| 1. |
- Baecklund, Eva, 1956-
(författare)
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Associations Between Rheumatoid Arthritis and Malignant Lymphomas
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Patients with rheumatoid arthritis (RA) are at increased risk of developing malignant lymphoma, although details about this association remain unclear. The aims of this thesis were to investigate risk factors for lymphoma in patients with RA and to characterize these lymphomas regarding subtype, presence of Epstein-Barr virus (EBV), clinical manifestations and prognosis.The Swedish hospital discharge register and the cancer register were used to identify RA patients with lymphoma. Two case-control studies were performed, one smaller including RA patients with lymphoma hospitalised in Uppsala health care region 1964-1983 (n=41) and one larger study of hospitalised RA patients with lymphoma in Sweden 1964-1995 (n=378). RA patients from the same cohorts, but without lymphoma, were matched as controls. Medical records for cases and controls were scrutinized for exposure information. The lymphoma tissues were reclassified according to the WHO classification, and presence of EBV was analysed by EBER in situ hybridisation.The most important risk factor for lymphoma development was high RA disease activity. No association was determined between treatment with traditional disease modifying drugs, non-steroidal anti-inflammatory drugs, aspirin, peroral and intra-articular corticosteroids and lymphoma risk. Diffuse large B-cell lymphoma (DLBCL) was more frequent in RA patients than in lymphoma patients in the general population and displayed stronger association with RA disease activity than other lymphoma subtypes. RA patients with DLBCL had increased extranodal involvement and more advanced lymphoma stage at presentation than DLBCL patients in general, and the prognosis was poor.A further subdivision of DLBCL into germinal centre (GC) and non-GC subtypes by the expression patterns of CD10, bcl-6 and IRF-4 showed a predominance of the non-GC subtype. This suggested peripheral activated B-cells as the cells of origin in these lymphomas.The presence of EBV was low in lymphomas in RA patients (12%).
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| 2. |
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| 3. |
- Hvatum, M., et al.
(författare)
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The gut-joint axis : cross reactive food antibodies in rheumatoid arthritis
- 2006
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Ingår i: Gut. - : BMJ. - 0017-5749 .- 1468-3288. ; 55:9, s. 1240-1247
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: Patients with rheumatoid arthritis ( RA) often feel there is an association between food intake and rheumatoid disease severity. To investigate a putative immunological link between gut immunity and RA, food antibodies were measured in serum and perfusion fluid from the jejunum of RA patients and healthy controls to determine the systemic and mucosal immune response. Methods: IgG, IgA, and IgM antibodies to dietary antigens were measured in serum and jejunal perfusion fluid from 14 RA patients and 20 healthy subjects. The antigens originated from cow's milk (alpha-lactalbumin, beta-lactoglobulin, casein), cereals, hen's egg ( ovalbumin), cod fish, and pork meat. Results: In intestinal fluid of many RA patients, all three immunoglobulin classes showed increased food specific activities. Except for IgM activity against beta-lactoglobulin, all other IgM activities were significantly increased irrespective of the total IgM level. The RA associated serum IgM antibody responses were relatively much less pronounced. Compared with IgM, the intestinal IgA activities were less consistently raised, with no significant increase against gliadin and casein. Considerable cross reactivity of IgM and IgA antibodies was documented by absorption tests. Although intestinal IgG activity to food was quite low, it was nevertheless significantly increased against many antigens in RA patients. Three of the five RA patients treated with sulfasalazine for 16 weeks had initially raised levels of intestinal food antibodies; these became normalised after treatment, but clinical improvement was better reflected in a reduced erythrocyte sedimentation rate. Conclusions: The production of cross reactive antibodies is strikingly increased in the gut of many RA patients. Their food related problems might reflect an adverse additive effect of multiple modest hypersensitivity reactions mediated, for instance, by immune complexes promoting autoimmune reactions in the joints.
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| 4. |
- Kirwan, John R, et al.
