Novel mechanisms of action of the biologicals in rheumatic diseases.
Biological drugs targeting pro-inflammatory or co-stimulatory molecules or depleting lymphocyte subsets made a revolution in rheumatoid arthritis (RA) treatment. Their comparable efficacy in clinical trials raised the point of the heterogeneity of RA pathogenesis, suggesting that we are dealing with a syndrome rather than with a single disease. Several tumor necrosis factor-alpha (TNF-α) blockers are available, and a burning question is whether they are biosimilar or not. The evidence of diverse biological effects in vitro is in line with the fact that a lack of efficacy to one TNF-α agent does not imply a non-response to another one. As proteins, biologicals are potentially immunogenic. It has been recently raised that anti-drug antibodies (ADA) may affect their bioavailability and eventually the clinical efficacy through local formation of immune complexes and directly by preventing the interaction between the drug and TNF-α. Regular monitoring of drug and ADA levels appears the best way to tailor anti-TNF-α therapies. Owing to the pleiotropic characteristics of the target, anti-TNF-α blockers may affect several mechanisms beyond rheumatoid synovitis. As TNF-α plays a pivotal role in the induction of early atherosclerosis, treatment with TNF-inhibitors may modulate cholesterol handling, in particular, cholesterol efflux from macrophages. Side effects are a major issue because of the systemic TNF-α blocking action. The efficacy of an anti-C5 monoclonal antibody fused to a peptide targeting inflamed synovia in experimental arthritis opened the way for new strategies: Homing to the synovium of molecules neutralizing TNF would allow to maximize the therapeutic action avoiding the side effects.
Division of Rheumatology, Istituto G Pini, Piazza C. Ferrari, 1, 20122, Milan, Italy.
Cecilia Beatrice
CB
Chighizola
Ennio Giulio
EG
Favalli
Pier Luigi
PL
Meroni
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000936:Antigen-Antibody Complex / Q000378:metabolism; D018501:Antirheumatic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D001688:Biological Products / Q000627:therapeutic use*; D001691:Biological Therapy; D002784:Cholesterol / Q000378:metabolism; D003182:Complement C5 / Q000276:immunology; D006801:Humans; D008212:Lymphocyte Depletion / Q000379:methods; D058990:Molecular Targeted Therapy; D012216:Rheumatic Diseases / Q000628:therapy*; D013583:Synovial Membrane / Q000187:drug effects* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D018501:Antirheumatic Agents; D001688:Biological Products; D003182:Complement C5; D014409:Tumor Necrosis Factor-alpha; D002784:Cholesterol