B-cell depleting therapies such as Ocrelizumab (Ocrevus), Ofatumumab (Kesimpta) or the newly approved Inebilizumab (Uplizna) for the treatment of NMOSD are currently very important tools for controlling active MS courses and for preventing relapses in NMOSD. The advantage of these active substances is their high efficacy, in addition to good tolerability. It can be assumed from current data that their effectiveness is comparable to that of Natalizumab (Tysabri), a monoclonal antibody that helped many patients with active MS in the early 2000s. Unfortunately, Natalizumab was associated with an increased occurrence of cases of progressive multifocal leukoencephalopathy (PML), a dangerous opportunistic viral infection of the brain, which has limited the use of Natalizumab in recent years.
Pros and Cons of B-cell-depleting Therapies
The gap left by Natalizumab was filled by B-cell-depleting therapies, initially by Rituximab (off-label) and then increasingly since 2018 by the approved MS therapies Ocrevus and Kesimpta. These showed a very advantageous side effect profile in their approval studies and above all did not show any problem with PML cases. Therefore, B-cell-depleting therapies are currently an important part of current MS therapy concepts because they are a) highly effective and b) very well tolerated.
Despite the positive study data, however, MS experts worldwide are considering the longer-term use of these B-cell-depleting therapies. In the approval studies, it was observed that in some of the treated patients the immunoglobulin levels in the blood decrease. In these cases, there is concern that a so-called secondary immunodeficiency syndrome may develop. (Short explanation: Immunoglobulins (antibodies) are an important (soluble) component of our immune system. Immunoglobulins have the task of capturing viruses, bacteria or their toxins that have entered the body. The predominant type of antibody in human blood is Immunoglobulin G – IgG).
Facts from the Studies
Here briefly the facts from the studies: In the Ocrelizumab studies, patients with continuous Ocrelizumab treatment showed a decrease in IgG levels by an average of 0.33 g/l or 3.0% per year. After 7 years of observation, 7.7% of the patients had an IgG level below the lower normal limit (in the Opera study program 5.65 g/l). In the Ofatumumab approval studies, the IgG level remained largely stable under continuous treatment with Ofatumumab on average (+1.1%). However, it should be noted that due to different exclusion, discontinuation and restart criteria, the immunoglobulin data of both study programs can only be compared to a limited extent. Despite these “more reassuring” study data from Ofatumumab, one should therefore keep an eye on the IgG levels when treating with Ofatumumab, considering the similar mode of action of both substances.
Now one must clearly differentiate: a decreased laboratory value for IgG is not synonymous with an immune defect. Especially since infections even occurred more frequently in persons with normal immunoglobulin levels within the studies. On the other hand, it is important to keep this aspect of B-cell-depleting therapies in mind. Especially with the knowledge that a B-cell-depleting therapy per se has been identified as a risk factor for infections (Infection Risks Among Patients With Multiple Sclerosis Treated With Fingolimod, Natalizumab, Rituximab, and Injectable Therapies) and a B-cell depleting therapy (also referred to as anti-CD20 therapy) during the pandemic was a statistically relevant risk factor for severe COVID19 courses (Anti-CD20 and Other Risk Factors Associated With COVID-19 Severity).
For this reason, in addition to the regular determination of immunoglobulins before and during therapy, a careful infection screening should be carried out before, during and possibly after treatment with B-cell-depleting therapies. The infection screening for bacterial infections (e.g., recurrent sinusitis, bronchitis, pneumonia) is more important and essential for the continuation of therapy or the initiation of substitution measures than the mere consideration of laboratory limit values.
I will discuss how to deal with this problem in the 2nd part of this article.