(författare)
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The effect of therapeutic glucocorticoids on the adrenal response in a randomized controlled trial in patients with rheumatoid arthritis
- 2006
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 54:5, s. 1415-1421
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To measure the effect of low-dose systemic glucocorticoid treatment on the adrenal response to adrenocorticotropic hormone (ACTH) in patients with rheumatoid arthritis (RA). METHODS: Patients with RA who took part in a randomized double-blind placebo-controlled trial of budesonide (3 mg/day and 9 mg/day) and prednisolone (7.5 mg/day) underwent a short (60-minute) test with injection of ACTH (tetracosactide hexaacetate) at baseline and the day after completing the 3-month treatment program. Plasma cortisol measurements at baseline and 3 months were compared within and between the treatment groups. Individual patients were classified as normal responders to ACTH or as abnormal responders if changes were >2 SD below the pretreatment value in the entire group of study patients. RESULTS: Short tests with ACTH injection were performed on 139 patients before beginning the study medication and on 134 patients after cessation of the medication. There were no changes in the placebo group. Mean plasma cortisol levels following treatment were reduced in all active treatment groups. In addition, mean values were significantly reduced for the 30-minute and 60-minute responses to ACTH. The maximum reduction (35%) occurred in the prednisolone group at 60 minutes. Following treatment, 34% of patients taking budesonide 9 mg and 46% of those taking prednisolone 7.5 mg failed to reach the normal maximum cortisol response to ACTH. Four patients failed to achieve the normal percentage increase in cortisol levels, but only 1 patient failed to meet both criteria. CONCLUSION: Low doses of a glucocorticoid resulted in depression of baseline and ACTH-stimulated cortisol levels after 12 weeks of therapy. Although the responsiveness of the hypothalamic-pituitary-adrenal axis in individual patients generally remained within the normal range, these changes should be investigated further.
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| 5. |
- Knight, Ann, 1957-
(författare)
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Clinical and Epidemiological Studies of Wegener´s Granulomatosis
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Wegener´s granulomatosis (WG) is an unusual, serious, systemic vasculitis with specific clinical findings. The studies in this thesis aim at broadening our understanding of the aetiology and outcome of WG.Patients with WG were identified in the In-patient Register 1975-2001. During this time the incidence increased three-fold, and neither ANCA-related increased awareness, nor diagnostic drift, seem to fully explain this trend, but it is still unclear if a true rise in incidence exists.Anti- neutrophil cytoplasmic antibodies (ANCA) have been presented as highly specific for vasculitis. In a series of consecutive cANCA/PR3-ANCA positive patients, we investigated the positive predictive value for ANCA, and the outcome of patients with a positive cANCA/PR3-ANCA but not vasculitis. These patients have a low future risk of developing vasculitis, possibly indicating that ANCA, in this setting, reflects neutrophil activating properties not specific to vasculitis.By linkage of the WG-cohort, and randomly selected population controls, to the Multi-generation register, we identified all first-degree relatives and spouses of patients and controls, totally encompassing some 2,000 patients and 70,000 relatives. Familial aggregation of WG was the exception, with absolute risks of < 1 per 1000.However, relative risks in first-grade relatives amounted to 1.56 (95% CI 0.35-6.90) such that a moderate familial aggregation cannot be excluded.In the WG-cohort, cancer occurrence and risk was compared to that of the general population. Patients with WG have an overall doubled risk of cancer, with particularly increased risks of bladder-cancer, haematopoietic cancers including lymphomas and squamous skin-cancer. In a case-control study nested within the WG-cohort, treatment with cyclophosphamide was compared among bladder-cancer patients and matched cancer-free controls. Absolute risk of bladder cancer as high as 10% some years after diagnosis were found, and this risk can partly be attributed to cyclophosphamide-treatment, with a dose-response relationship.
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| 6. |
- Kristjánsson, Guðjón, 1962-
(författare)
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Food Antigen Sensitivity in Coeliac Disease Assessed by the Mucosal Patch Technique
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A diagnosis of coeliac disease (CD) in adults relies on the presence of a structurally abnormal intestinal mucosa, followed by a clear clinical remission on a gluten-free diet. There is a clear need for a rapid, simple, safe and sensitive method to determine the type and intensity of inflammation in the gut mucosa in clinical practice. The overall aims of our studies were to develop and evaluate a new technique, “the mucosal patch technique”, to characterize rectal local inflammatory process after rectal food challenge in patients with CD. In study 1 we evaluated the potential of the new technique. The technique was well tolerated and easily applied. Pronounced neutrophil and eosinophil involvement in ulcerative colitis (UC) was demonstrated. With the high sensitivity of the technique, low-degree mucosal neutrophil activation could also be quantified in patients with collagen colitis,UC in clinical remission and in patients with irritable bowel syndrome. In study 2 and 3 the aim was to elucidate the dynamics of the rectal inflammatory response and nitric oxide (NO) production after rectal gluten challenge. We found a pronounced neutrophil activation in coeliac patients after rectal gluten challenge. This activation was apparent 4 hours after challenge and remains for at least 48 hours. A more modest eosinophil activation started 1-2 hours later and remained at least for 48 hours. The biphasic pattern of neutrophil and eosinonphil activation after challenge suggests a biphasic inflammatory reaction. The activation of neutrophils and eosinophils precedes a pronounced enhancement of mucosal NO production. Some of our coeliac patients displayed signs of an inflammatory reaction after rectal corn gluten challenge. In study 4 the aim was to investigate the local inflammatory reaction to gluten and cow’s milk protein in CD patients in remission. The findings indicate that not only gluten sensitivity but also cow’s milk (CM) protein sensitivity is common in CD. The data support the hypothesis that CM sensitivity may contribute to persistent symptoms in coeliac patients on gluten-free diet.
