Rheumatoid Arthritis: Schmidt RE

Behrens GM, Schmidt RE. · Abteilung Klinische Immunologie und Rheumatologie, Medizinische Hochschule Hannover, Hannover, Germany. · Dtsch Med Wochenschr. · Pubmed #17570090 No free full text.

This publication has no abstract.

Ulbricht KU, Schmidt RE, Witte T. · Abteilung Klinische Immunologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. · Autoimmun Rev. · Pubmed #12848967 No free full text.

Abstract: Alpha-fodrin is a part of the membrane skeleton and expressed in the majority of mammalian cells. It is cleaved in apoptosis by caspase 3. One of the cleavage products, a 120-kDa protein, represents a neoantigen. Antibodies against that cleavage product of alpha-fodrin have originally been described in a murine model of Sjögren's syndrome. In addition, they are also present in up to 93% of patients with Sjögren's syndrome, depending on the stringency of the classification used. Although antibodies against alpha-fodrin are observed in other diseases characterized by chronic apoptosis, they are a valuable laboratory marker in the evaluation of Sjögren's syndrome.

Straub RH, Kittner JM, Heijnen C, Schedlowski M, Schmidt RE, Jacobs R. · Department of Internal Medicine I, University Medical Center Regensburg, Germany. · J Rheumatol. · Pubmed #12180725 No free full text.

Abstract: OBJECTIVE: To investigate the pituitary and adrenal hormone response after an intravenous epinephrine challenge in patients with rheumatoid arthritis (RA) and controls. METHODS: Fifteen untreated female patients with RA (age 51.5 +/- 3.2 yrs) and 7 healthy female controls (48.0 +/- 4.3 yrs) were infused with epinephrine (0.05 microg/kg/min) for about 20 min. Plasma levels of adrenocorticotropic hormone (ACTH), and serum levels of cortisol, 17-hydroxyprogesterone (17OHP), and dehydroepiandrosterone sulfate (DHEAS) were analyzed at baseline and shortly after cessation of epinephrine infusion (20 min). RESULTS: At baseline and after epinephrine infusion, serum levels of cortisol (p = 0.045) and 17OHP (p = 0.021) were higher in controls compared to patients with RA. In contrast, at baseline and after epinephrine infusion, plasma levels of ACTH and serum levels of DHEAS were similar in controls and patients. After epinephrine infusion, only the patients with RA had a significant decrease of serum cortisol (p = 0.026) and serum 17OHP (p = 0.026). Plasma levels of ACTH (p = 0.073) and serum levels of DHEAS (p = 0.055) tended to decrease. CONCLUSION: Serum cortisol and 17OHP (cortisol precursor) were lower in patients with RA compared to controls despite similar ACTH levels. Simulation of an adrenomedullary stress response by epinephrine infusion decreased serum cortisol and 17OHP in patients but not in controls. Such a response may play an unfavorable role during a typical stress reaction in patients with RA that may lead to a more proinflammatory situation.

Barthel C, Yeremenko N, Jacobs R, Schmidt RE, Bernateck M, Zeidler H, Tak PP, Baeten D, Rihl M. · Clinic for Immunology and Rheumatology, Hannover Medical School (MHH), Carl-Neuberg-Strasse 1, Hannover 30625, Germany. · Arthritis Res Ther. · Pubmed #19490633 links to  free full text

