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Failure of distinction between self and non-self is regarded a critical event in the pathogenesis of several human diseases such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, myasthenia gravis, uveoretinitis or diabetes mellitus. Autoagressive immune reactions driven by activated autoreactive lymphocytes are a characteristic feature of these autoimmune diseases. The mechanisms by which the pathogenic control of autoreactive lymphocytes deviates from physiology can be studied in appropriate animal models under well-defined experimental conditions. Experimental models of autoimmune diseases in rodent inbred strains allow for the genetic mapping of susceptibility loci and might help to identify candidate genes also relevant to the pathogenesis of human diseases. Finally, the experimental models are valuable tools to develop rational immunotherapeutic strategies. Interesting features of some of the models employed for such research will be introduced in this review.

Neue Therapieprinzipien und Fortschritte in der Diagnostik haben es ermoglicht, bei Erkrankungen des rheumatischen Formenkreises und hier besonders bei der rheumatoiden Arthritis (RA) ein Krankheitsbild fruh zu definieren und durch eine fruhzeitig begonnene Medikation bei einem betrachtlichem Anteil der Patienten eine niedrige Krankheitsaktivitat oder Remission zu erzielen. Mit der zusatzlichen Entwicklung neuer Parameter zur Analyse der Krankheitsaktivitat stellte sich eine internationale Arbeitsgruppe von Rheumatologen und Rheumapatienten – in Anlehnung an die Optimierung der Therapie von Patienten mit einem Hypertonus oder Diabetes – die Aufgabe, einen Behandlungsplan fur die RA zu entwickeln mit dem Ziel, so haufig wie moglich eine Remission zu erzielen. Diese Treat-To-Target-Empfehlungen wurden von nationalen Arbeitsgruppen, so auch in Deutschland, hinsichtlich ihrer Umsetzbarkeit in die Infrastruktur des deutschen Gesundheitswesens diskutiert und Moglichkeiten zur Implementierung erortert. Am Modell der RA wurden wichtige Aktionselemente und Postulate fur eine verbesserte Versorgung von Menschen mit der Volkskrankheit Rheuma aufgestellt, die in dem vorliegenden Manuskript im Einzelnen diskutiert werden.

Nach ahnlichen Beispielen wie dem Diabetes mellitus II und der Hypertonie wurde auch fur rheumatische Erkrankungen versucht, durch die Etablierung eines Treat-To-Target (T2T)-Programms den klinischen Verlauf rheumatischer Erkrankungen zu verbessern. Dennoch bleibt festzustellen, dass die Rheumatologie als eine anerkannte Disziplin der Inneren Medizin nicht entsprechend ihrer wissenschaftlichen, klinischen und soziookologischen Bedeutung an deutschen Universitatsklinika vertreten ist. Zur Frage, wie die universitare Rheumatologie zur Implementierung des T2T-Programms beitragen kann, kommen mehrere Ansatzpunkte in Betracht, die die Verbesserung der Aus- und Weiterbildung, die Schaffung klinisch-wissenschaftlicher Schwerpunkte, die Erarbeitung von Leitlinien, die Initiierung kontrollierter Studien und die Etablierung von Langzeitkohorten sowie die Einbettung pathogenetischer und therapeutischer Erkenntnisse in internationale Netzwerke und uberregionale Symposien umfassen.

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Demyelinating polyneuropathy with anti-myelin associated glycoprotein (anti-MAG) antibodies is an immune mediated disorder characterized by proximal and distal symmetric weakness. Electrophysiological measurements depict features characteristic for demyelination, including prolonged distal latency, retarded conduction velocity, delayed or absent F-waves, and, rarely, partial conduction block. We report on a 65-year-old patient who was diagnosed with demyelinating polyneuropathy and anti-MAG antibodies five years before admission. Despite immunosuppressive agents and extracorporeal therapy (plasmapheresis) the disease progressed as assessed by clinical symptoms and neurological tests. Laboratory results showed an increase of serum immunoglobulin M and anti-MAG antibodies over time. Because of progressive disease we decided to treat the patient with immunoadsorption followed by application of the anti-CD20 antibody, rituximab. Six cycles of selective immunoadsorption were performed over three-weekly intervals with a repetitively used column (Globaffin); each cycle consisted of four consecutive daily treatments. Starting at cycle 4 the anti-CD20 antibody rituximab was administered with 375 mg/m(2) after immunoadsorption. The pretreatment anti-MAG antibody level of 10,000 U/mL, indicating disease activity, initially increased during treatment to a maximum of 30,559 U/mL. However, after completion of the six cycles, the anti-MAG level had decreased to 2348 U/mL; 16 months after the last immunoadsorption cycle the anti-MAG level had increased to 4134 U/mL, while the conduction velocity and compound motor action potentials remained stabile. Immunoadsorption in combination with a monoclonal anti-CD20 antibody in patients with demyelinating polyneuropathy with anti-MAG is effective and can be used an alternative treatment option in patients with progressive disease.

For the purgating of pathogenic antibodies or immune complexes (IC), several adsorbers have been developed. The staphylococcal protein A-based PROSORBA® adsorber shows very limited adsorption volume of circulating autoAb and/or circulating IC. In our small pilot trial, similar changes of humoral diagnostic parameters and cellular characteristics were observed in the PROSORBA®-treated patients and in a patient successfully treated with TNF Ab for rheumatoid arthritis, suggesting a TNF antagonising effect of PROSORBA®. We propose as a hypothesis an adsorber-catalysed conversion of a small, tissue penetrating, hardly detectable, non-complement-binding, TNF-inducing dimeric IgG1-rheumatoid factor (RF) into an endogeneously clearable species of aggregated and complement-binding IC. The pathophysiological backgrounds of SPA and IgG1-RF are broadly discussed.

