Management of Musculoskeletal Manifestations in Inflammatory Bowel Disease

Figure 2

The mechanisms of action of various drugs on the gut-synovial axis. SSA and ATA agents restore increased permeability of the inflamed gut mucosa, thus preventing exposure of PAMPs (pathogen associated molecular patterns) and DAMPs (danger associated molecular patterns) to mucosal APCs. Moreover, SSA directly inhibits phagocytosis and intracellular processing of the ingested antigens, thus reducing MHC restricted presentation of processed peptides to naïve T cells, T cells activation, and subsequent release of inflammatory cytokines. ATA agents downregulate T cell clonal proliferation in gut and in synovium by inhibiting release of proinflammatory cytokines and promoting apoptosis of activated T cells. ATA agents also induce regulatory T cell phenotypes and directly neutralize soluble and membrane bound TNFα molecules. Antimetabolites (azathioprine, methotrexate, and leflunomide) inhibit pyrimidine synthesis, thus preventing clonal proliferation of activated T lymphocytes. Rituximab prevents secretion of antibodies directed against autoreactive antigens present in synovium by inhibiting B cells via CD20 antagonism. Ustekinumab directly inhibits IL12 and IL23 mediated Th1 and Th17 cell responses both in gut and in synovium. NSAIDs inhibit production of prostaglandins and mitigate local inflammation. Interaction between α4β7 integrin expressed on the surface of activated lymphocytes and MadCAM-1 expressed on high endothelial venules is inhibited by antibodies designed against integrin molecules—Natalizumab and vedolizumab (more gut specific). Most of these agents execute similar cellular and anti-inflammatory effects both in gut and in synovium, thus providing a significant treatment overlap. SSA: sulfasalazine, ATA: anti-TNFα, NSAIDs: nonsteroidal anti-inflammatory drugs, APCs: antigen presenting cells, MadCAM-1: mucosal addressin cell adhesion molecule-1, PG: prostaglandin, and LT: leukotriene.