MS and co-morbid autoimmunity
In my experience, the most common co-morbid autoimmune disease in people with MS, outside of thyroid disease post-alemtuzumab, is MS-associated uveitis.
Does having multiple sclerosis increase your risk of having another autoimmune disease? This is a question that is always asked. In general, the risk of having a second comorbid autoimmune disease is low. Having MS seems to protect you from getting some autoimmune diseases, for example, rheumatoid arthritis (RA). The reason for the negative association between MS and RA is likely to be related to genetic factors. The genetic factors that predispose you to MS protect you from getting RA and vice versa.
There are a few exceptions. It seems as if people with MS are at a slightly higher risk of developing autoimmune thyroid disease, both Grave’s disease and Hashimoto's Thyroiditis, pernicious anaemia and uveitis. This does not mean pwMS don’t get other autoimmune diseases. I have looked after patients with MS who have comorbid RA, sacroiliitis, type 1 diabetes, psoriasis, inflammatory bowel disease (IBD), Sjögren's syndrome, autoimmune hepatitis, autoimmune kidney disease (e.g. IgA nephropathy), celiac disease, uveitis, scleritis and myasthenia gravis. In my experience, the most common comorbid autoimmune disease, outside of thyroid disease post-alemtuzumab, is MS-associated uveitis (see below).
Having another co-morbid autoimmune disease often makes treating MS and another autoimmune disease difficult, as some disease-modifying therapies for one disease may make the other disease worse. For example, anti-TNF-alpha therapies for RA and IBD are well known to trigger MS relapses (see paper 1 below). On the other hand, anti-CD20 therapies seem to work reasonably well for both MS, RA and sacroiliitis. However, anti-CD20 therapies may make IBD worse. I have two patients with MS and comorbid IBD, who we are treating with natalizumab, which seems to be working for both conditions. The latter is not surprising as natalizumab is licensed as a treatment for IBD.
Recently, I have seen a patient with comorbid uveitis and MS. The uveitis predated their MS and was being treated with an anti-TNF-alpha therapy when they developed very active MS. Whether or not the anti-TNF-alpha therapy triggered their MS is a moot point (see paper 1 below). We elected to treat their MS with an anti-CD20 treatment based on a small case series (see paper 2 below), which suggested that MS-related uveitis also responds to anti-CD20 therapy.
They were, therefore, started on an anti-CD20 therapy that seems to be working for their MS. They became relapse-free, and their latest MRI showed no evidence of activity. However, their uveitis has now flared up, and the question is whether or not the anti-CD20 therapy for MS had negatively impacted their uveitis. We are now having to consider changing their DMT to another class to cover both their uveitis and MS. The evidence base for which DMT to choose in this patient after an anti-CD20 therapy is very poor.
What is uveitis, and how does it present?
Uveitis is an inflammatory condition affecting the uvea, the middle layer of the eye, which consists of the iris, ciliary body, and choroid. This condition can lead to eye redness, pain, blurred vision, light sensitivity, and floaters. About 1-3% of pwMS have comorbid uveitis, an order of magnitude more common, i.e. 10x higher incidence, than you would expect in the general population (see paper 3 below).
Types of Uveitis
Anterior Uveitis: Affects the front part of the uvea and is the most common form.
Intermediate Uveitis or pars planitis: This condition involves the middle part of the uvea and is the most common form of uveitis associated with MS.
Posterior Uveitis: Affects the back part of the uvea.
Panuveitis: Involves all layers of the uvea.
Causes of Uveitis
Comorbid autoimmune disorders (e.g., rheumatoid arthritis, lupus, MS, ….)
Sarcoidosis
Infections (e.g., herpes, HIV, tuberculosis, syphilis, parasitic infections, …)
Trauma to the eye
Certain cancers affecting the eye (e.g. lymphoma, leukaemia, melanoma, …)
Drug reactions (e.g. Rifabutin and Cidofovir)
Symptoms of Uveitis
The symptoms of uveitis can vary depending on the type and severity but commonly include:
Eye Redness: Inflammation causes noticeable redness in the white of the eye.
