Fecal incontinence in systemic sclerosis is secondary to neuropathy.

OBJECTIVES: Systemic sclerosis (SSc) is a chronic multi-system autoimmune disorder with gastrointestinal tract (GIT) involvement in up to 90% of patients and anorectal involvement occurs in up to 50% of patients. The pathogenesis of gastrointestinal abnormalities may be both myogenic and neurogenic. We aimed to identify which anorectal physiological abnormalities correlate with clinical symptoms and thus understand the pathophysiology of anorectal involvement in SSc. METHODS: In total, 44 SSc patients (24 symptomatic (Sx) (fecal incontinence) and 20 asymptomatic (ASx)) and 20 incontinent controls (ICs) were studied. Patients underwent anorectal manometry, rectal mucosal blood flow (RMBF), rectal compliance (barostat), and rectoanal inhibitory reflex assessment (RAIR). RESULTS: Anal squeeze pressure was lower in the IC group compared with both the ASx and Sx groups (IC: 46.95 (30-63.9)) vs. ASx: 104.6 (81-128.3) vs. (Sx: 121.4 (101.3-141.6); P < 0.05). Resting pressure was lower in the IC group. RMBF and rectal compliance did not differ between groups. Anal, but not rectal, sensory threshold, was significantly attenuated in Sx patients (Sx: 10.4 (8.8-11.4) vs. ASx: 6.7 (5.7-7.7) vs. IC: 8.5 (6.5-10.4); P < 0.05). There was a positive correlation between anal sensory thresholds and incontinence score in SSc patients (r = 0.54; P < 0.05). RAIR was absent in 11/24 Sx patients but only in 2/20 ASx and in 1/20 IC patients. CONCLUSIONS: Fecal incontinence in SSc is related to neuropathy as suggested by absent RAIR and higher anal sensory threshold and is related less so to sphincter atrophy and rectal fibrosis.

Registries in systemic sclerosis: a worldwide experience.

SSc is a multisystem disease characterized by an unpredictable course, high mortality and resistance to therapy. The complexity and severity of SSc is a growing burden on the health-care systems. As a result, researchers are seeking new therapeutic strategies for effectively managing these patients. Disease registries are used to support care management efforts for groups of patients with chronic diseases and are meaningful to capture and track key patient information to assist the physicians in managing patients. For these reasons, SSc surveys, research associations and consortiums are pivotal to conduct ongoing research and data collection to enhance disease knowledge and support research projects. Currently, there are several national SSc registries in the UK, Germany, USA, Canada, Brazil and Australia. There is also an international registry established by the European League Against Rheumatism scleroderma trial and research (EUSTAR) called minimal essential data set (MEDS) Online, which collects data from over 8000 patients from 92 centres worldwide, including 21 European centres and 9 centres outside Europe. By collecting, analysing and disseminating data on disease progression and patient responses to long-term disease management strategies, registries help to improve understanding of the disease and keep medical professionals up to date on the latest advances.

Signaling pathways regulating intercellular adhesion molecule 1 expression by endothelin 1: comparison with interleukin-1beta in normal and scleroderma dermal fibroblasts.

OBJECTIVE: Endothelin 1 (ET-1) has been implicated in the pathogenesis of fibrotic and inflammatory diseases, including scleroderma. In addition to modulating vascular tone and extracellular matrix turnover, ET-1 up-regulates cell surface adhesion molecules including intercellular adhesion molecule 1 (ICAM-1), which is key to cell-cell and cell-matrix adhesion and leukocyte infiltration. This study was undertaken to delineate the signal transduction pathways utilized by ET-1 and compare them with those adopted by proinflammatory cytokine interleukin-1beta (IL-1beta) in normal and scleroderma dermal fibroblasts. METHODS: Protein expression induced by ET-1 and IL-1beta on normal dermal fibroblasts, with or without signaling inhibitors, was detected by enzyme-linked immunosorbent assay, while messenger RNA (mRNA) levels were analyzed by LightCycler polymerase chain reaction. Expression of protein kinase Cdelta (PKCdelta) and PKCepsilon protein in normal dermal fibroblasts and scleroderma dermal fibroblasts was determined by Western blotting, and PKCepsilon involvement in ET-1 signaling was confirmed through transfection of an ICAM-1 promoter construct into murine PKCepsilon-/- fibroblasts. NF-kappaB activation was confirmed via electrophoretic mobility supershift assay, and analysis of the ICAM-1 promoter region was achieved via transfection of deletion constructs into human dermal fibroblasts. RESULTS: In normal dermal fibroblasts, ET-1 induced ICAM-1 mRNA and surface protein expression in a dose- and time-dependent manner via both receptor subtypes, ET(A) and ET(B); antagonism of both abolished the ET-1 response. MEK was involved in the signaling cascade, but phosphatidylinositol 3-kinase and p38 MAPK were not. Key to the cascade was activation of NF-kappaB, achieved by ligation of either receptor subtype. PKCepsilon activation led to downstream activation of MEK and, in part, NF-kappaB. IL-1beta signaling required NF-kappaB and MEK activation, along with activation of PKCdelta. ET-1 and IL-1beta each utilized the same ICAM-1 promoter region and the same NF-kappaB site at -157 bp. Responses to ET-1 and IL-1beta differed in scleroderma dermal fibroblasts, with ET-1 sensitivity decreasing and IL-1beta responses remaining intact. Expression of PKCepsilon and PKCdelta in scleroderma dermal fibroblasts was also altered. CONCLUSION: The findings of this study indicate that differences in sensitivity to ET-1 and IL-1beta in scleroderma dermal fibroblasts may be explained by altered expression of the PKC isoforms and cytokine receptors.