What to do when immunoglobulin levels are lowered by B-cell depletion? – In the first post on this topic, I outlined how important B-cell-depleting therapies are for the treatment and stabilization of especially (highly) active MS patients. Fortunately, this therapeutic principle has shown a very good effectiveness within the approval studies as well as a positive side effect profile and good tolerability.
However, there is concern that the decrease in immunoglobulin G (IgG) levels observed in some patients in the approval studies could lead to problems with infectious diseases in the long run. In other words, a so-called secondary immunodeficiency syndrome may develop in some patients as a result of therapy. Given this problem – on the one hand a very effective and important medication, on the other hand a certain (quite justified) concern, which is amplified in the media and on social networks – the disease-related competence network Multiple Sclerosis (KKNMS) published a statement on this topic in early December, summarizing current knowledge and giving concrete recommendations for action. These recommendations will be briefly summarized and explained below.
KKNMS Statement on Immunoglobulin Levels Under MS Therapy
First, IgG and IgM levels should be measured before starting therapy. If there is already a (constitutionally induced) reduction in IgG levels at this point, the choice of therapy should be reconsidered if possible. Now, according to the study data (see Immunoglobulins and B-cell Depletion Part 1), it can be expected that immunoglobulin levels will progressively decrease under therapy in a portion of those treated. Therefore, the IgG (and optionally also the IgM) serum levels should be checked at least yearly, preferably every six months, under therapy. Patients should also preferably ensure that this monitoring measure is carried out.
If an IgG level below the normal limits is detected, this is initially no reason to initiate measures, especially if the lower normal limit is only slightly exceeded. Much more important for assessing the situation is the question of recurrent infections, especially of bacterial origin.
This should be regularly asked about during presentations in the MS outpatient clinic. I would recommend that those affected keep a diary of infectious diseases if necessary. Because often one does not have the data present at the doctor’s appointment if one does not write it down. However, I would also like to note that in otherwise healthy adults, two to five (respiratory) infections per year are “normal” – and especially if you have small children of preschool age, it can happen that one catches it frequently.
Countermeasure: Increase IgG by Infusion
So, isolated IgG deficiency without increased susceptibility to infection is currently (usually) not an indication for substitution therapy with intravenous immunoglobulins. However, if repeated or severe infections occur in addition, supplementation with immunoglobulins (i.e., protein solutions containing purified IgG from foreign donors) may be considered.
For a substitution, a once-monthly dose of 0.4 – 0.6 g/kg body weight can be used, which is continuously adapted so that the IgG level before the next immunoglobulin administration (nadir) is still within the normal range. If laboratory tests detect an IgM or IgA deficiency, it should be noted for completeness that IgG substitution does not make sense here.
In general, in a situation with increased susceptibility to infection, it must of course be discussed whether therapy can and should be continued. Here, however, the risk of the underlying disease, i.e., the activity of MS, plays a crucial role, as well as which alternatives are available at all.
No reason for panic, but: stay vigilant
So, vigilance regarding IgG levels is good and important, panic or scaremongering is certainly inappropriate given the current data situation. However, we clinically active doctors are now encouraged to think – in collaboration with the manufacturers – about concepts for how we will deal with B-cell depleting therapies in the future and in the long term.
One possibility would be dose adjustments over time to prevent hypogammaglobulinemia. However, under these dose adjustments, the effectiveness of the therapy should of course not suffer. Therefore, controlled studies on the effectiveness of reduced dose regimens would be desirable. Or, also a perspective, drugs become available that modulate B cells but do not reduce immunoglobulins. Let’s see what the next developments in this field bring…