Abstract: INTRODUCTION: We previously described the presence of nerve growth factor receptors in the inflamed synovial compartment. Here we investigated the presence of the corresponding nerve growth factors, with special focus on nerve growth factor (NGF). METHODS: mRNA expression levels of four ligands (NGF, brain derived growth factor (BDNF), neurotrophin (NT)-3, NT-4) and their four corresponding receptors (tyrosine kinase (trk) A, trkB, trkC, NGFRp75) were determined in the synovial fluid (SF) cells of 9 patients with rheumatoid arthritis (RA) and 16 with spondyloarthritis (SpA) and compared with 7 osteoarthritis (OA) patients. NGF was also determined in synovial tissue (ST) biopsies of 10 RA and 10 SpA patients. The production of NGF by monocytes and lymphocytes was assessed by flow cytometry of SF cells, synovial tissue derived fibroblast-like synoviocytes (FLS) were assessed by ELISA on culture supernatant. RESULTS: SF cell analysis revealed a clear BDNF and NGF mRNA expression, with significantly higher NGF expression in RA and SpA patients than in the OA group. NGF expression was higher in ST samples of RA as compared to SpA. Using intracellular FACS analysis, we could demonstrate the presence of the NGF protein in the two inflammatory arthritis groups on both CD3+ T lymphocytes and CD14+ cells, i.e. monocytes/macrophages, whereas cultured FLS did not produce NGF in vitro. CONCLUSIONS: Neurotrophins and especially NGF are expressed in the synovial fluid and tissue of patients with peripheral synovitis. The presence of neurotrophins as well as their receptors, in particular the NGF/trkA-p75 axis in peripheral synovitis warrants further functional investigation of their active involvement in chronic inflammatory arthritis.

Witte T, Matthias T, Bierwirth J, Schmidt RE. · Department of Clinical Immunology, Medical School Hannover, Hannover, Germany. · Ann N Y Acad Sci. · Pubmed #17894005 No free full text.

Abstract: The significance of antibodies against alpha-fodrin compared to antibodies against Ro (SSA) as markers of Sjögren's syndrome has been controversially discussed. We therefore compared the association of alpha-fodrin and Ro antibodies with dry eyes and dry mouth in the general population. In 168 "normal" participants, the prevalence of IgA antibodies against alpha-fodrin was 5% and of IgG antibodies against alpha-fodrin was 3%. IgA antibodies against alpha-fodrin were present in 3 of 4 and IgG antibodies against alpha-fodrin in 2 of 4 participants with the combination of dry eyes and dry mouth (P = 0.0002 and 0.005). Only one participant had antibodies against Ro and had dry eyes but normal saliva production. Antibodies against alpha-fodrin are associated with sicca syndrome and may be valuable diagnostic markers in patients with Sjögren's syndrome lacking Ro antibodies.

Sack U, Conrad K, Csernok E, Frank I, Haass M, Krieger T, Seyfarth M, Schlosser U, Schmidt RE, Witte T. · Institute of Clinical Immunology and Transfusion Medicine, Medical Faculty of the University of Leipzig, Leipzig, Germany. · Ann N Y Acad Sci. · Pubmed #17785287 No free full text.

Abstract: The German Regional Group of EASI was established during the annual Meeting of the German Society of Immunology in Kiel in September 2005. Since this initial informative meeting, an active core group of about a dozen rheumatologists, immunologists, and laboratory specialists has been generating starter projects. In general, these projects do focus on clinically associated diagnostic questions, and do integrate a variety of specialists with profound knowledge in several related subjects. The aims of the German EASI group are to contribute to the definition of standards and to improve patient care. Therefore, the group is establishing guidelines for the diagnosis of autoimmune diseases, to standardize and improve their quality, combining the experience of clinical and laboratory specialists. The diagnostic activities focus currently on systemic lupus erythematosus (SLE) and on rheumatoid arthritis. These activities include laboratory investigations and diagnosis through clinical manifestations. Standardized diagnostics cannot be based solely on vague symptoms and positive laboratory tests. In laboratory diagnostics, standardization and implementation of objective methods for the detection of autoantibodies has been identified as a central challenge. Here, immune fluorescence techniques and the evaluation of RibP are used as first parameters that could improve SLE diagnostics. Furthermore, guidelines and proposals from scientific medical organizations, and in particular from other national EASI groups will be adapted to the German health system. A cornerstone of implementation is the identification and logistic preparation of existing serum banks, the definition of gaps that should be bridged, and, particularly, the definition and collection of adequate control groups. Through these measures, the German EASI group will provide a standardized diagnostic model of autoimmune disorders throughout Europe starting in the field of rheumatology. Diagnostics may become more rational, efficient, faster, and cost-efficient. Patients with autoimmune rheumatic disorders will profit from receiving an earlier and more accurate diagnosis, which again will allow earlier therapeutic intervention and lead to a better long-term clinical outcome.

