 21], participants with recently diagnosed CIS were given suberythemal narrowband UVB phototherapy 3 times per week for 8 weeks. As detailed elsewhere [21], the participants had been diagnosed within the last 120 days and at the start of the trial they had not yet started any disease-specific drug treatment. This meant the trial was evaluating the effect of NB-UVB phototherapy only and not a treatment that was adjunct to disease-modifying treatments (DMTs). The participants were followed for 12 months. Twenty patients were recruited into the Pho CIS trial; ten were randomly selected to receive narrowband UVB therapy in the clinic rooms of a dermatologist. The remaining ten participants were given equal standard care and had blood sampled at the same regular time intervals as the active participants. To our knowledge, this was the largest trial giving NB-UVB to people with MS, and the first for participants so early in their disease course [21]. Other smaller trials [22, 23] confirmed the safety of NB-UVB for MS patients with long-standing disease; in both trials emphasis was placed on the ability of NB-UVB to increase serum 25(OH)D3 levels. As reported [21], in the PhoCIS trial most participants were serum vitamin D-sufficient upon enrolment (> 80 nmol/L). They were otherwise prescribed oral vitamin D.

Additionally, the trial’s relevance is broader than CIS alone. This is because the diagnostic criteria of MS as used for PhoCIS participants have broadened over time, with the 2017 revision to the McDonald criteria for MS [24, 25]. Consequently, the PhoCIS trial data are now applicable to a wider range of MS patients. The inclusion of assessments for IgG antibody-containing bands (oligoclonal bands) in cerebral spinal fluid has been a key driver of this diagnostic change, and 54–82% of patients with CIS now meet MS criteria at first diagnosis, compared to the previous criteria.

5 Clinical outcomes in the PhoCIS trial

After 12 months, all participants in the control arm (CIS patients not receiving phototherapy) had progressed to definite MS as determined by new lesions on their MRI [21]. In contrast, only 7 of 10 participants in the treatment arm (CIS patients receiving phototherapy) had progressed to MS. Although suggestive of a benefit of NB-UVB, the result was not statistically significant [21].

As published [21], those participants who received NB-UVB self-reported less fatigue and enjoyed greater social functioning. Of those participants receiving NB-UVB, all enjoyed the treatment and completed the 24 sessions of phototherapy despite their need to commute regularly to the dermatology clinic for treatment.

6 Scientific analyses of longitudinal sera from participants in the PhoCIS trial

Similar to many other autoimmune conditions, there is no singular biomarker that is casual or predictive in MS. The PhoCIS trial’s extensive serial blood samples were taken at baseline, and after 1, 2, 3, 6 and 12 months of their participation. Serum and peripheral blood mononuclear cells were biobanked as previously published [21]. These samples continue to provide a breadth of insights into MS and the impact of NB-UVB on the immune repertoire.

There were short-term changes in frequencies of circulating leukocytes associated with NB-UVB phototherapy in the CIS participants [26]. Of note, there were significant short-term (for up to 3 months) increases in the frequency of naïve B cells and decreases in switched memory B cells in phototherapy-treated individuals. Since B cells are increasingly targeted by MS therapies and likely drive many autoimmune processes, the functional impact of NB-UVB on B cells was next investigated. For this purpose, B cells from participants at the start of the trial (day 1) and after phototherapy for 8 weeks (day 60) were studied side by side in a single experiment. As published [27], narrowband UVB phototherapy reduced TNF production by B-cell subsets from the PhoCIS participants that were stimulated in vitro via a polyclonal activator of the Toll-like Receptor-7. The outcome suggested treatment-associated priming effects that were detected upon subsequent polyclonal B-cell activation; this result supported effects of phototherapy lasting as long as the lifespan of the cells. A separate study of mRNA levels in peripheral blood mononuclear cells from PhoCIS participants isolated at baseline and after 3 months (first 2 months including NB-UVB phototherapy) suggested that NB-UVB may help to stabilise the higher Arginase 1 mRNA expression in cells from patients with CIS and MS [28]. In summary, NB-UVB phototherapy modulated circulating cells confirming both systemic effects and a reduction of the inflammatory function of those cells.

The sera from the PhoCIS participants were also subjected to proteomic analyses. In an untargeted analysis, serum samples from baseline and day 90 were investigated using the Olink Target 96 Inflammation panel [29]. Sera from the NB-UVB cohort had significant downregulation in 23 of the 92 inflammatory proteins investigated, while sera from those not receiving phototherapy showed no changes. The data also showed that the anti-inflammatory effect of NB-UVB persisted for 30 days beyond the 60-day period of treatment.

Recent aggregation of inflammatory biomarkers has changed the search for a single predictive answer or target. Aided by extensive computational analysis, pooling broad proteomic variances into biological pathways has provided new assays to the neurologist. The clinically validated MS Disease Activity (MSDA) test panel (Octave Biosciences) is a prime example. This assay of 18-proteins has been validated based on associations between algorithm score and clinical/radiographic assessments of people with MS and trained based on the presence/absence of gadolinium-positive (Gd+) lesions [30]. Serial MSDA is impacting clinical decision making and therapeutic choices in MS care [31].