Pain: Often a sharp or aching pain in the eye.
Blurred Vision: Inflammation can interfere with vision clarity.
Light Sensitivity: Discomfort when exposed to bright light.
Floaters: Spots or shadows drifting in the field of vision.
Diagnosis and Treatment
Diagnosis typically involves an eye exam and may require blood tests or imaging studies to identify the underlying cause. Treatment focuses on reducing inflammation and relieving symptoms, commonly using corticosteroids or immunosuppressants. In some cases, addressing the underlying condition causing uveitis is crucial for effective management. Early diagnosis and treatment are essential to prevent complications such as glaucoma, cataracts, or permanent vision loss.
I would be interested to know if any of you have uveitis and MS or any other comorbid autoimmune conditions and how this has impacted the management of your MS. I think it may be time for someone to review the literature on the treatment of MS in conjunction with other comorbid autoimmune diseases to provide some guidance on what DMTs to use to cover both diseases.
Paper 1 - Anti-TNF-alpha therapy and MS
Background: Perhaps the most informative experiments in human disease are clinical trials and notably, responses to specific therapies can be highly-informative to help understand disease pathogenesis. There are reagents that inhibit a variety of different autoimmune conditions, such as CD20 memory B cell depleters that are active in both multiple sclerosis (MS), rheumatoid arthritis (RA) and other conditions, suggesting influences on common immune mechanisms in different diseases. However, a notable exception seemed to be the use of tumour necrosis factor (TNF) inhibitors that limits RA, yet seem to, rarely, trigger demyelination and induce MS. This was first seen with TNF-inhibiting monoclonal antibodies and TNF-receptor-immunoglobulin fusion proteins. However, this is also seen with tyrosine and Janus kinase inhibitors that inhibit RA, yet induce demyelinating disease in some individuals PURPOSE: To provide an overview, from a B cell centric perspective, that may underpin the biology that links arthritis treatments to the development of demyelinating disease.
Conclusions: It is apparent that the disease modifying anti-rheumatoid drugs that cause demyelination share a number of common features. These agents tend to inhibit TNF-receptor signalling, augment or exhibit limited inhibitor activity on class-switched memory B cells and importantly appear to be relatively excluded from the central nervous system (CNS). They will thus not target ectopic B cell follicles in the CNS, unlike that occurring in peripheral autoimmunity as seen with anti-TNF treatments in RA. Agents such as ibudilast and some Janus kinase inhibitors that inhibit TNF and clearly penetrate the CNS do not appear to induce demyelination and may even be neuroprotective. It remains to be established whether selection or development of CNS penetrant agents may avoid CNS-complications of treatments for RA. Clearly, further studies are warranted.
Paper 2 - Anti-CD20 therapy in patients with comorbid MS and uveitis
Background and purpose: Approximately 1% of patients with multiple sclerosis (MS) have uveitis, but data on the effects of immunotherapies for MS on MS-associated uveitis are scarce. The aim of this study was to investigate the ophthalmological outcomes in patients with MS-associated uveitis treated with anti-CD20 therapy.
Methods: A retrospective study of 12 eyes of six patients with MS-associated uveitis, refractory to previous immunotherapies, was conducted. Uveitis activity was assessed before initiation of anti-CD20 therapy and at regular follow-up visits. Primary outcome measures were: vitreous haze score; retinal vasculitis score, determined on fluorescein angiography images; macular edema, as quantified by central retinal thickness (CRT) on optical coherence tomography; and visual acuity (VA). Secondary outcomes included number of annualized uveitis or MS relapses, disease activity on cerebral magnetic resonance imaging (cMRI) and Expanded Disability Status Scale (EDSS) score.
