Although blockade of the CD40-CD40L pathway with BI 655064 in MTX-IR patients with RA resulted in marked changes in clinical and biological parameters, including reductions in activated B-cells, autoantibody production and inflammatory and bone resorption markers, with a favourable safety profile, clinical efficacy was not demonstrated in this small phase IIa study.
CD40 rs1883832 is associated with decreased risk of Graves' disease, especially in Asian; CD40rs1883832 is associated with increased risk of multiple sclerosis; CD40 -1C>T (rs1883832) is not associated with the susceptibility of Hashimoto's thyroiditis, systemic sclerosis or Asthma; there is insufficient data to fully confirm the association between CD40rs1883832 and systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Behçet's disease (BD), myasthenia gravis (MG), Crohn's disease (CD), ulcerative colitis (UC), Sarcoidosis, Fuch uveitis syndrome (FUS), Vogt-Koyanagi-Harada syndrome (VKH), Kawasaki disease (KD), giant cell arteritis (GCA) or Immune thrombocytopenia (ITP).
In conclusion, our data suggest that therapeutic CD40-CD40L blocking agents may prove efficacious not only in early and established RA, but also in inhibiting the progression of the disease from arthralgia or UA to RA.
Second, we demonstrate that subjects homozygous for the RA risk allele have ∼33% more CD40 on the surface of primary human CD19+ B lymphocytes than subjects homozygous for the non-risk allele (P = 10(-9)), a finding corroborated by expression quantitative trait loci (eQTL) analysis in peripheral blood mononuclear cells from 1,469 healthy control individuals.
Polymorphisms of the genes encoding CD40 and growth differentiation factor 15 and in the 9p21.3 region in patients with rheumatoid arthritis and cardiovascular disease.
Although CD40 has recently been identified in genome-wide association study as a novel rheumatoid arthritis susceptibility gene such an association has not been documented for SLE.
The genes CD40 and nuclear receptor coactivator 5 (NCOA5), located in a 400-kb region surrounding CD40, have been reported to be associated with increased risk for rheumatoid arthritis and other autoimmune diseases.
In particular, recent discoveries highlight the importance of the CD40/NF-kappaB signaling pathway in RA, based on genetic association with several genes relevant to this pathway, including CD40, TRAF1, TNFAIP3, and REL.
In this large UK cohort, strong association of the CD40 gene with susceptibility to RA was found, and weaker evidence for association with RA in the CCL21 locus.