Bucillamine use for rheumatoid arthritis and type 2 diabetes mellitus are associated with neural epidermal growth factor-like 1 (NELL1)-associated membranous nephropathy

Membranous nephropathy (MN) is a disease characterized by deposition of immune complexes on the glomerular basement membrane. More than 10 specific antigens for MN including M-type phospholipase A2 receptor (PLA2R), thrombospondin type-1 domain-containing 7A (THSD7A), exostosin 1/exostosin 2 (EXT1/EXT2) and neural epidermal growth factor-like 1 (NELL1) have so far been identified. Since the clinicopathologic characteristics of each type of MN in Japanese are not well understood, we first examined 107 cases of MN by immunohistochemistry for four antigens (PLA2R, THSD7A, EXT1, and NELL1) (MN-cohort). Of those 107 cases, 40% were PLA2R-positive, 13% were NELL1-positive, 11% were THSD7A-positive, 5% were EXT1-positive, 2% were PLA2R and NELL1-double-positive, and 29% were quadruple-negative. In one case of PLA2R and NELL1-double-positive, the first biopsy showed PLA2R-positive and the second biopsy showed PLA2R and NELL1-double-positive. Of the 16 cases of NELL1-positive, 12.5% had colon cancer, 18.8% had rheumatic diseases treated with bucillamine, and 63% had type 2 diabetes mellitus (T2DM). Next, 34 patients diagnosed with MN who had rheumatoid arthritis (RA) were examined (RA-MN cohort). Of those 34 patients, 79% were NELL1-positive, 6% were PLA2R-positive, and 15% were quadruple-negative. In the RA-MN cohort, 56% had a history of bucillamine use. In conclusion, NELL1-associated MN is a common MN in patients with RA using bucillamine and may also be associated with T2DM.