Drug resistance in rheumatological diseases

Abstract

Rheumatological diseases are chronic inflammatory diseases that involve joints, skin, vessels, and other organ systems. Steroids, DMARDS, and various biological agents are used to control the disease activity by interfering at various levels of the inflammatory cascade. Long term use of the above-mentioned agents is required for treatment, which leads to resistance against these agents. Drug resistance involves various mechanisms that are not completely understood. Proposed mechanisms involve drug uptake and drug efflux transporters, e.g., P-glycoprotein, multidrug resistance protein-1, and organ anion transporters-3, Antidrug antibodies against various anti-TNF drugs, down regulation of Receptors, reprogramming of stimulatory signals, and genetic polymorphisms. Drug resistance is also complicated by non-compliance and the emergence of drug-related adverse effects. Different strategies are proposed to overcome drug resistance that includes the use of a combination of drugs that increase the intracellular concentration of drugs as well as bypass or suppress the multidrug resistance. Alternative agents with slightly different mechanisms of action but similar end targets can also be prescribed. Modification of intracellular signal transduction is also one way to overcome resistance. However, further studies are required to get more insight into the mechanisms of resistance. This will pave new ways to overcome drug resistance, helping in more effective control of disease progression. In this chapter, we will be giving an overview of major rheumatologic diseases, followed by the major drugs used to treat them, the mechanisms of action and mechanisms of resistance to these drugs, and the proposed evidence-based steps to overcome that resistance.