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| 7. |
- Kristjansson, Gudjon, et al.
(författare)
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Gut mucosal granulocyte activation precedes nitric oxide production : studies in coeliac patients challenged with gluten and corn
- 2005
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Ingår i: Gut. - : BMJ. - 0017-5749 .- 1468-3288. ; 54:6, s. 769-774
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: To elucidate the dynamics of nitric oxide (NO) production induced by rectal gluten challenge and the relation between NO production and mucosal granulocyte activation. Subjects and METHODS: Release of rectal NO was measured in 13 patients with coeliac disease and in 18 controls before and after rectal wheat gluten challenge. Rectal gas was collected with a rectal balloon using a newly developed instrument/technique, the "mucosal patch technique". The instrument allows simultaneous measurements of concentrations of granulocyte mediators in the rectal mucosa. We measured myeloperoxidase (MPO), eosinophil cationic protein (ECP), and histamine. For comparison, we made similar measurements after corn (maize) gluten challenge. RESULTS: In all coeliac patients rectal NO concentration increased after gluten challenge and reached a peak after 15 hours (mean 9464 (SEM 2393) parts per billion (ppb); range 250-24982). The maximum MPO and ECP increase occurred five hours after challenge. A correlation was found between mucosal MPO and NO production at 15 hours. Six of the patients showed an increase in NO production 15 hours after rectal corn gluten challenge but this was much smaller than after gluten challenge. No increases were seen in the control group after either challenge. CONCLUSION: Mucosal activation of neutrophils and eosinophils precedes pronounced enhancement of mucosal NO production after rectal wheat gluten challenge in patients with coeliac disease. Some of our coeliac patients displayed signs of an inflammatory reaction, as measured by NO and granulocyte markers, after rectal corn gluten challenge.
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| 8. |
- Kristjánsson, Gudjon, et al.
(författare)
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Kinetics of mucosal granulocyte activation after gluten challenge in coeliac disease
- 2005
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Ingår i: Scandinavian Journal of Gastroenterology. - 0036-5521 .- 1502-7708. ; 40:6, s. 662-669
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To elucidate the dynamics of the rectal inflammatory response to rectal gluten challenge in coeliac disease by measuring inflammatory mediators released by activated neutrophils, eosinophils and mast cells/basophils. MATERIAL AND METHODS: The release of myeloperoxidase (MPO), eosinophilic cationic protein (ECP) and histamine was measured continuously during the early challenge period (3-6 h after gluten challenge) in coeliac patients (n = 9) and healthy controls (n = 5). A segmental perfusion technique was used to carry out this part of the study. Another method, the mucosal patch technique, was used to enable studies of the late challenge period (5-48 h after gluten challenge) in coeliac patients (n = 10) and healthy controls (n = 15). RESULTS: During the early challenge period the MPO levels began to increase as early as 3 h after challenge and increased progressively (p < 0.001) during the next 3 h. A decline in MPO levels was seen 15 h after challenge and another phase of increasing levels at 24 h. The MPO values declined 48 h after challenge but still remained significantly increased (p < 0.05). The ECP levels started to increase 4 h after challenge and increased progressively during the next 2 h (p < 0.05). The ECP kinetics during the late challenge period was similar as for MPO but the relative increase in ECP was more modest. No increase in histamine was found except in one patient who had a transient, early increase of histamine (3-5 h after challenge). No signs of inflammatory reaction to gluten were seen in the controls. CONCLUSIONS: There is a pronounced neutrophil activation in coeliac patients after rectal gluten challenge. This activation is apparent 4 h after challenge and remains for at least 48 h. A more modest eosinophil activation defined by ECP levels starts 1-2 h later and also remains for at least 48 h. The biphasic pattern of MPO and ECP after challenge suggests a biphasic inflammatory reaction.
