African American patients with multiple sclerosis who experience early B cell repletion after anti-CD20 therapy carry distinct genetic polymorphisms that affect immune system pathways, according to new research published in Frontiers in Immunology. The study provides insights into why some patients may require personalized treatment approaches for optimal therapeutic outcomes.
Study Design and Patient Characteristics
Researchers at NYU MS Care Center analyzed 43 African American MS patients receiving anti-CD20 therapy, identifying 20 patients as "early repleters" who showed B cell recovery within 6-7 months after infusion. The remaining 23 patients were classified as "normal repleters" with standard B cell depletion patterns.
Early repleters were defined as patients with CD19+ B cell percentages >0.5% within 6 months or >1.5% within 7 months after anti-CD20 infusion. The study population was predominantly female (80% in early repleters, 87% in normal repleters) with mean ages of 38.7 and 42.3 years respectively.
Genetic Analysis Reveals Key Polymorphisms
Using the Immunoarray Beadchip platform, researchers analyzed 247,814 single nucleotide polymorphisms (SNPs) related to immune system processes. Of these, 189,777 SNPs were found in at least two early repleter patients, with 6,471 showing significant overrepresentation in the early repleter group.
The analysis identified 1,887 SNPs of interest with odds ratios ≥1, including variants in genes crucial for immune function. Notably, four SNPs with p-values <0.001 were associated with genes TGFBR3, SH2D4B, TMEM241, and WWOX, all known to play roles in immune system function and B cell development.
Pathway Enrichment Analysis
Pathway analysis using g:Profiler revealed that SNPs overrepresented in early repleters mapped to genes enriched in several key immune pathways:
- Cell surface receptor signaling (adjusted p=5.94E-05, normalized enrichment score=13.1)
- Intracellular signal transduction (adjusted p=0.02, NES=12.0)
- Immune response (adjusted p=0.002, NES=10.7)
- Leukocyte activation (adjusted p=3.06E-6, NES=5.08)
- Lymphocyte activation (adjusted p=1.7E-5, NES=4.2)
The researchers identified 228 genes with known B cell differentiation-related functions that were overrepresented in early repleters (adjusted p-value=1.9E-262, NES=12.5), including key transcription factors BACH2 and IRF1, as well as TNFSF13B, the gene encoding BAFF.
Clinical Outcomes and Drug Concentrations
Despite faster B cell repletion, early repleters showed similar clinical outcomes to normal repleters. Neurologist-diagnosed relapses occurred in 20% of early repleters versus 22% of normal repleters, with mean annual relapse rates of 4.1% and 5.3% respectively (p=0.849).
New MRI lesions were observed in 20% of early repleters compared to 13% of normal repleters, with mean annual lesion formation rates of 4.1% and 2.7% respectively (p=0.796).
Ocrelizumab concentration levels showed no significant differences between groups, ruling out drug bioavailability as a primary factor. However, two early repleter patients (4.6%) developed anti-ocrelizumab antibodies, higher than the 0.4% prevalence reported in clinical trials.
BAFF Levels and B Cell Survival Factors
Serum B cell activation factor (BAFF) levels were significantly higher in normal repleters compared to early repleters (p=0.02), consistent with the expected reciprocal relationship between BAFF levels and peripheral B cell populations. The lower BAFF levels in early repleters likely reflect increased consumption due to more rapid B cell repopulation.
Notably, rs2582869, an intron variant SNP in TNFSF13B (encoding BAFF), was overrepresented in early repleters. This same SNP has been associated with non-Hodgkin's lymphoma, suggesting potential functional significance.
Connection to MS Risk Genes
Seven SNPs previously identified as non-MHC risk alleles for MS in African Americans were overrepresented in early repleters, including variants in WWOX, DDAH1, STAT3, CLEC16A, IL2RA, BACH2, and PHGDH. This overlap suggests that mechanisms predisposing to MS development may also contribute to faster B cell repopulation after anti-CD20 therapy.
Super-Repleters and Inflammatory Pathways
Within the early repleter group, researchers identified seven "super-repleters" with circulating B cell levels >2% at 4 months post-therapy. These patients showed overrepresentation of 45 SNPs compared to other early repleters, including genes involved in inflammatory pathways: IL17RE, IL2RB, IL17RD, IL1R1, IL23R, and IL1RL2.
Clinical Implications and Future Directions
The findings have important implications for personalizing anti-CD20 therapy in African American MS patients. As clinical practice trends toward extended dosing intervals to minimize infectious complications, understanding genetic factors that influence B cell repletion becomes crucial for optimizing treatment outcomes.
The study authors note that while early B cell repletion with immature subsets may have a good short-term prognosis, longer-term outcomes warrant investigation. Recent evidence suggests that suboptimal B cell depletion may be associated with progression independent of relapses.
Study Limitations and Future Research
The single-center study with limited patient numbers represents a key limitation, though the researchers employed rigorous multi-step statistical approaches to minimize false discoveries. The study did not investigate the functional impact of identified SNPs on gene transcription levels, focusing instead on identifying genetic polymorphisms for future larger-scale validation studies.
Future research will integrate single-cell gene expression analysis with genetic polymorphisms to better understand immune cell transcriptomes and develop personalized therapeutic strategies. The prospective identification of MS patients with these genetic variants could potentially guide individualized dosing intervals for CD20-depleting therapy to minimize disease progression risk in those with rapid B cell repletion.