In the 1970s and 1980s the course of rheumatoid arthritis (RA) could be defined as fateful despite the introduction of methotrexate as well as other immunosuppressive treatments. In most patients at this time RA was combined with an early disability due a progressive destruction of joints. In addition, comorbidity was known to be one of the major causes for a decreased life expectancy. These less than optimal options for treating RA patients led to intensive research in the pathogenesis with the aim to develop new treatment principles. Based on the increasing knowledge of pathogenically important mechanisms, so-called biologicals were developed targeting T and B cells and proinflammatory cytokines, such as tumor necrosis factor alpha. Over the past 10 years the repertoire of biologicals for treating RA has steadily and significantly increased, which was necessary especially for those patients classified as non-responders to available biological compounds. In the present overview cellular structures, T and B cells as well as cells of the monocyte/macrophage system are discussed as targets for immune interventions.

Apoptosis and phagocytosis of apoptotic cells are crucial processes. At best the phagocytic machinery detects and swallows all apoptotic cells in a way that progression to secondary necrosis is avoided. Otherwise, inflammation and autoimmune diseases may occur. Most apoptotic cells are phagocytosed instantaneously in a silent fashion; however, some dying cells escape their clearance. If the cells are not cleared early, they lose membranes due to extensive shedding of membrane surrounded vesicles (blebbing) and shrink. It is unclear how apoptotic cells compensate their massive loss of plasma membrane. Here, we demonstrate that endoplasmic reticulum- (ER) resident proteins (calnexin, the KDEL receptor and a dysfunctional immunoglobulin heavy chain) were exposed at the surfaces of shrunken late apoptotic cells. Additionally, these cells showed an increased binding of lectins, which recognize sugar structures predominantly found as moieties of incompletely processed proteins in ER and Golgi. In addition the ER resident lipophilic ER-Tracker™ Blue-White DPX, and internal GM1 were observed to translocate to the cell surfaces during late apoptosis. We conclude that during blebbing of apoptotic cells the surface membrane loss is substituted by immature membranes from internal stores. This mechanism explains the simultaneous appearance of preformed recognition structures for several adaptor proteins known to be involved in clearance of dead cells.

Infliximab is effective in improving signs and symptoms of joint/skin involvement, functional status, and quality of life in patients with psoriatic arthritis (PsA). Using IMPACT trial data, we assessed the effect of infliximab (IFX) on structural damage in PsA.Patients with active PsA were randomly assigned to receive placebo (PBO/IFX) or infliximab 5 mg/kg (IFX/IFX) at weeks 0, 2, 6, and 14, with the primary endpoint at week 16. The PBO group received infliximab loading doses at weeks 16, 18, and 22. Thereafter, all patients received infliximab 5 mg/kg every 8 weeks through week 50. Hand/feet radiographs were obtained at weeks 0 and 50. Total radiographic scores were determined using the PsA modified van der Heijde-Sharp (vdH-S) score. Projected annual rate of progression was calculated by dividing x ray score by disease duration (years).As reported previously, 65% of infliximab treated patients versus 10% of PBO treated patients achieved an ACR20 response at week 16 (p0.001). At week 50, 69% of patients achieved an ACR20 response. Radiographs (baseline and week 50) were available for 72/104 patients. At baseline, estimated mean annual rate of progression was 5.8 modified vdH-S points/year. Mean (median) changes from baseline to week 50 in the total modified vdH-S score were -1.95 (-0.50) for PBO/IFX and -1.52 (-0.50) for IFX/IFX patients (p = NS). At week 50, 85% and 84% of patients in the PBO/IFX and IFX/IFX groups had no worsening in the total modified vdH-S score.Infliximab inhibits radiographic progression in patients with PsA through week 50.

Contains fulltext : 49783.pdf (Publisher’s version ) (Closed access) BACKGROUND: In recent clinical trials in patients with psoriatic arthritis (PsA), the response criteria and disease activity measures that have been used were those developed for rheumatoid arthritis. However, these have not yet been validated in PsA. OBJECTIVE: To compare the responsiveness and discriminative capacity of the psoriatic arthritis response criteria (PsARC), American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) response criteria and the Disease Activity Score (DAS) and core-set measures in patients with PsA and peripheral arthritis, using the data from two randomised placebo-controlled trials of tumour necrosis factor inhibitors. METHODS: In an infliximab trial, 104 patients with active PsA were randomised to receive placebo or infliximab for 16 weeks. In an etanercept trial, 60 patients with active PsA were randomised to receive placebo or etanercept for 12 weeks. Data from baseline and the end of the intervention phase were used from each study. Responsiveness was assessed using the standardised response mean and effect size. Capacity to discriminate between the active drug and placebo was assessed using t values or a chi2 test. Measures were ranked in order of their t value or chi2 value. RESULTS: The EULAR criteria performed better in discriminating the active drug from placebo than the ACR20 improvement criteria, which in turn performed better than the PsARC. It was also found that the pooled indices (DAS and DAS28) were generally more responsive, and performed better in discriminating active drug from placebo, than the single core-set measures. CONCLUSION: Response criteria and pooled indices developed for rheumatoid arthritis are useful for the assessment of arthritis in PsA clinical trials.

s in previous years, the consensus group to consider the use of biological agents was constituted by rheumatologists from the Universities of Erlangen, Leiden, and Vienna in Europe in cooperation with other Universities in the USA, Canada, and Europe. Pharmaceutical industry support was obtained from a number of companies, but these institutions had no part in the decisions about the specific programme or about the academic participants at this conference.