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| 9. |
- Kristjánsson, Gudjon, et al.
(författare)
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Mucosal reactivity to cow's milk protein in coeliac disease
- 2007
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Ingår i: Clinical and Experimental Immunology. - : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 147:3, s. 449-455
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Tidskriftsartikel (refereegranskat)abstract
- Patients with coeliac disease (CD) on a gluten-free diet may still have gastrointestinal symptoms. On clinical grounds cow's milk (CM) protein sensitivity may be suspected. Here, using rectal protein challenge, we investigated the local inflammatory reaction to gluten and CM protein in adult patients with CD in remission. Rectal challenges with wheat gluten and dried CM powder were performed in 20 patients with CD and 15 healthy controls. Fifteen hours after challenge the mucosal reaction was recorded by the mucosal patch technique with measurements of local release of neutrophil and eosinophil granule constituents; myeloperoxidase (MPO) and eosinophil cationic protein (ECP). We measured the mucosal production of nitric oxide (NO) simultaneously. Six of the patients who reacted to CM were also challenged with alpha-lactalbumin and casein. In 18 of 20 patients gluten challenge induced neutrophil activation defined as increased MPO release and increased NO synthesis. Ten of these 20 patients showed a similarly strong inflammatory reaction to CM challenge. Six of the CM sensitive patients were challenged with specific CM proteins: casein and alpha-lactalbumin. Casein, in contrast to alpha-lactalbumin, induced an inflammatory response similar to that produced by CM. A mucosal inflammatory response similar to that elicited by gluten was produced by CM protein in about 50% of the patients with coeliac disease. Casein, in particular, seems to be involved in this reaction.
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| 10. |
- Lidén, Maria, et al.
(författare)
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Gluten sensitivity in patients with primary Sjögren's syndrome
- 2007
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 42:8, s. 962-967
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To evaluate the rectal mucosal response to gluten as an indication of gluten sensitivity in patients with primary Sjögren's syndrome (pSS). Material and methods. Rectal challenges with wheat gluten were performed in 20 patients with pSS and 18 healthy control subjects. Fifteen hours after challenge the mucosal production of nitric oxide (NO) was measured. Results. Five patients with pSS had a significant increase in the luminal release of NO after the rectal gluten challenge, indicating gluten sensitivity. All were HLA-DQ2 and/or -DQ8-positive. Two of the patients with increased NO had antibodies against transglutaminase and a duodenal biopsy showed an absolutely flat mucosa consistent with coeliac disease in one of the patients. Before gluten challenge, 15 of the Sjögren's syndrome (SS) patients reported gastrointestinal symptoms, and 8 reported intolerance to various food products. No correlation was found between gluten sensitivity and self-reported food intolerance or gastrointestinal symptoms. Conclusions. Rectal mucosal inflammatory response after gluten challenge is often seen in patients with pSS, signifying gluten sensitivity. However, this reactivity is not necessarily linked to coeliac disease.
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| 11. |
- Lidén, Maria, 1954-
(författare)
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Gut Mucosal Reactivity to Gluten and Cow´s Milk Protein in Rheumatic Diseases
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis comprised patients with chronic rheumatic diseases. The studies aimed to elucidate food sensitivity by measuring mucosal inflammatory reactivity and thereby a possible link between the gut and joints. In all the studies, the mucosal path technique was used to evaluate the rectal mucosal response to rectal challenge with gluten and/or cow’s milk protein (CM). In some patients with primary Sjögren’s syndrome (pSS) and the genetic susceptibility genes HLA DQ2, mucosal reactivity measured with nitric oxide (NO) was found after rectal gluten challenge without detectable serum antibodies to gluten or transglutaminase. This gluten sensitivity was not linked to coeliac disease. After rectal CM challenge, a rectal mucosal inflammatory response measured with NO and myeloperoxidase (MPO) was detected in 38% of pSS patients, all of whom fulfilled the criteria for irritable bowel syndrome. In a questionnaire study of self-experienced adverse reactions to food, 27% of patients with rheumatoid arthritis (RA) reported intolerance to various foods and CM in particular. After rectal CM challenge performed in RA patients (n=27), strong mucosal reactivity to CM was observed in a few patients and a moderate increase in 23%. After gluten challenge, a moderate increase in mucosal reactivity was found in 35% of patients. No correlation to self-perceived intolerance and mucosal reactivity measured with NO and MPO was seen. Inflammation of the gut is a prominent feature of spondyloarthropathies (SpA). After rectal challenges with CM protein and gluten, an increase in rectal NO production was seen in 26% and 19% respectively (p<0.001). An increase in the mucosal release of MPO as a sign of neutrophil activation was seen in the CM- and gluten-sensitive patients. NO production in SpA patients was more enhanced compared with RA and pSS patients and could contribute to the increased barrier permeability described in SpA patients.