Momot T, Koch S, Hunzelmann N, Krieg T, Ulbricht K, Schmidt RE, Witte T. · Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. · Arthritis Rheum. · Pubmed #15146426 links to  free full text

Abstract: OBJECTIVE: Scleroderma is an autoimmune disorder of unknown etiology. A genetic contribution has been demonstrated, and genes influencing activation of the immune system have been potentially identified as candidate genes in this process. The repertoire of killer cell immunoglobulin-like receptors (KIRs) that are involved in the activation of T cells and natural killer cells is highly variable. Recently, an association of KIR2DS2 with vasculitis in patients with rheumatoid arthritis has been reported. Because scleroderma is characterized by an involvement of the vascular system, we sought to determine whether KIR2DS2 is associated with scleroderma. METHODS: We typed 9 KIR genes in 102 patients with scleroderma and in 100 blood donors, using polymerase chain reaction on genomic DNA. RESULTS: Twelve patients with scleroderma, compared with only 2 blood donors, had KIR phenotypes characterized by the presence of the activating KIR2DS2 and the absence of the corresponding inactivating KIR2DL2 (P = 0.005). CONCLUSION: The genetic combination of KIR2DS2+ and KIR2DL2- is associated with scleroderma.

Witte T, Matthias T, Oppermann M, Helmke K, Peter HH, Schmidt RE, Tishler M. · Abteilung Klinische Immunologie, Medizinische Hochschule, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. · J Rheumatol. · Pubmed #14528510 No free full text.

Abstract: OBJECTIVE: To compare the prevalence of antibodies against alpha-fodrin in Sjögren's syndrome (SS) classified according to San Diego and European Community Study Group (ESG) criteria. METHODS: The prevalence and mean concentrations of IgA and IgG autoantibodies against alpha-fodrin were determined and compared in patients with SS classified either according to San Diego criteria or to criteria of the ESG by ELISA. RESULTS: IgA antibodies against alpha-fodrin were detected in 88% and IgG antibodies against alpha-fodrin in 64% and either of these antibodies in 93% of 85 patients classified according to San Diego criteria. Antibodies against Ro were present in 38% of these sera. IgA antibodies against alpha-fodrin were detected in 61%, IgG antibodies against alpha-fodrin in 51%, and any of these antibodies in 73% of 51 patients classified according to the ESG criteria. The mean concentrations of both IgA and IgG antibodies against alpha-fodrin that seem to correlate with disease activity were higher in patients classified according to the San Diego criteria. CONCLUSION: Antibodies against alpha-fodrin are detectable in almost all sera obtained from patients with SS classified according to the San Diego criteria and are significantly more prevalent than antibodies against Ro. The lower prevalence of the autoantibodies in patients classified according to the ESG criteria reflects the lower specificity of these criteria for SS.

Hundt M, Posovszky C, Schmidt RE. · Department of Clinical Immunology, Hannover Medical School, Germany. · Immunobiology. · Pubmed #12607726 No free full text.

Abstract: A new symptom-complex is described characterized by manifestations of autoimmune disease, infectious lymphadenopathy, double negative T cells, and impaired activation-induced cell death that developed in late adolescence. Similarities, but also significant differences, to autoimmune lymphoproliferative syndromes (ALPS, Canale-Smith syndrome) and autoimmune lymphoproliferative disease (ALD, Dianzani syndrome), were observed. The main clinical features were recurrent bacterial infections with subsequent lymphadenopathy due to autoimmune neutropenia. Laboratory results revealed a large proportion of alphabetaTCR positive, CD4 negative, CD8 negative, peripheral T cells, and a decreased apoptosis upon activation with phytohemagglutinin and interleukin 2, but normal Fas-mediated apoptosis. Genetic investigations excluded mutations in Fas gene death domain and in the 4 exons of Fas ligand gene. Despite unknown pathogenesis, this new syndrome might belong to the growing group of diseases with defects in apoptosis.