Collagen type II (CII) is a relevant joint-specific autoantigen in the pathogenesis of rheumatoid arthritis (RA). Whereas the reasons for the breakage of self tolerance to this major cartilage component are still enigmatic, T cell responses to glycosylated CII determinants in RA patients indicate that post-translational modifications play a role. Since the conversion of arginine into citrulline by peptidylarginine deiminases (PAD) in some non-joint-specific antigens such as filaggrin or fibrin has been shown to give rise to RA-specific humoral immune responses, we investigated whether PAD modification of cartilage-specific CII might affect its recognition by circulating autoantibodies in early RA. In vitro treatment with purified PAD led to arginine deimination of native CII or of synthetic CII peptides as evidenced by amino acid analysis. The citrullination resulted in modified recognition of the immunodominant CII epitope C1(III) (amino acid residues 359-369) by murine and human antibodies. In a cohort of early RA patients (n=286), IgG antibodies directed toward a synthetic citrullinated C1(III) peptide (citC1(III)-P) were detectable with a prevalence of 40.4%. The partial autoantibody cross-reactivity between citC1(III)-P and citrullinated peptides mimicking epitopes of the cytoskeletal autoantigen filaggrin suggests that autoimmunity to cartilage-specific modified self might be a critical intermediate bridging recognition of PAD-modified extra-articular autoantigens with the disruption of tolerance to native cartilage constituents.

Systemic sclerosis (SSc, scleroderma) is a connective tissue disease of unknown etiology. Perivascular inflammatory infiltrates and endothelial apoptosis with an impaired angiogenesis are observed in early stages of the disease, whereas later stages are characterized by an excessive accumulation of extracellular matrix proteins in the skin and various internal organs. Consistent with the ongoing endothelial cell damage, various markers of endothelial cells such as endothelin-1, sICAM-1, s-VCAM-1 and thrombomodulin are found in high levels in the serum of SSc patients. Surprisingly, the vascular endothelial growth factor (VEGF), a potent angiogenic molecule, is overexpressed in the skin of patients with SSc despite insufficient angiogenesis. Interestingly, patients suffering from diffuse SSc and patients without finger tip ulcers show higher VEGF levels compared to age- and sex-matched controls. These results indicate that a controlled overexpression of VEGF might help to protect against the manifestation of ischemic conditions. On the other hand, data from animal models indicate that a long-term, uncontrolled overexpression of VEGF might have paradox effects on the formation of new vessels leading to capillary changes similar to those observed in SSc. In addition to the impaired angiogenesis, defective vasculogenesis might contribute to the vascular symptoms of SSc.

It is the objective of the EULAR executive committee to promote actions and/or projects aimed at improving the knowledge and/or the recognition of musculoskeletal disorders. The chief aim is to contribute to the improvement of outcome of patients with rheumatic disorders. Apart from the projects devoted to education and research, projects aimed at facilitating the conduct of clinical studies or at improving the management of musculoskeletal disorders are welcome. Such studies can be categorised in four sections: It is the objective of the EULAR executive committee to maintain and to homogenise a high level of intrinsic quality and comparability of such studies. To achieve such an objective it appeared that the definition and publication of standardised procedures for the elaboration, evaluation, dissemination, and implementation of recommendations might be a relevant and useful starting point. Obviously these standardised operating procedures should not be a barrier to acceptance of a project if not all points are satisfied but might be important to consider before starting a project. These recommendations are not mandatory in themselves but can be used flexibly. At each step of such projects (application, elaboration, dissemination, etc), the individual items summarised in table 1 should be discussed. The reader is invited to visit the EULAR website (http://www.eular.org) to check the most recently updated version of these procedures. ### A Which wording? The three proposals are “points to consider”, “recommendations”, “guidelines”. It is the opinion of the EULAR executive committee members that, on the one hand, “guidelines” might appear too constraining and that, on the other hand, “points to consider” might be considered as too open. Recommendations can …

Background: Cytokines and T cell regulatory proteins play an important role in the pathogenesis of Wegener’s granulomatosis (WG). Objective: To investigate cytokine and cytotoxic T cell antigen-4 (CTLA4) gene polymorphisms and HLA class II alleles in generalised WG. Methods: The distribution of cytokine and cytotoxic T cell antigen 4 (CTLA4) gene polymorphisms and HLA class II alleles was analysed in 32 patients with generalised WG and 91 healthy controls. Genotyping was carried out for HLA-DRB1 and HLA-DQB1 and for polymorphism of the genes encoding TNFα (−238, −308, −376), TGFβ (codon 10 and 25), IFNγ (+874), IL6 (−174), IL10 (−592, −819, −1082), CTLA4 (−318, +49), and the (AT) n repeats of the CTLA4 gene. In addition, stratification analysis was carried out according to the presence (n = 15) or absence (n = 17) of end stage renal disease. Results: An increase in the IFNγ +874 T/T (odds ratio (OR) = 3.14) and TNFα –238 G/A (OR = 5.01) genotypes was found in WG patients. When ESRD positive and negative patients were compared, the IFNγ +874 A/A and the CTLA4 −318 C/C genotypes were found more often in the ESRD subgroup (OR = 10.6 and OR = 2.25). WG patients without ESRD had a higher frequency of the IL10 GCC/ACC promotor genotype (OR = 0.13) and long CTLA4 (AT) n repeats (OR = 0.4). No effect was seen for HLA-DR and –DQ markers. Conclusions: Disease susceptibility and clinical course in WG may be associated with distinct polymorphisms of cytokine and CTLA4 genes.

