Review article: pathogenesis and clinical manifestations of gastrointestinal involvement in systemic sclerosis

Abstract

Background: Gastrointestinal tract (GIT) involvement is a common cause of debilitating symptoms in patients with systemic sclerosis (SSc). There are no disease modifying therapies for this condition and the treatment remains symptomatic, largely owing to the lack of a clear understanding of its pathogenesis.

Aims: To investigate novel aspects of the pathogenesis of gastrointestinal involvement in SSc. To summarise existing knowledge regarding the cardinal clinical gastrointestinal manifestations of SSc and its pathogenesis, emphasising recent investigations that may be valuable in identifying potentially novel therapeutic targets.

Methods: Electronic (PubMed/Medline) and manual Google search.

Results: The GIT is the most common internal organ involved in SSc. Any part of the GIT from the mouth to the anus can be affected. There is substantial variability in clinical manifestations and disease course and symptoms are nonspecific and overlapping for a particular anatomical site. Gastrointestinal involvement can occur in the absence of cutaneous disease. Up to 8% of SSc patients develop severe GIT symptoms. This subset of patients display increased mortality with only 15% survival at 9 years. Dysmotiity of the GIT causes the majority of symptoms. Recent investigations have identified a novel mechanism in the pathogenesis of GIT dysmotility mediated by functional anti-muscarinic receptor autoantibodies.

Conclusions: Despite extensive investigation, the pathogenesis of gastrointestinal involvement in systemic sclerosis remains elusive. Although treatment currently remains symptomatic, an improved understanding of novel pathogenic mechanisms may allow the development of potentially highly effective approaches including intravenous immunoglobulin and microRNA based therapeutic interventions.

Figure 1

Pathogenesis of SSc: Unknown environmental factors in a genetically susceptible host trigger initial endothelial cell injury. This results in release of reactive oxygen species, chemokines, cytokines, and growth factors. The local cytokine milieu leads to recruitment and activation of chronic inflammatory cells, including T- and B-lymphocytes and macrophages. B-cells evolve into plasma cells that produce M₃-R antibodies, which occupy the extracellular loop-2 of the M₃-R on the intestinal smooth muscle and prevent acetylcholine released from the synaptic terminal to act on the receptor. The CD4+ T cells under influence of IL-4 differentiate into Th2 subtype. Th2 cells secrete pro-fibrogenic cytokines IL-4 and IL-13, which along with IL-6 stimulate TGF-β production. Fibroblasts are activated into myofibroblasts by action of TGF-β. Myofibroblasts produce excess collagen, which causes structural damage and fibrosis, distorting the normal architecture of the tissue, leading to dysmotility.

Figure 2

SScIgG binding to colon: Transverse section of rat colon demonstrating specific binding of SScIgG to the smooth muscle and myenteric plexus as evidenced by increase immunofluorescence (green) intensity.

Figure 3

Vascular Involvement in GIT SSc A. Hematoxylin and eosin stain (40X) of gastric biopsy specimen demonstrating GAVE, B. Hematoxylin and eosin stain (200X), arrows point to microthrombi.

Figure 4

Fibrosis of GIT in SSc: A.10X, B.40X Fibrosis within the muscularis propria causing atrophy of the smooth muscle cells, C.10X, D.40X. Trichrome stain highlighting the fibrosis.

Figure 5

Radiological features of SSc: A. Upper GI series demonstrating a dilated and patulous esophagus B. Longitudinal approximation of the folds of the valvulae conniventes leading to hide-bound appearance of small bowel C. Barium enema demonstrating a wide mouth diverticulum in the colon (encircled)

Figure 6

Upper GI endoscopy in SSc A. Esophageal stricture B. Barret’s esophagus C. GAVE. Adapted from “Gastric antral vascular ectasia (watermelon stomach) in patients with systemic sclerosis”. Watson M et al. Arthritis and rheumatism 1996; 39(2): 342. Reprinted with permission