Results: After a median (interquartile range [IQR]) treatment time of 28.5 (8-43) months, anti-CD20 therapy was associated with an improvement of vitreous haze score (p = 0.002), retinal vasculitis score (p = 0.001), CRT (p = 0.002), and VA (p = 0.007). The median (IQR) annualized uveitis relapse rate declined from 0.59 (0.56-0.94) before to 0 (0-0.49) after the start of anti-CD20 therapy. The median (IQR) annualized MS relapse rate declined from 0.62 (0.26-2.84) before to 0 (0-0) after the start of anti-CD20 therapy. After initiation of anti-CD20 therapy, there was no disease activity on cMRI, and EDSS score improved (n = 2) or remained stable (n = 4). No severe adverse events were observed.
Conclusion: These findings suggest that anti-CD20 therapy may be a valuable treatment option for MS-associated uveitis.
Paper 3 - Profile of uveitis in pwMS
Introduction: Uveitis may occur during approximately 1-3% of MS patients, corresponding to 10 times higher than in the general population. The development of uveitis is not currently considered as an inflammatory relapse of MS. There are no clinical guidelines for treating. MS with concomitant uveitis requiring systemic treatment.
Purposes: To analyze clinical and therapeutic characteristics of uveitis in patients with MS and the impact of MS treatment on the progression of uveitis.
Materials & methods: We conducted a retrospective, observational, multicenter study in France about 54 patients.
Results: The form of MS most frequently associated with uveitis in our study was the relapsing-remitting form (85%). The mean time of onset of uveitis was 15 months before the diagnosis of MS. The most frequent form of uveitis was bilateral panuveitis (43%), non-granulomatous (61%), synechial (52%) and non-hypertonic (93%) with progressive onset (65%) and chronic course (66%).
Conclusion: MS-associated uveitis occurs most frequently before the diagnosis of relapsing-remitting MS in the form of panuveitis or intermediate uveitis, which is mildly inflammatory and whose main complications are macular edema, cataract and venous vasculitis. Despite their chronicity, these uveitis cases have a good visual prognosis and teriflunomide appears to have a positive effect on progression.
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Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have problems, please tell your healthcare professional, who will be able to help you.
Firstly, thank you so much Prof G for raising the topic of MS and co-morbid autoimmune disease. I have been a bit of a lone wolf in raising this topic within my recent voluntary capacity with the MS Society.
To let you understand, my brother and I have MS, and personally, I have an additional six autoimmune diseases. My first developed when I was 11 (Juvenile Arthritis) followed by Graves disease at 13/14. It set the ball rolling towards diagnoses of Lupus/SLE, Addison's disease, Vitiligo, Oral Lichen Planus and MS in adulthood. Our Mum also happens to have IBD and RA, so we are an "autoimmune family" if you will. However, to get back to your point regarding DMTs and the difficulties encountered by those of us unfortunate enough to have accumulated our share of ADs, I have experienced this firsthand and it is a dreadfully lonely and frustrating place to be as a patient. A lack of awareness of how isolated people living with MS and other ADs are among the MS community and the particular challenges we face, merely compounds this sense of loneliness. I have also found it to be quite difficult on the part of healthcare professionals who are often unsure as to what is best to do with you (because as you rightly say, the evidence base is not particularly strong), and this often makes the patient feel as if they are nothing but a nuisance for being a "complex patient". If I had a pound for every time a Consultant has advised me of my complexity, I would be very wealthy indeed.
I would love to see the profile raised for those of us living with MS and other ADs. We do exist. Up to 25% of those with one autoimmune disease go on to develop another and for those much rarer types such as myself, we have the delight of trying to manage three or more ADs (MAS), however, just because we are rare, it doesn't mean that the difficulties experienced in relation to our complex care needs are not a constant challenge and ultimately have a profound impact on how well, or otherwise, we can treat both our MS as well as our other conditions.
Thank you again for kindly raising this. I truly hope more awareness will be generated among the wider MS community.
This is really interesting! I had Lem back in 2016/17 and since I’ve been relapse-free. However, I have chronic migraine and I suffer greatly with very red, sore eyes. I have what I would call “flare ups” where my vision blurs, the whites of my eyes go very red and gritty feeling. I also have a number of large (and small) floaters. I’ve never been diagnosed with anything other than “dry eye” and treated with drops. I have an Ophthalmology appointment coming up, so will question this.