BACKGROUND AND OBJECTIVE Adult-onset Stilĺs disease (AOSD) is a rare entity. The course of the disease can be mild or severe, acute or chronic. The intention of this survey was to evaluate the longterm efficacy of TNF blockade in patients with severe and active AOSD. PATIENTS AND METHODS Eight patients with the diagnosis of AOSD, according to the diagnostic criteria developed by Yamaguchi in 1992, and pretreatment with either high dosage steroid or more intensive immunosuppressive therapy were treated with infliximab in a dosage of 3 - 5 mg/kg at time pointsduring week 0, 2 and 6. Later on, the treatment regimen was adapted to the individual needs of the patients. The follow-up period was between one and five years. RESULTS Seven patients responded to treatment with infliximab. Symptoms like fever, arthralgia, hepato-splenomegaly and serological parameters instantly improved. Five of these patients remained in remission over years after discontinuation of therapy. One of the responding patients needed permanent intensive treatment with TNF-blockers to control his severe chronic arthritis. Three patients experienced infusion reactions. One responding patient was therefore switched to etanercept and kept on this therapy. The one patient, who had not responded to infliximab also had no benefit from consecutive treatment with etanercept or adalimumab. CONCLUSION Anti-TNF therapy can have a lasting beneficial effect on the course of AOSD. Five of eight patients remained in remission even after termination of therapy.

Objective To evaluate the efficacy and safety of repeated administration of infliximab plus methotrexate (MTX) over a 2-year period in patients with rheumatoid arthritis (RA) who previously experienced an incomplete response to MTX. Methods Four hundred twenty-eight patients were randomly assigned to receive MTX plus placebo or infliximab at a dose of 3 or 10 mg/kg plus MTX for 54 weeks, with an additional year of followup. The protocol was later amended to allow for continued treatment during the second year. Of 259 patients who entered the second year of treatment, 216 continued to receive infliximab plus MTX for 102 weeks. Ninety-four of these 259 patients experienced a gap in therapy of >8 weeks before continuing therapy. Infusions were administered at weeks 0, 2, and 6, followed by treatment every 4 weeks or every 8 weeks (alternating with placebo infusions in the interim 4-week visits) at a dose of 3 or 10 mg/kg for a total of 102 weeks (including the gap in therapy). For safety and efficacy assessments, data on the patients who were randomized to receive treatment, irrespective of whether treatment was administered for 102 weeks, were evaluated using all actual observations available. The efficacy measures included the Health Assessment Questionnaire (HAQ) (physical function), Short Form 36 health survey (SF-36) (health-related quality of life), total radiographic scores (structural damage), and the American College of Rheumatology 20% improvement criteria (ACR20) (signs and symptoms). Results The infliximab plus MTX regimens resulted in significantly greater improvement in HAQ scores (P ≤ 0.006) and SF-36 physical component summary scores (P ≤ 0.011) compared with the MTX-only group. There also was stability in the SF-36 mental component summary score among patients who received the infliximab plus MTX regimens. Median changes from baseline to week 102 in the total radiographic score were 4.25 for patients who received the MTX-only regimen and 0.50 for patients who received the infliximab plus MTX regimen. The proportion of patients achieving an ACR20 response at week 102 varied from 40% to 48% for the infliximab plus MTX groups compared with 16% for the MTX-only group. Conclusion Throughout 102 weeks of therapy, infliximab plus MTX provided significant, clinically relevant improvement in physical function and quality of life, accompanied by inhibition of progressive joint damage and sustained improvement in the signs and symptoms of RA among patients who previously had an incomplete response to MTX alone.

A phase I study of the bispecific antibody MDX-H210 in combination with granulocyte colony-stimulating factor (G-CSF) was performed in stage IV breast carcinoma patients, overexpressing HER-2/neu. MDX-H210, constructed by crosslinking antigen binding fragments (F(ab') fragments) of monoclonal antibody (mAb) H22 to Fc gamma receptor I (FcgammaRI), and mAb 520C9 to HER-2/neu, respectively, mediates the lysis of tumour cells in vitro, and in human FcgammaRI transgenic mouse models. The proto-oncogene HER-2/neu is overexpressed in approximately 30% of breast cancer patients, and represents a promising target for antibody-based immunotherapy. Fc gamma receptor I (CD64) is an effective trigger molecule, which is expressed on monocytes/macrophages, immature dendritic cells, and G-CSF-primed polymorphonuclear cells (PMN). Patients received G-CSF (Filgrastim) for 8 consecutive days, and cohorts of three patients were treated on day 4 with escalating, single doses of MDX-H210. A total of 30 patients were included, and treatment was generally well tolerated, without reaching dose-limiting toxicity. Side effects consisted mainly of fever and short periods of chills, which were timely related to elevated plasma levels of interleukin 6 and tumour necrosis factor alpha. In the last two cohorts, MDX-H210 plasma levels exceeded 1 microg ml(-1), and on circulating myeloid cells >50% saturation of FcgammaRI was found until day 4. These effector cells were highly effective in antibody-dependent cell-mediated cytotoxicity. Immunohistochemical analyses of tumour biopsies in individual patients documented infiltration of monocytes and PMN after MDX-H210 infusion. Although the clinical course of the disease was not altered by the single dose of MDX-H210, a favourable toxicity profile--even at high doses--and remarkable biological effects were seen when combined with G-CSF. Therefore, the combination of G-CSF and MDX-H210 should be evaluated in further immunotherapeutical strategies.