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| 12. |
- Melin, Jan, et al.
(författare)
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Ischemia-induced renal expression of hyaluronan and CD44 in diabetic rats.
- 2006
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Ingår i: Nephron. Experimental nephrology. - : S. Karger AG. - 1660-2129. ; 103:3
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND/AIMS: Unilateral renal ischemia during 30 min causes severe, non-reversible renal damage in diabetic (DM) rats, but not in nondiabetic rats. Hyaluronan (HA) is a glycosaminglycan involved in various forms of renal injury. We examined the role of HA and CD44, a major receptor for HA, in the development of postischemic renal injury in DM rats. METHODS: The left renal artery of streptozotocin diabetic Wistar rats was clamped for 30 min. The HA content in the kidneys was measured. A biotinylated HA-binding probe was used to localize HA. Inflammatory cells and other cells expressing CD44 were identified by immunohistochemistry. RESULTS: In ischemic DM kidneys the renal HA-content started to increase already after 24 h and significantly so after 1-8 weeks after ischemia/reperfusion (I/R). The relative water content of the kidneys increased in parallel. HA started to appear in the cortex of ischemic DM kidneys 1 week after I/R. In contrast, the non-DM ischemic kidneys showed no increase of HA and water content after 1-8 weeks after I/R. The tubular cells in the cortex and outer medulla demonstrated increased staining for CD44. In the same compartments the increased numbers of infiltrating inflammatory cells also expressed CD44. CONCLUSION: HA-accumulation in the renal cortex might contribute to the renal damage seen after transient ischemia in DM rats by promoting inflammation through interaction between HA and CD44 expressing inflammatory cells. Furthermore, HA accumulation may contribute to an interstitial renal edema.
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| 13. |
- Smerud, Hilde Kloster, et al.
(författare)
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Gluten sensitivity in patients with IgA nephropathy
- 2009
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Ingår i: Nephrology, Dialysis and Transplantation. - : Oxford University Press (OUP). - 0931-0509 .- 1460-2385. ; 24:8, s. 2476-2481
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Coeliac disease is more frequent in IgA nephropathy (IgAN) patients compared to the healthy population. Several hypotheses postulate that food antigens like gluten may be involved in the onset of IgAN. METHODS: In this study, we used a recently developed mucosal patch technique to evaluate the rectal mucosal inflammatory reaction to gluten in patients with IgAN (n = 27) compared to healthy subjects (n = 18). The rectal mucosal production of nitric oxide (NO) and release of myeloperoxidase (MPO) and eosinophil cationic protein (ECP) were measured. Serum samples were analysed for IgA and IgG antigliadin antibodies (AGA), IgA antibodies against tissue transglutaminase and IgA endomysium antibodies. RESULTS: Gluten reactivity, defined as increase in MPO and/or NO after gluten exposure, was observed in 8 of 27 IgAN patients. The prevalence of HLA-DQ2 and DQ8 was not increased among gluten-sensitive patients, and the total prevalence among IgAN patients was the same as for the normal population. An elevated serum IgA AGA response was seen in 9 of 27 IgAN patients. The increase in IgA AGA did not correlate with the gluten sensitivity as measured by NO and/or MPO. A specific serum IgG AGA response was seen in one patient only. Antibodies against tissue transglutaminase and endomysium were not observed. CONCLUSION: It is concluded that approximately one-third of our IgAN patients have a rectal mucosal sensitivity to gluten, but without signs of coeliac disease, and we hypothesize that such sub-clinical inflammation to gluten might be involved in the pathogenesis of IgAN in a subgroup of patients.
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