Abstract
In order to identify pathogenic correlates of refractory rheumatoid arthritis (RA), antibodies against anti-cyclic citrullinated protein (ACPAs) were investigated in RA patients in whom the dysregulated immune system had been ablated by high-dose chemotherapy (HDC) and autologous haematopoietic stem cell transplantation (HSCT). Six patients with refractory RA were extensively characterized in terms of levels of total immunoglobulins, RA-specific autoantibodies (ACPAs and rheumatoid factor) and antibodies against rubella, tetanus toxoid (TT) and phosphorylcholine before and after HDC plus HSCT. Additionally, the avidity of ACPAs was measured before and after treatment and compared with the avidity of TT antibodies following repeated immunizations. Synovial biopsies were obtained by arthroscopy before HDC plus HSCT, and analyzed by immunohistochemistry. In the three patients with clinically long-lasting responses to HDC plus HSCT (median 423 days), significant reductions in ACPA-IgG levels after therapy were observed (median level dropped from 215 to 34 arbitrary units/ml; P = 0.05). In contrast, stable ACPA-IgG levels were observed in three patients who relapsed shortly after HDC plus HSCT (median of 67 days). Clinical responders had ACPA-IgG of lower avidity (r = 0.75; P = 0.08) and higher degree of inflammation histologically (r = 0.73; P = 0.09). Relapse (after 38 to 530 days) in all patients was preceded by rising levels of low avidity ACPA-IgG (after 30 to 388 days), in contrast to the stable titres of high avidity TT antibodies. In conclusion, humoral autoimmune responses were differentially modulated by immunoablative therapy in patients with synovial inflammation and low avidity ACPA-IgG autoantibodies as compared with patients with high levels of high avidity ACPA-IgG. The distinct clinical disease course after immunoablative therapy based on levels and avidity of ACPA-IgG indicates that refractory RA is not a single disease entity.
Highlights
Rheumatoid arthritis (RA) is a systemic, chronic and progressive disease that requires long-term immunosuppressive treatment, in which disease-modifying antirheumatic drugs (DMARDs) play a central role
After treatment with High-dose chemotherapy (HDC) plus haematopoietic stem cell transplantation (HSCT) all patients exhibited an improvement in clinical disease activity, with a lowest median Disease Activity Score for 44 joints (DAS44) of score 1.95
The improvements in DAS44 score were temporary, and patients were off DMARD therapy for a median duration of 174 days
Summary
Rheumatoid arthritis (RA) is a systemic, chronic and progressive disease that requires long-term immunosuppressive treatment, in which disease-modifying antirheumatic drugs (DMARDs) play a central role. High-dose chemotherapy (HDC) followed by autologous haematopoietic stem cell transplantation (HSCT) is employed in the treatment of patients with refractory autoimmune diseases, including systemic lupus erythematosus (SLE), systemic sclerosis and RA [4]. ACPA = anti-cyclic citrullinated protein antibody; AU = arbitrary units; DAS44 = Disease Activity Score for 44 joints; DMARD = disease-modifying antirheumatic drug; ELISA = enzyme-linked immunosorbent assay; HDC = high-dose chemotherapy; HSCT = haematopoietic stem cell transplantation; NaSCN = sodium thiocyanate; PC-IgM = anti-phosphorylcholine of the IgM isotype; RA = rheumatoid arthritis; RF = rheumatoid factor; RL-IgG. A recent review of the European Group for Blood and Marrow Transplantation/ European League Against Rheumatism registry for autologous HSCT in autoimmune disease [5] showed that sustained improvements were common in patients with systemic sclerosis and systemic lupus erythematosus, whereas in RA temporary improvements with subsequently relapsing disease was the most common clinical course. The therapeutic mechanism of HDC plus HSCT is conceptually similar for all autoimmune diseases, it is currently unclear why HDC plus HSCT exhibited inferior efficacy in RA
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