As in previous years, the consensus group to consider the use of biological agents was constituted by rheumatologists from the Universities of Erlangen, Leiden, and Vienna in Europe in cooperation with universities in the United States, Canada, and Europe. Pharmaceutical industry support was obtained from a number of companies, but these institutions had no part in the decisions about the specific programme or about the academic participants at this conference. The 158 rheumatologists and bioscientists from 21 countries who attended the consensus conference were chosen from a worldwide group of doctors and other scientists interested in the use of biological agents for the treatment of immune mediated inflammatory diseases. The perspective of this consensus is from the treating doctor’s point of view, rather than from the perspective of those paying for their use. The number of attendees and participants was limited so that not everyone who might have been appropriate could be invited. Additional information has come to light in the past year, both corroborating the major positive effect these drugs have had in rheumatoid arthritis (RA) and other immune mediated inflammatory diseases, as well as documenting possible new and unexpected adverse events. Therefore an update of the previous consensus statement seems both appropriate and necessary ( Ann Rheum Dis2002;61(suppl II):ii2–7 [OpenUrl][1][FREE Full Text][2] ). The consensus statement is annotated to document the credibility of the data supporting it as much as possible. This annotation is that of Shekelle et al and is described in appendix 3.99 All participants reviewed relevant clinical published articles relating to tumour necrosis factor (TNF) and interleukin 1 (IL1) blocking agents. They were given a draft consensus statement and were asked to revise the document in small discussion groups; open discussion of the revisions led to a final document, representing this updated consensus statement. Individual patients differ in the aggressiveness of … [1]: {openurl}?query=rft.jtitle%253DAnnals%2Bof%2Bthe%2BRheumatic%2BDiseases%26rft.stitle%253DAnn%2BRheum%2BDis%26rft.issn%253D0003-4967%26rft.aulast%253DFurst%26rft.auinit1%253DD%2BE%26rft.volume%253D61%26rft.issue%253D90002%26rft.spage%253Dii2%26rft.epage%253D7%26rft.atitle%253DUpdated%2Bconsensus%2Bstatement%2Bon%2Bbiological%2Bagents%2Bfor%2Bthe%2Btreatment%2Bof%2Brheumatoid%2Barthritis%2Band%2Bother%2Brheumatic%2Bdiseases%2B%2528May%2B2002%2529%26rft_id%253Dinfo%253Apmid%252F12379612%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/ijlink?linkType=FULL&journalCode=annrheumdis&resid=61/suppl_2/ii2&atom=%2Fannrheumdis%2F62%2Fsuppl_2%2Fii2.atom

Objective. To investigate the efficacy and safety of leflunomide beyond 2 years in a multinational, openlabel extension of 2 phase III double-blind studies. Methods. Patients with rheumatoid arthritis (RA) who received leflunomide (100 mg/day for 3 days, 10 mg/day or 20 mg/day thereafter) in the 2 phase III studies and who completed 2 years of treatment were offered inclusion in the open-label extension phase and were maintained on the same dosage of leflunomide. The American College of Rheumatology revised criteria for 20% improvement (ACR20), ACR50, and ACR70 response rates, the Stanford Health Assessment Questionnaire (HAQ) scores, and C-reactive protein (CRP) levels were assessed. Safety measures included monitoring of adverse events and laboratory values. Results. A total of 214 patients (mean age 57 years) were treated with leflunomide for >2 years; 74.8% of the patients were female. The mean disease duration was 4.1 years (range 0.1–26.6 years), and in 44% of patients, RA was first diagnosed within 2 years of entry into the phase III studies. The mean duration of leflunomide treatment was 4.6 years (range 2.8–5.8 years), and 32% of patients had received no previous treatment with disease-modifying antirheumatic drugs. ACR20, ACR50, and ACR70 response rates and HAQ scores at 1 year were maintained through year 4 or until the end point. No new types of adverse events were observed, and liver function was normal at baseline and at the end point in the majority of patients. Conclusion. The improvements in both functional ability and physician-based efficacy measures seen with leflunomide after 1 year were maintained for up to 5 years (maximum treatment duration 5.8 years), demonstrating that the early efficacy of leflunomide in patients with RA is sustained long-term, and that the long-term safety profile of leflunomide is no different from that observed in phase III trials.

Item does not contain fulltext OBJECTIVE: The objective of this study was to verify the usefulness of a simple disease activity index (SDAI) for rheumatoid arthritis (RA). METHODS: The SDAI is the numerical sum of five outcome parameters: tender and swollen joint count (based on a 28-joint assessment), patient and physician global assessment of disease activity [visual analogue scale (VAS) 0-10 cm] and level of C-reactive protein (mg/dl, normal

Contains fulltext : 142630.pdf (Publisher’s version ) (Closed access) OBJECTIVES: To evaluate efficacy, dose response, safety, and tolerability of adalimumab (D2E7) in disease modifying antirheumatic drug (DMARD) refractory patients with longstanding, active rheumatoid arthritis (RA). METHODS: During a 12 week, double blind, placebo controlled study, 284 patients were randomly allocated to receive weekly subcutaneous injections of adalimumab 20 mg (n = 72), 40 mg (n = 70), or 80 mg (n = 72) or placebo (n = 70) without concomitant DMARDs. RESULTS: Adalimumab significantly improved the signs and symptoms of RA for all efficacy measures. ACR20 responses with adalimumab were significant at each assessment versus placebo (p

A s in previous years, the consensus group to consider the use of biological agents was formed by an organising committee constituted of rheumatologists from the Universities of Erlangen, Leiden, and Vienna in Europe in cooperation with universities in the United States, Canada, and Europe. Pharmaceutical industry support was obtained from a number of companies, but these institutions had no part in the decisions about the specific programme or about the academic participants at this conference. The 158 rheumatologists and bioscientists from 22 countries who attended the consensus conference were chosen from a worldwide group of people felt to have experience or interest in the use of biological agents for the treatment of rheumatoid arthritis (RA) and other rheumatic diseases. Unfortunately, the number of attendees and participants was limited so that not everyone who might have been appropriate could be invited. Additional information has come to light in the past year, both corroborating the major positive effect these drugs have had in RA and documenting possible new and unexpected adverse events. In addition, the first of a new class of targeted biological agents, interleukin 1 (IL1) blocking agents, has become available. Therefore an update of the previous consensus statement1 seems both appropriate and necessary. In the present update the consensus statement is annotated to document the credibility of the data supporting it as much as possible. This annotation is that of Shekelle et al and is described in appendix 3.2 All participants reviewed relevant clinical published articles relating to tumour necrosis factor (TNF) and IL1 blocking agents. They were given a draft consensus statement and were asked to revise the document in small discussion groups; open discussion of the revisions led to a final document, representing this updated consensus statement. Individual patients differ in the aggressiveness of their …

