Immunodeficiency after MS treatments, a rising concern

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You can read the full text of this review article for free on the internet, but in a nutshell the article is about secondary immunodeficiency after immunosuppressive treatments. Immunoglobulins or antibodies are produced at a basal level in all of us to protect against infections. However, when you are low in antibodies you’re at an increased risk of infections. This ranges from a common cold, to more serious infections such as herpes infections, listeria and COVID19.

Typically, this is put down to many of our immunosuppressants targeting B-cells (see Table below), but can be seen with natalizumab even; which makes me think that immune system homeostasis is key. Treatments where I’ve had to personally manage immunoglobulin deficiency is with ocrelizumab, cladribine, alemtuzumab, and HSCT.

As well as an individual developing treatment-related immunodeficiency, the duration of the immunodeficiency is equally important. This can anywhere between 6 months to 2 years after an induction therapy or de-escalation to a less immunosuppressive agent. Those with grade 3-4 lymphopenia are more susceptible.

Long-term studies are clearly needed to look at this in more detail (easy to do with real-world cohorts), but in the mean time we need to consider the duration of MS treatments. We need to factor into this pre-existing health issues (for e.g. pre-existing lung conditions, splenectomy) and an older age (the immune system ages with you). As a general rule, my policy is to check baseline immunoglobulin levels in order to pick up a pre-existing immunodeficiency (this needs to be directed to an immunologist for further investigations), vaccinate patients before starting treatment, use induction treatments or for a shorter duration when using highly-active DMTs wherever possible, and refer to immunologist to consider IV immunoglobulin where they remain well below acceptable levels for a long duration.

DrugIgG decrease per year
Rituximab– 0.42 g/L per year [33]
Ocrelizumab– 0.32 g/L per year (–3.0% per year) [35]
OfatumumabNo definitive data available [38,39,40]
AlemtuzumabFirst year: – 0.23 g/L per year (–2.5%)
Second year: – 0.69 g/L per year (–7.7%)
First 2 years: – 0.915 g/L per year (–10%) [45]
Table: Decrease in immunoglobulin G (IgG) following B-cell therapy

Abstract

Review CNS Drugs. 2021 Oct 16. doi: 10.1007/s40263-021-00863-4. Online ahead of print.

Secondary Immunodeficiency and Risk of Infection Following Immune Therapies in Neurology

Fabian Szepanowski  Clemens WarnkeGerd Meyer Zu Hörste  Anne K Mausberg Hans-Peter Hartung Christoph Kleinschnitz Mark Stettner

Secondary immunodeficiencies (SIDs) are acquired conditions that may occur as sequelae of immune therapy. In recent years a number of disease-modifying therapies (DMTs) has been approved for multiple sclerosis and related disorders such as neuromyelitis optica spectrum disorders, some of which are frequently also used in- or off-label to treat conditions such as chronic inflammatory demyelinating polyneuropathy (CIDP), myasthenia gravis, myositis, and encephalitis. In this review, we focus on currently available immune therapeutics in neurology to explore their specific modes of action that might contribute to SID, with particular emphasis on their potential to induce secondary antibody deficiency. Considering evidence from clinical trials as well as long-term observational studies related to the patients’ immune status and risks of severe infections, we delineate long-term anti-CD20 therapy, with the greatest data availability for rituximab, as a major risk factor for the development of SID, particularly through secondary antibody deficiency. Alemtuzumab and cladribine have relevant effects on circulating B-cell counts; however, evidence for SID mediated by antibody deficiency appears limited and urgently warrants further systematic evaluation. To date, there has been no evidence suggesting that treatment with fingolimod, dimethyl fumarate, or natalizumab leads to antibody deficiency. Risk factors predisposing to development of SID include duration of therapy, increasing age, and pre-existing low immunoglobulin (Ig) levels. Prevention strategies of SID comprise awareness of risk factors, individualized treatment protocols, and vaccination concepts. Immune supplementation employing Ig replacement therapy might reduce morbidity and mortality associated with SIDs in neurological conditions. In light of the broad range of existing and emerging therapies, the potential for SID warrants urgent consideration among neurologists and other healthcare professionals.

About the author

Neuro Doc Gnanapavan

3 comments

  • Thanks for this post, I have been looking at IgGs after ocrelizumab but didn’t see a decrease in year 1 so I was wondering what is the extent of the decrease and this post answers part of my questions. So I ask the remaining 🙂 Should we see this decrease from time zero or the onset of the decrease occur somewhat later? Also, is there a correlation of the decrease with patient age? I would expect older people to decrease faster than young because their plasma cells are older.
    Thank you again

  • Let’s see…….OCR gave me anemia and sporadic allergic reactions. TERI gave me osteoporosis. While CLAD left me with mild heart damage. Secondary issues related to DMTs need more attention for sure. Thanks for the post!

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