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Gastrointestinal Manifestations and Pathophysiological Mechanisms in Systemic Sclerosis
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
2010 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Systemic sclerosis (SSc) is a rare systemic, autoimmune disease characterized by vascular changes and fibrosis of the skin and internal organs.

Patients with SSc more frequently than healthy controls reported upper gastrointestinal (GI) symptoms, which was more abundant in the diffuse cutaneous form (dcSSc) of the disease than in the limited (lcSSc). One-third of a population-based cohort of 79 SSc patients reported faecal incontinence, compared to 11% in 158 healthy matched controls (p<0.001), and this symptom negatively influenced general well-being and social life. Impaired rectal sensibility, rectal bleeding, irritable bowel syndrome-like symptoms, abdominal pain, the need for manual assistance at defecation, and the use of oral laxatives were more common in patients than in controls. SSc patients reported lower scores in both physical and mental scales of the SF-36 questionnaire than controls, indicating worse health-related quality of life.

Gastric emptying was slower in patients than in controls, and a higher prevalence of delayed gastric emptying in patients with dcSSc indicated more severe GI tract involvement than in lcSSc. Electrogastrographic recordings did not correlate to gastric emptying results, indicating factors other than defective myoelectric signals contributed to disturbed gastric function.

SSc patients with faecal incontinence had lower anal squeeze pressures than patients without this symptom. Only patients with faecal incontinence had ultrasonographic abnormalities in the internal and external anal sphincters, and absence of the rectoanal inhibitory reflex. Thus, faecal incontinence in SSc patients may depend on both neurogenic and structural mechanisms. A discrete increase in fibre density observed in a majority of SSc patients might have implications from a disease mechanistic perspective.

Sera from 47% of 70 SSc patients had the capacity to induce interferon (IFN)-α, production which correlated to the presence of anti-RNP and anti-SSA autoantibodies. Increased serum levels of IFN-inducible protein were associated with vascular manifestations, and increased serum levels of IFN-α with digital ulcers. Increased serum levels of monocyte chemoattractant protein-1 or IFN-α were associated with lung fibrosis. An activated type I IFN system previously observed in several other systemic autoimmune diseases is also present in SSc and may contribute to vascular pathology and the pro-fibrotic process.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis , 2010. , s. 58
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 568
Nationell ämneskategori
Reumatologi och inflammation
Forskningsämne
Medicinsk vetenskap
Identifikatorer
URN: urn:nbn:se:uu:diva-123479ISBN: 978-91-554-7823-0 (tryckt)OAI: oai:DiVA.org:uu-123479DiVA, id: diva2:314580
Disputation
2010-06-09, Rudbeckssalen, Dag Hammarskjölds väg 20, Uppsala, 09:15 (Svenska)
Opponent
Handledare
Tillgänglig från: 2010-05-18 Skapad: 2010-04-27 Senast uppdaterad: 2010-05-18
Delarbeten
1. Delayed gastric emptying in patients with diffuse versus limited systemic sclerosis, unrelated to gastrointestinal symptoms and myoelectric gastric activity.
Öppna denna publikation i ny flik eller fönster >>Delayed gastric emptying in patients with diffuse versus limited systemic sclerosis, unrelated to gastrointestinal symptoms and myoelectric gastric activity.
2003 (Engelska)Ingår i: Scand J Rheumatol, Vol. 32, s. 348-Artikel i tidskrift (Refereegranskat) Published
Identifikatorer
urn:nbn:se:uu:diva-64985 (URN)
Tillgänglig från: 2005-04-25 Skapad: 2005-04-25 Senast uppdaterad: 2011-01-13
2.
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3. Physiological and structural abnormalities in patients with systemic sclerosis and faecal incontinence
Öppna denna publikation i ny flik eller fönster >>Physiological and structural abnormalities in patients with systemic sclerosis and faecal incontinence
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(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nyckelord
Systemic sclerosis, faecal incontinence, physiology
Nationell ämneskategori
Reumatologi och inflammation
Forskningsämne
Medicinsk vetenskap
Identifikatorer
urn:nbn:se:uu:diva-123467 (URN)
Projekt
Doktorsavhandling
Tillgänglig från: 2010-04-27 Skapad: 2010-04-27 Senast uppdaterad: 2013-08-15
4. Type I interferon system activation and association with disease manifestations in systemic sclerosis
Öppna denna publikation i ny flik eller fönster >>Type I interferon system activation and association with disease manifestations in systemic sclerosis
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2010 (Engelska)Ingår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 69, nr 7, s. 1396-1402Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

OBJECTIVES: To study the presence of interferogenic autoantibodies in systemic sclerosis (SSc) and their correlation with clinical manifestations, serum levels of interferon alpha (IFNalpha) and chemokines of importance in the disease process. METHODS: Peripheral blood mononuclear cells (PBMCs) or purified plasmacytoid dendritic cells (pDCs) from healthy donors were stimulated with sera from patients with SSc (n=70) or healthy individuals (n=30), together with necrotic or apoptotic cell material. The IFNalpha produced and serum levels of IFNalpha, IFN-inducible protein-10 (IP-10)/chemokine (C-X-C motif) ligand 10, monocyte chemoattractant protein-1 (MCP-1)/(C-C motif) ligand-2 (CCL-2), macrophage inflammatory protein-1alpha (MIP-1alpha)/CCL-3 and RANTES/CCL-5 were measured and correlated with the presence of autoantibodies and clinical manifestations in the patients with SSc. RESULTS: Sera from both diffuse SSc and limited SSc contained interferogenic antibodies, which correlated with the presence of anti-ribonucleoprotein and anti-Sjögren syndrome antigen autoantibodies. The pDCs were responsible for the IFNalpha production which required interaction with FcgammaRII and endocytosis. Increased serum levels of IP-10 were associated with vascular manifestations such as cardiac involvement (p=0.027) and pulmonary arterial hypertension (p=0.036). Increased MCP-1 or IFNalpha serum levels were associated with lung fibrosis (p=0.019 and 0.048, respectively). Digital ulcers including digital loss were associated with increased serum levels of IFNalpha (p=0.029). CONCLUSION: An activated type I IFN system previously seen in several other systemic autoimmune diseases is also present in SSc and may contribute to the vascular pathology and affect the profibrotic process.

Nyckelord
interferon, systemic sclerosis, autoantibodies
Nationell ämneskategori
Reumatologi och inflammation
Forskningsämne
Medicin
Identifikatorer
urn:nbn:se:uu:diva-123475 (URN)10.1136/ard.2009.121400 (DOI)000279667000030 ()20472592 (PubMedID)
Tillgänglig från: 2010-04-27 Skapad: 2010-04-27 Senast uppdaterad: 2017-12-12Bibliografiskt granskad

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