Redistribution, post-translational modifications and coclustering with viral antigens contribute to the immunogenicity of apoptotic cell-derived autoantigens. Almost all known targets of the humoral autoimmune response in systemic lupus erythematosus (SLE) are cleaved by caspases or granzyme B during apoptosis. Antibodies against retroviral proteins can frequently be detected in the sera of SLE patients without overt retroviral infections. These antibodies may represent cross-reactive antibodies or may have been induced by proteins encoded by endogenous retroviral sequences. We used Tera-1 cells that abundantly express a group-specific antigen of human endogenous retroviruses, HERV-K10gag polyprotein, to investigate its processing during apoptosis. Tera-1 cells induced to undergo apoptosis showed an altered HERV-K10gag processing compared with viable cells. In addition, granzyme B was able to cleave HERV-K10gag isolated from viable Tera-1 cells. Similar to nuclear autoantigens, endogenous retroviral proteins are cleaved during the execution phase of apoptosis. These post-translational modifications may result in the generation of T-cell neoepitopes or a changed epitope hierarchy of retroviral proteins. Therefore, immunogenicity of retroviral antigens in SLE patients may result from a similar mechanism as described for nuclear autoantigens.

Trotz der in der Therapie der Rheumatoiden Arthritis (RA) erarbeiteten Fortschritte, die durch die TNFα-Blockade erzielt werden konnten, ist es notwendig, die Studienlage weiter zu optimieren (Etanercept/MTX Studie mit Erfassung radiologischer Daten; Veroffentlichung der D2E7 Studienergebnisse; Kombination von D2E7 mit MTX). Daruber hinaus werden neue Immunbiologika (PEG-TNFRI, PEG-TNFα-Antikorper, loslicher TNFRI; CTLA4Ig, CD40Ligand-Antikorper, Antikorper gegen IFN-γ, IL-6, IL-12, IL-15, IL-18, Complemente) oder Hemmstoffe der TNFα-Translation (Peptide, Anti-Sense-Konstrukte) oder TNFα-Syntheseinduktion (Inhibitoren des NFκB, der p38 MAP-Kinase, Phosphodiesterase IV, des TNFα converting enzymes) getestet. Prinzipiell davon unterscheiden sich Antagonisten der Complement-Convertase oder Collagenase sowie Ansatze zur Vakzinierung oder T-Zell-Anergisierung. Fur Patienten mit MTX-Unvertraglichkeit ist die Testung alternativer Basistherapeutika in Kombination mit den TNFα-Blockern wichtig, auch eine Kombination mit anderen Immunbiologika (anti-CD4-Antikorper, IL-4, IL-10, IL-1RA) ist sinnvoll. Der Einsatz von TNFα-Blockern bei Patienten mit einer Fruh-RA ist derzeit in Studien unter Erprobung. Damit verbunden ist die Frage, inwieweit eine Auslassstudie, in der nach Remissionsinduktion mit TNFα-Blockern und MTX entweder die Therapie nur mit dem DMARD weitergefuhrt wird oder auf ein anderes Basistherapeutikum in Monotherapie oder Kombination umgestellt wird (z.B. Leflunomid/MTX), ein anhaltendes krankheitsinaktivierendes Ergebnis erzielen kann.

Die Therapie entzundlich-rheumatischer Erkrankungen hat in den letzten Jahren deutliche Fortschritte gemacht. So konnte die Progression der rheumatoiden Arthritis in vielen Fallen verlangsamt werden, die Lebenserwartung bei den primar systemischen Vaskulitiden oder beim systemischen Lupus erythematodes konnte deutlich gesteigert werden. Der vorliegende Beitrag stellt nicht nur die gegenwartige Standardtherapie verschiedener entzundlich rheumatischer Erkrankungen dar, sondern gibt auch einen Uberblick uber neueste Therapiestrategien, die in Zukunft das therapeutische Spektrum deutlich erweitern werden. So kann beispielsweise der Einsatz von TNF-α-blockierenden Substanzen die Therapie dieser Erkrankungen effektiv bereichern. Die Zielrichtung weiterer Forschung ist damit gestellt.

Zur Behandlung der rheumatoiden Arthritis als chronische inflammatorische Autoimmunerkrankung steht keine kausale Therapie zur Verfugung. Die etablierten Therapieregimes mit Basistherapeutika fuhren lediglich zur Verlangsamung der Progression, zudem sind sie deutlich nebenwirkungsbelastet. Die zytokinmodulierende Therapie stellt dagegen ein neues Konzept zur Behandlung der rheumatoiden Arthritis zur Verfugung. Der vorliegende Beitrag zeigt die aktuellen Ergebnisse von Forschung und klinischen Studien. Die Erfolge in der Anwendung der Tumornekrosefaktor-α-Blockade erlauben die Hoffnung, dass mit Hilfe von Immunbiologika schon in naher Zukunft eine effektivere Therapie der rheumatoiden Arthritis etabliert werden kann.