This assay was used to investigate the effect of NB-UVB in the PhoCIS trial [29]. All participants started with similar MSDA scores. After 90 days, on average, the difference in MSDA scores was 1.7 points lower (out of 10) for participants given NB-UVB compared with those in the control arm. When the MSDA scores were broken down into 4 activity pathways [29], the general score and scores for immunomodulation, neuroinflammation, and neuroaxonal integrity were significantly reduced, but not that for myelin biology. The MSDA scores also allowed for measures of change in disease severity [29]. As previously reported, after 90 days, the majority of those in the control group (63%) had MSDA scores suggesting high disease severity with likely increased Gd+ lesions. By comparison, only 11% of those who had received NB-UVB treatment had MSDA scores at 90 days suggestive of high disease severity. The majority of those receiving NB-UVB (89%) could be defined at 90 days of moderate risk for more Gd+ lesions.

A smaller study of neurofilament light chain levels, a marker of neuro-axonal damage in the central nervous system, in the sera of participants of the PhoCIS trial supported the findings from evaluations of the MSDA [32]. In that study, there was a significant cumulative suppressive effect of NB-UVB on serum neurofilament light chain levels for the first 3 months [32].

It is notable that no analyses were able to distinguish between the readouts of the three participants who received phototherapy and did not relapse, and the other 7 who received phototherapy but relapsed to patent MS by 12 months. Reasons may be many and may reflect the recruitment of only 20 participants. Thus, the results of the PhoCIS trial are biased towards a greater understanding of the mechanisms by which NB-UVB is anti-inflammatory, rather than pinpointing the biomarkers that were altered and correlated with direct clinical benefit. The use of the proteomic assay giving MSDA scores and MS-specific severity ratings provided support to suggestions of benefit by NB-UVB to PhoCIS participants, but a larger study will be needed to confirm clinical benefit.

7 What is the future for NB-UVB for treating MS?

MS is an autoimmune disorder of the central nervous system, characterised in its early stages by inflammatory cells transitioning from the periphery into the CNS with no curative therapies. With over 70 years of documented latitude gradient, the translational application of NB-UVB as a safe and effective adjunctive therapy for clinical and quality of life improvements is a logical extension. In a meta-analysis of NB-UVB added to recalcitrant dermatological patients on biologics resulted in significant improvements in 9 out of 10 published studies [33]. Given there are no MS approved therapies with a light-sensitive warning, adding at-home NB-UVB phototherapy to MS therapy is promising.

In the PhoCIS trial, sera and circulating peripheral blood mononuclear cells from the participants were studied longitudinally; we propose that blood molecules and cells are intermediaries in MS development and reflect modifications due to NB-UVB phototherapy. The proteomic analyses of PhoCIS sera provided a plausible account of an ability of NB-UVB to reduce drivers of systemic inflammatory processes. Whilst we wait for a larger confirmatory trial, another consideration is that NB-UVB could be used as an adjunct to prescribed DMTs. NB-UVB phototherapy is cheap to deliver [8] and would add little further cost to patient care. In addition, at-home phototherapy with NB-UVB as a confirmed safe, effective and attractive therapy for patients with psoriasis [9, 10], provides a realistic option for people with MS.

Another proposed benefit of NB-UVB phototherapy for MS patients is for treatment of the fatigue associated with their disease. The MS-targeted proteomic analysis using the MS Disease Activity (MSDA) test panel uncovered significant correlations between levels of self-assessed fatigue and MS-inflammation biomarkers in the sera from the PhoCIS participants (manuscript in preparation) and provides objective support for an ability of NB-UVB phototherapy to reduce MS-associated fatigue. This finding highlights the potential of NB-UVB to relieve fatigue and is the basis for design of the Silent Symptoms Trial for MS patients that is currently seeking approval and funding. This approach is supported by studies of patients with psoriasis given NB-UVB phototherapy [5] and a study of Egyptian MS patients given broadband UVB (3 times weekly for 4 weeks); their postural control and cognitive functions significantly improved [34].

8 From dermatology to other autoimmune conditions: use of NB-UVB

The analyses of biobanked cells and sera from participants in the PhoCIS trial have given valuable insights into how NB-UVB may be immunomodulatory, and its potential use for treatment of other systemic inflammatory conditions. The pathogenesis of type 1 diabetes involves destruction of the β cells of the pancreas by inflammatory cells. A latitude gradient for this condition has also been reported (for review, [35]) and gives some support to the potential of childhood sunshine exposure as a modulator of disease initiation, and by inference, NB-UVB radiation for treatment. In Western Australia and using NASA satellite data, the risk of type 1 diabetes was 42% lower in boys, but not girls, born to mothers exposed to UVR levels in the highest quartile during the third trimester. Similarly, there was a lower risk of type 1 diabetes in boys living at sites of high UV radiation in their first year of life [36]. The reason for the sex difference is not clear but suggests further studies are required. In consideration of the metabolic components of diabetes, there has been multiple reports of reduced obesity and symptoms of metabolic syndrome after exposure to UV radiation [37, 38]. Thus, exposure to UVB may reduce development of diabetes by multiple pathways, involving both immune and non-immune cells (for review, [39]).

