B-cell Depletion in Offspring to Women With MS and Rituximab Treatment Before or During Pregnancy

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system affecting more women than men and typically manifests during reproductive ages (1). The disease and associated treatments therefore have a large impact on family planning. While trying to conceive most clinicians recommend discontinuation of disease-modifying drug use (DMD) before conception unless the risk of disease worsening outweighs the risk to the fetus (2,3). Patients with active disease may need to continue DMD treatment until conception or even during pregnancy. Furthermore, given that nearly half of all pregnancies are unplanned (4-6) women with MS may occasionally become pregnant during or shortly after receiving treatment. As such, gathering information on the effect of pregnancy exposure to DMD is crucial for the management of reproductive issues in women with MS.

Rituximab, a chimeric monoclonal B cell-depleting anti-CD20 antibody, is frequently used off-label for the treatment of MS in Sweden (7). The drug targets CD20 on the cell surface of B cells and effectively depletes them. Previously recommendations of rituximab was withdrawn at least one year prior to a planned pregnancy. Given the pharmacokinetics with a halftime of around 24 days current Swedish guidelines accept a minimum of 3-4 months between last infusion and conception. Rituximab is a chimeric antibody of the immunoglobulin G1 kappa type and is therefore actively transported over the blood-placenta barrier, mainly during the third trimester but starting already in the second trimester. Small case series and reports show that rituximab administered during the third trimester suppresses neonatal b-cell development (8-12). After six months, usually, b-cells levels normalize but effects may not be clinically apparent at birth but may influence response to vaccinations early in life and increase susceptibility to infections.

Severe combined immunodeficiency (SCID) is included in the Swedish national neonatal disease screening program, testing is performed at Centrum för Medfödda Metabola Sjukdomar (CMMS), in parallel with screening tests for other diseases, on blood samples in the form of dry blood spots (DBS) taken within 48 hours after birth. The SCID screening consists of assessing markers of T and B cell production, T-cell receptor excision circles (TREC) (13) and kappa-deleting recombination excision circles (KREC)(14) , respectively. Both are circular fragments of DNA that are excised during the gene rearrangements necessary for the formation of functional T- and B-cell receptors. KRECs are formed during the rearrangement of the kappa light chain gene and occurs in the bone marrow at the small pre-B-cell stage. CD20 is already expressed on the surface of these B-cell precursors and they may therefore be targeted by rituximab and other monoclonal anti-CD20 antibodies (15). Each cell forms one KREC copy, which by necessity is passed to only one of the cells after cell division. Consequently, a proportion of mature B-cells in the circulation will also carry KRECs, and because they express CD20 they may be depleted by rituximab.

We hypothesize that if rituximab inhibits B-cell formation in the fetus of a pregnant mother treated with the drug, this can be detected in the form of reduced KREC results. A case report that describes a child of a rituximab treated mother that had reduced KREC results at birth has been published suggesting that such effects occur (16). It has also been shown that broad immunosuppressants, in particular the purine analogue azathioprine, cause some KREC results that are under the cutoff in the neonatal screening in Sweden (17). More knowledge is needed regarding the safety of rituximab for the fetus during pregnancy to facilitate clinical decisions in this complex situation, being able to identify offspring with insufficient B-cell counts and consequently at higher risks for infection and influence of vaccination responds. Such knowledge will facilitate clinical decisions and may help identify offspring with insufficient B cell counts and consequently at higher risks for infection and poor vaccine response.

The experimental plan includes a retrospective part as well as a prospective part.