Background: Neutralization of tumor necrosis factor α (TNF-α) for three to six months reduces the symptoms and signs of rheumatoid arthritis. However, the capacity of this approach to effect a more sustained benefit and its effect on joint damage are not known. Methods: We treated 428 patients who had active rheumatoid arthritis despite methotrexate therapy with placebo or infliximab, a chimeric monoclonal antibody against TNF-α in intravenous doses of 3 or 10 mg per kilogram of body weight every 4 or 8 weeks in combination with oral methotrexate for 54 weeks. We assessed clinical responses with use of the criteria of the American College of Rheumatology, the quality of life with a health-status questionnaire, and the effect on joint damage radiographically. Results: The combination of infliximab and methotrexate was well tolerated and resulted in a sustained reduction in the symptoms and signs of rheumatoid arthritis that was significantly greater than the reduction associated with methotrexate therapy alone (clinical response, 51.8 percent vs. 17.0 percent; P

The guideline "Joint Swelling" is addressed to primary care physicians--general practitioners, internists or orthopedists without special experience in rheumatology. It provides a framework for interviewing patients, as well as for physical, laboratory and imaging examinations and for selection of treatment appropriate to the level of primary care. Situations which call for urgent evaluation and criteria for referral to rheumatologists are described. The appendix contains comments on signs and symptoms to differentiate arthralgia from joint swelling and on the diagnostic value of a history of joint swelling without confirmation by the physician. Further recommendations for the evaluation of patient history and physical and technical examinations are given in a tabular form. The significance of laboratory and imaging procedures is discussed.

Die Leitlinie „Gelenkschwellung” richtet sich an den Hausarzt – Allgemeinarzt oder hausarztlicher Internist – sowie an den nicht spezialisierten Orthopaden. Sie beschreibt die Anamnese, die problemorientierte klinische Untersuchung, die labormedizinische und bildgebende Diagnostik sowie therapeutische Masnahmen, die auf der primararztlichen Ebene einzuleiten sind. Situationen, die sofortiger Abklarung bedurfen und Uberweisungsindikationen zum Spezialarzt werden genannt. Der Anhang enthalt Erlauterungen zur Differenzierung der Symptome von Gelenkschmerz und Gelenkschwellung, zur Wertigkeit der anamnestischen Angabe einer fruheren Gelenkschwellung ohne Nachweis durch den Arzt und zu Gelenkschwellungen aus mechanischer Ursache. In tabellarischer Form werden nahere Hinweise zur Anamnese und Untersuchung gegeben und die Bedeutung der labormedizischen und bildgebenden Diagnostik diskutiert.

Growth factor deprivation-induced apoptosis plays an important role in several cellular systems. However, knowledge of the molecular mechanisms involved are restricted to a few murine models or tumor cell lines. Therefore, we aimed studying signaling pathways leading to apoptosis in activated human peripheral T cells after IL-2 withdrawal. Lymphoblasts from patients with CD 95 (Fas/APO-1)-deficiency revealed that functional CD95 was not required to induce apoptosis after IL-2 withdrawal. Moreover, apoptosis induction in response to various cytotoxic stimuli was found to be mediated in the absence of functional CD95 but was affirmatorily influenced by IL-2 signaling. Immunoblots showed no downregulation of Bcl-2 or Bcl-xL and no upregulation of Bax, whereas decreased mitochondrial membrane potential was readily measurable 24 h after cytokine deprivation. Tetrapeptide inhibitors showed limited efficacy in preventing apoptosis whereas the caspase inhibitor zVAD-FMK potently blocked induction of apoptosis. Cleavage of different fluorogenic substrates revealed multiple caspase enzyme activities in lymphoblasts, which were not negatively affected by the fas mutation. Starting at 8 h after IL-2 withdrawal, upregulation of active caspase-3 but not of caspase-8 could be detected. Taken together, our data argue for molecular mechanisms of cytokine deprivation-induced apoptosis in activated human lymphocytes independent of CD95.

We employed reverse transcription polymerase chain reaction (RT-PCR) to detect alternatively spliced CD36 mRNA in human peripheral blood mononuclear cells (PBMC). Sequencing of cloned cDNA revealed alternatively spliced mRNA molecules in 13 out of 39 clones. We observed exon skipping of up to 10 out of 12 coding exons in eight alternative transcripts. Additionally, in five of the transcripts, alternative splice donor or acceptor sites were used during mRNA maturation. Considering the CD36 molecule serves many functions in coagulation, host defence, lipid metabolism, and scavenging, we speculate that the proteins encoded by the alternatively spliced mRNA molecules may be involved in regulation of both CD36 gene expression and function.

Objective. Most information available about the disease course of patients with systemic lupus erythematosus (SLE) is restricted to the first 5 yr after disease onset. Data about the disease course 10 yr after disease onset are rare. The aim of this multicentre study was to describe the outcome of SLE patients with a disease duration of >10 yr. Methods. Outcome parameters were the SLE Disease Activity Index (SLEDAI ), the European Consensus Lupus Activity Measure (ECLAM ), the Systemic Lupus International Collaborative Clinics/American College of Rheumatology Damage Index (SLICC/ACR), a global damage index (DI ) and required treatment. In 10 diVerent European rheumatology centres, all SLE patients who were evaluated in the last 3 months of 1994, and who had been diagnosed with SLE at least 10 yr ago, were included in the study. Results. It should be stressed that our results are confined to a patient cohort, defined by a disease duration of at least 10 yr, and who are still under clinical care at the diVerent centres in Europe. These SLE patients still showed some disease activity, related to symptoms of the skin and musculoskeletal systems, next to the presence of renal involvement. A total of 72% of the patients needed treatment with prednisolone (7.5 mg). The cumulative damage was overall related to clinical features of the central nervous system (14%) and renal involvement (14%), next to deforming arthritis (14%), osteoporosis (15%) and hypertension (40%). The prevalences of obesity, Cushing appearance and diabetes are highly suggestive that the ongoing treatment and that in the past might have had an impact on the total sum of endorgan damage. Conclusions. After 10 yr, a high proportion of patients in our cohort continued to show evidence of active disease, defined by the SLEDAI as well as ECLAM. The DI was related to the involvement of the central nervous system, renal involvement and the presence of hypertension.