Kittner JM, Jacobs R, Pawlak CR, Heijnen CJ, Schedlowski M, Schmidt RE. · Department of Clinical Immunology, Hannover Medical School, Germany. · Rheumatology (Oxford). · Pubmed #12209038 links to  free full text

Abstract: OBJECTIVE: To investigate whether in rheumatoid arthritis (RA) patients the immunological changes induced by adrenaline are different from healthy controls (HC). METHODS: Fifteen female RA patients and 14 HC were infused with 1 micro g/kg adrenaline over 20 min. Blood was drawn before, immediately after, and 1 h after the end of infusion. Lymphocyte subpopulations, cytokine production and natural killer cell cytotoxicity were determined. RESULTS: Subjects exhibited mild cardiovascular changes with no differences between patients and controls. CD16(+)CD56(+)CD3(-) NK cells increased by a factor of 5.7, CD3(+) T cells by 1.5, monocytes by 1.6 and PMN by 1.2 in both groups. The numbers of IL-8- and IL-10-producing monocytes were higher in patients and presented a larger increase after infusion. NK cytotoxic activity was higher in RA patients and increased after infusion in both groups. Activated monocytes and T cells were preferentially recruited in patients and controls. Values returned to baseline 1 h later. CONCLUSION: We describe an altered response to adrenaline in patients with RA with both pro- and anti-inflammatory effects. Additionally, activated T cells and monocytes recruited to the peripheral blood may influence disease activity.

Jacobs R, Pawlak CR, Mikeska E, Meyer-Olson D, Martin M, Heijnen CJ, Schedlowski M, Schmidt RE. · Division of Clinical Immunology, Hannover Medical School, 30623 Hannover, Germany. · Rheumatology (Oxford). · Pubmed #11511755 links to  free full text

Abstract: OBJECTIVE: To study whether patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) differ from healthy individuals in their immune responses to acute psychological stress. METHODS: The phenotype and function of peripheral blood lymphocytes were analysed before and after stress exposure in patients and healthy subjects. RESULTS: Natural killer (NK) cell numbers increased transiently in all groups under stress. NK activity, however, increased in healthy controls only. We observed a stress-induced increase in interleukin (IL)-4-producing (IL-4(+)) cells in SLE patients only, whereas interferon (IFN) gamma(+) cell numbers increased due to stress in all three groups. An analysis of supernatants from phytohaemagglutinin (PHA) cultures revealed increased IFN gamma and IL-10 levels in healthy subjects but not in SLE or RA patients after stress exposure. CONCLUSIONS: These data demonstrate that RA and SLE patients differ in their immune response to stress from healthy controls. Changes in cytokine patterns might be responsible for stress-induced exacerbation of disease activity in RA and SLE patients.

Rautenstrauch J, Schnarr S, Zeidler H, Schmidt RE. · Medizinische Hochschule Hannover Zentrum Innere Medizin Abteilung Rheumatologie. · Z Rheumatol. · Pubmed #11383054 No free full text.

This publication has no abstract.

Witte T, Matthias T, Arnett FC, Peter HH, Hartung K, Sachse C, Wigand R, Braner A, Kalden JR, Lakomek HJ, Schmidt RE. · Abteilung Klinische Immunologie, Medizinische Hochschule Hannover, Germany. · J Rheumatol. · Pubmed #11093442 No free full text.