Although trials are needed, inflammatory bowel disease (IBD) (Crohn’s disease, ulcerative colitis) may also be susceptible to immunomodulation by NB-UVB. Not only have latitude gradients been reported in Europe and the USA [40] but higher sunlight exposure in summer has been associated with a significant decrease in IBD incidence [41]. In links between NB-UVB phototherapy and the gut, the human intestinal microbiome has also been shown to change with 3 exposures over a single week [42].

There are also associations between higher cumulative UV exposure and decreased risk of rheumatoid arthritis (RA), another autoimmune disease. In the Nurses’ Health Study of 106,000 women followed from 1976 to 2008, higher cumulative average UV-B exposure was associated with decreased RA risk; those in the highest versus lowest category had a 21% decreased RA risk [43]. UV radiation exposure has also been linked with protection against autoimmune thyroid disorders [44].

Together, these studies suggest that environmental UV radiation, as in sunlight, may regulate the inflammation associated with autoimmune disease, and that NB-UVB may provide a safe and cost-effective adjunctive treatment for reducing disease manifestations. If natural sunlight exposure can regulate disease outcomes, the potential of a safe treatment surrogate must be considered in future trials.

Although COVID-19 infections are not an autoimmune condition per se, NB-UVB was trialled as an innovative approach to reduce the inflammation in patients hospitalised with COVID-19. As shown in the 28-day morbidity data, 7 days treatment with NB-UVB significantly reduced patient deaths, probably due to stabilisation of the systemic inflammation and cytokine storm associated with COVID-19 infections [45].

When autoimmune conditions are viewed in a broader sense, the translational application of NB-UVB can be assessed anew. Modulating the immune system at the pathway level, rather than blocking a single molecule, should help explain why NB-UVB may be useful beyond skin disease alone. An example is embedded in dermatology where most biologic drugs which are built to hit one narrow target and turn it off in isolation (for example, IL-17 or IL-23 for psoriasis, IL-4/13 for eczema, JAK–STAT for vitiligo) work very well in their main disease but generally do not help all three conditions and can even trigger new eczema or vitiligo in some patients. By contrast, NB-UVB is already used in routine care for psoriasis, eczema, and vitiligo, and recommended by the American Academy of Dermatology, supporting the idea that a pathway-level intervention can cut across multiple diagnoses [4]. In this context, the PhoCIS findings suggest that NB-UVB behaves as a broad immune pathway therapy, providing a rationale where similar upstream effects could help in systemic autoimmune diseases. These diseases would be those that show links to latitude or sunlight exposure and/or similar immune dysregulation, such as type 1 diabetes, IBD, long COVID, RA, and autoimmune thyroid disease.

9 Conclusions and challenges

This perspective began describing the use of NB-UVB for safe and effective treatment of inflammatory skin conditions. With benefits to non-irradiated psoriatic skin, and cellular changes in lymph nodes draining irradiated skin, there was a realisation of immunomodulatory effects of NB-UVB beyond the irradiated skin sites. However, until recently, there has been little enthusiasm to harness these immunomodulatory effects for therapeutic use. With a cue from the latitude gradients recorded for prevalence and severity of MS, an intervention trial was described using NB-UVB for patients with early MS. The cellular and proteomic analyses of sera from this trial provided valuable insights into the scope of the general anti-inflammatory actions of NB-UVB. MS and inflammatory skin conditions like psoriasis are initiated by immune responses to different disease-specific antigens. However, the proteomic data suggested that NB-UVB may regulate inflammatory pathways potentially fundamental in many human autoimmune diseases.

We propose that NB-UVB may be used as a treatment, or adjunctive treatment, for systemic inflammatory conditions beyond dermatology and neurology. On current evidence, autoimmune diseases that might be rational candidates for NB-UVB trials share several features: (i) a positive latitude gradient and/or inverse association with ambient UV irradiance (e.g., MS, type 1 diabetes, some IBD phenotypes); (ii) dominant Th1/Th17-skewed or B-cell–mediated inflammation that is known to be modulated by UV-induced pathways (Tregs, tolerogenic dendritic cells, altered B-cell cytokine profiles); and (iii) a window for early intervention where attenuating systemic inflammation could plausibly modify long-term outcomes. Specialists treating autoimmune diseases must be encouraged to consider that NB-UVB may regulate common pathways associated with the inflammatory cascades that maintain disease-specific processes. Patients facing chronic conditions should also be encouraged to consider increased exposure to moderate non-erythemal amounts of sunshine, and the interventional option of therapeutic NB-UVB in the clinic and at home. We hope this perspective has provided an overview to encourage future randomised trials of NB-UVB administered to skin to treat various organ-specific autoimmune diseases.

Data availability

No datasets were generated or analysed during the current study.

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March 27, 2026

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