In den letzten Jahren haben sich unsere Kenntnisse uber die Wirkung von Zytokinen mit zunehmender Beschleunigung erweitert. Sicher sind noch nicht alle Effekte der Zytokine bekannt oder gar verstanden, dennoch hat sich die Einteilung in proinflammatorische und antiinflammatorische Zytokine sowie Antizytokinmolekule unter pragmatischen Gesichtspunkten sehr bewahrt. Auch bei der rheumatoiden Arthritis (RA) werden im entzundeten Gelenk Zytokine produziert, wobei – ersichtlich am klinischen Befund – offenbar kein Gleichgewicht von pro- und antiinflammatorischen Zytokinen sondern ein Ubergewicht proinflammatorischer Zytokine vorliegt. Daher liegt nah, mittels geeigneter Masnahmen proinflammatorische Zytokine zu hemmen, um auf diese Weise in den pathogenetischen Mechanismus der RA in einem sehr fruhen Stadium einzugreifen. Uber die Grundlagen, Strategien und Ergebnisse dieser Therapiemasnahmen wird an dieser Stelle eine Ubersicht gegeben.

To study whether an expansion of HIV-1-specific CTL is contributing to the skewed TCR repertoire in HIV-1-infection, we characterized the TCR usage of CTL clones specific for a conserved epitope in HIV-1 reverse transcriptase (RT/476-484). CTL clones from three HIV-1-infected patients displayed highly similar TCR usage and used the identical Vβ6.1 and Vα2.5 gene segments. CTL clones from two patients showed a very high degree of similarity within the TCR complementarity-determining region-3 (CDR-3). In accordance with the similar molecular structure, all three CTL clones also exhibited a similar functional activity with regard to recognition of variant peptides and cytokine secretion pattern. In one subject clonal expansion of a single CTL specificity could be shown over a 10-mo period. TCR spectratyping of PBMC from two patients revealed a marked expansion of CDR-3 segments of a certain length within the Vβ6-family. Sequence analysis of these CDR-3 yielded sequences identical to the RT/476-484-specific CTL previously isolated from the same patients. This analysis demonstrates that clonal expansion of HIV-1-specific CTL is contributing to the skewed TCR repertoire in HIV-1-infected patients.

Die Heberden-Arthrose betrifft hauptsachlich das weibliche Geschlecht im mittleren Alter und wird bei Frauen autosomal dominant und bei Mannern autosomal rezessiv vererbt. Wir berichten uber den Fall eines mannlichen Patienten bei dem bereits im Alter von 12 Jahren eine Heberden-Arthrose der Fingergelenke auftrat. Im Laufe von mehr als 15 Jahren waren diese Veranderungen bei dem Patienten weder klinisch noch radiologisch progredient. Bei der HLA-Typisierung fand sich der Haplotyp HLA A1, B8 und DR4, passend zu anderen Studien, die eine erhohte Frequenz von HLA A1, B8 bei familiarer Polyarthrose berichten.

The expression of TNF-alpha and its receptors in the rheumatoid synovial membrane was investigated using immunohistochemistry and immunocytofluorescence. TNF-alpha+ cells (< 10% of all cells) were found in all regions, predominantly in sublining and diffuse infiltrates. The highest percentage of TNF-R+ cells was found in the lining layer (50-90%), with a slight predominance of TNF-R55. In the sublining, fewer cells expressed TNF-R (approximately 50%), mostly TNF-R75. TNF-R75+ cells were also detectable in diffuse infiltrates and lymphoid aggregates (10-50%). These contained only individual TNF-R55+ cells. In diffuse infiltrates, there were slightly more TNF-R55+ cells than in lymphoid aggregates (in both cases < 10%). In sequential sections, TNF-alpha+ cells localized mostly in the vicinity of TNF-R+ cells. Macrophage-like cells appeared to be the predominant TNF-R+ cell type. CD3+ T cells in lymphoid aggregates expressed exclusively TNF-R75. Subsequently, the expression of membrane-bound TNF-alpha, TNF-R55 and TNF-R75 was tested by FACS analysis in isolated RA synoviocytes (n = 7 patients). Only four specimens expressed mTNF-alpha, and that on a low percentage of cells (2 +/- 2.4%; mean +/- SD). In contrast, all specimens expressed higher percentages of TNF-R55 and TNF-R75 (21 +/- 1% and 14 +/- 7.1%, respectively). These results demonstrate that: (1) the percentage of cells expressing soluble/transmembrane TNF-alpha is greatly outnumbered by the percentage of cells expressing TNF receptors; and (2) TNF-alpha-expressing cells are localized in regions expressing substantial levels of TNF receptors. Therefore, the known pro-inflammatory and pro-arthritic effects of TNF-alpha are probably mediated by local interactions between the receptors and their soluble and transmembrane ligands.

OBJECTIVE: To investigate whether MHC class II expression on myeloid cells of patients with treatment-naive early rheumatoid arthritis (RA) correlates with disease progression. METHODS: Monocytes were isolated by negative selection from the peripheral blood of 15 patients with early RA (disease duration < or =12 months), differentiated to macrophages and analysed for MHC class II expression by flowcytometry. The phenotypical data were correlated with clinical disease progression for up to 45 months. RESULTS: Before treatment was initiated, in vitro differentiated macrophages of 10/15 early RA patients expressed MHC class II comparable with macrophages from healthy controls. In sharp contrast, macrophages of the remaining five patients expressed significantly fewer MHC class II molecules. In contrast to patients with normal levels of myeloid cell MHC class II expression, who developed a smouldering, non-progressive disease, patients with decreased expression of MHC class II on macrophages early in their disease developed a continuously active disease as demonstrated by persistently increased disease activity scores (chi(2) = 4.54, P < 0.02) and progressive bone destructions (chi(2) = 5.66, P < 0.02) despite aggressive therapy. CONCLUSION: The level of myeloid cell MHC class II expression in recent onset RA allows a reliable distinction between patients who develop active and destructive RA and patients with a smouldering, slowly progressive disease.