Abstract: OBJECTIVE: To determine the prevalence of IgA and IgG autoantibodies against alpha-fodrin in patients with primary and secondary Sjögren's syndrome (SS) and controls. METHODS: An ELISA detecting IgA and IgG antibodies against alpha-fodrin was developed. We examined the prevalence of IgA and IgG antibodies against alpha-fodrin in patients with primary and secondary SS, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA) and blood donors. RESULTS: IgA antibodies against alpha-fodrin were detected in 64% of patients with primary SS (n = 85), 47% of patients with secondary SS and SLE (n = 15), and 86% of patients with secondary SS and RA (n = 7). IgA autoantibodies against alpha-fodrin were detected in only one of 160 sera obtained from blood donors and in one of 50 and 2 of 12 sera obtained from SLE and RA patients without sicca syndrome, respectively. The prevalence of IgG antibodies against alpha-fodrin in SS was lower: they were detected in 55% of sera obtained from patients with primary SS, 40% of patients with secondary SS and SLE, and in 43% of patients with secondary SS and RA. Three of 160 sera from blood donors and one of 50 and 5 of 12 sera from SLE and RA patients without sicca syndrome, respectively, contained IgG antibodies against alpha-fodrin. CONCLUSION: IgA rather than IgG antibodies against alpha-fodrin are specific for and frequently observed in primary and secondary SS and are useful markers for this autoimmune disorder.

Witte T, Hartung K, Sachse C, Matthias T, Fricke M, Kalden JR, Lakomek HJ, Peter HH, Schmidt RE. · Abteilung Klinische Immunologie, Medizinische Hochschule Hannover, Germany. · Rheumatol Int. · Pubmed #10776689 No free full text.

Abstract: The prevalence and clinical and laboratory associations of IgM, IgG and IgA rheumatoid factors (RF) were determined in 352 patients with systemic lupus erythematosus (SLE). IgM, IgG, and IgA class RF were detected in 17.9%, 20.5%, and 20.5% of the sera, respectively. RF were associated with sicca syndrome, hypergammaglobulinemia, high titer of antinuclear antibodies, anemia, SSA- and SSB-antibodies, and with the presence of HLA-DR3. RF correlated negatively with nephritis and livedo racemosa. Moreover, we observed an association of RF and parameters of inflammatory activity such as elevated erythrocyte sedimentation rate (ESR) and leukopenia. Analysis of immunoglobulin classes revealed that laboratory parameters of inflammatory activity, SSA- and SSB-antibodies and HLA-DR3 correlated with IgA RF only. IgA RF define a subgroup of SLE patients characterized by distinct autoimmune phenomena and high disease activity in the absence of nephritis.

Lombardi MS, Kavelaars A, Schedlowski M, Bijlsma JW, Okihara KL, Van de Pol M, Ochsmann S, Pawlak C, Schmidt RE, Heijnen CJ. · Department of Immunology, University Hospital for Children and Youth, 'Het Wilhelmina Kinderziekenhuis', 3584 EA Utrecht, The Netherlands. · FASEB J. · Pubmed #10094932 links to  free full text

Abstract: Beta2-Adrenergic and chemokine receptor antagonists delay the onset and reduce the severity of joint injury in rheumatoid arthritis. beta2-Adrenergic and chemokine receptors belong to the G-protein-coupled receptor family whose responsiveness is turned off by the G-protein-coupled receptor kinase family (GRK-1 to 6). GRKs phosphorylate receptors in an agonist-dependent manner resulting in receptor/G-protein uncoupling via subsequent binding of arrestin proteins. We assessed the activity of GRKs in lymphocytes of rheumatoid arthritis (RA) patients by rhodopsin phosphorylation. We found a significant decrease in GRK activity in RA subjects that is mirrored by a decrease in GRK-2 protein expression. Moreover, GRK-6 protein expression is reduced in RA patients whereas GRK-5 protein levels were unchanged. In search of an underlying mechanism, we demonstrated that proinflammatory cytokines induce a decrease in GRK-2 protein levels in leukocytes from healthy donors. Since proinflammatory cytokines are abundantly expressed in RA, it may provide an explanation for the decrease in GRK-2 expression and activity in patients. No changes in beta2-adrenergic receptor number and Kd were detected. However, RA patients showed a significantly increased cAMP production and inhibition of TNF-alpha production by beta2-adrenergic stimulation, suggesting that reduced GRK activity is associated with increased sensitivity to beta2-adrenergic activation.

Witte T, Bierwirth J, Schmidt RE, Matthias T. · No affiliation provided · J Rheumatol. · Pubmed #16881136 links to  free full text

This publication has no abstract.