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

Abstract

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.

NELL1 membranous nephropathy: clinical associations provide mechanistic clues

“…MN in the setting of hematopoietic stem cell transplant and graft-versus-host disease (GVHD) can occur with the NELL1 antigen ( 29 ) although is much more commonly associated with the protocadherin FAT1 antigen ( 18 ). Autoimmune disease, seen in 0-31% of reported patients ( 13 , 26 , 36 , 37 ), including sarcoidosis ( 40 , 41 ), rheumatoid arthritis (especially patients treated with bucillamine) ( 37 – 39 ) and others may also be associated with NELL1 MN. Finally, NSAIDs have also been associated with NELL1 MN ( 26 , 34 , 40 ) (up to 27%), though are also associated with the PCSK 6 antigen ( 21 ) and clinical correlations between NSAID cessation and remission are currently less well-documented than for thiol- or mercury- associated NELL1 MN.…”

“…The first went into remission but relapsed with high-titer anti-PLA2R antibodies (without anti-NELL1 antibodies) ( 27 ), and the second progressed to have a positive serum anti-PLA2R antibody (with persistent anti-NELL1 antibodies) ( 50 ). A third patient had an initial biopsy with PLA2R+ NELL1- MN (no serum available), treated conservatively, with relapse >10 years later and biopsy demonstrating dual PLA2R+ NELL1+ MN with corresponding serum antibodies to both PLA2R and NELL1 ( 37 ). In two cases, PLA2R glomerular staining is described as weak with an incomplete capillary loop distribution and was associated with a negative serum anti-PLA2R antibodies at the time of biopsy ( 35 , 45 , 49 ), which may represent false-positive tissue reactivity.…”