Management of Musculoskeletal Manifestations in Inflammatory Bowel Disease

Abstract

Musculoskeletal manifestations are the most common extraintestinal manifestations in inflammatory bowel diseases. Some appendicular manifestations are independent of gut inflammation and are treated with standard anti-inflammatory strategies. On the other hand, axial involvement is linked to gut inflammatory activity; hence, there is a considerable amount of treatment overlap. Biological therapies have revolutionized management of inflammatory bowel diseases as well as of associated articular manifestations. Newer mechanisms driving gut associated arthropathy have surfaced in the past decade and have enhanced our interests in novel treatment targets. Introduction of biosimilar molecules is expected in the US market in the near future and will provide an opportunity for considerable cost savings on healthcare. A multidisciplinary approach involving a gastroenterologist, rheumatologist, and physical therapist is ideal for these patients.

Figures

Figure 1

Effects of NSAIDs and selective COX-2 inhibitors. Phospholipase A2 acts on the membrane phospholipids to yield arachidonic acid (AA). AA is metabolized by either cyclooxygenase (COX) or lipoxygenase (LOX) pathway. Two unique COX isoenzymes convert AA into prostaglandin endoperoxides. COX-1 is expressed constitutively in most cells, including GI mucosal cells. In contrast, COX-2 is expressed by inflammatory cells in response to a variety of stimuli including microbial products and cytokines. COX-1 generates prostanoids responsible for “housekeeping” function; they help with vasodilatation, preserving mucosal flow, and induction of platelet aggregation in response to vascular injury to prevent blood loss. COX-2 induction plays a part in leucocyte activation, adherence, and angiogenesis through effects on NFκB and IL8. Reactive oxygen species generated due to enzymatic activities of COX and LOX also stimulate NFκB and perpetuate the cycle. Inhibition of COX-2 prevents this inflammatory cascade and is responsible for clinical effects of NSAIDs and selective COX-2 inhibitors. NSAIDs, in addition, also block COX-1 pathway leading to mucosal injury, vasoconstriction, mucosal ischemia, and increased vascular permeability. NSAIDs may also lead to direct epithelial damage and mitochondrial uncoupling of oxidative phosphorylation. Dashed red line indicates enzymatic inhibition.

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.