[Early recognition and screening consultation: a necessary way to improve early detection and treatment in rheumatology? : Overview of the early recognition and screening consultation models for rheumatic and musculoskeletal diseases in Germany]. / Früh- und Screeningsprechstunden: Ein notwendiger Weg zur besseren Frühversorgung in der internistischen Rheumatologie? : Rheumatologische Früh- und Screeningsprechstundenmodelle in Deutschland.

In order to reduce the prognostically relevant time interval between the initial manifestation of a rheumatic and musculoskeletal disease and diagnosis as well as the consecutive initiation of an appropriate treatment, several rheumatological centers in Germany have improved the access to initial rheumatologic evaluation by establishing early recognition/screening clinics at their respective sites. Corresponding models located at Altoetting·Burghausen, Bad Pyrmont, Berlin Buch, Duesseldorf, Heidelberg, Herne, Mannheim as well as supraregional/multicenter initiatives Rheuma Rapid, RhePort and Rheuma-VOR are presented in this overview along with the respective characteristics, potential advantages and disadvantages, but also first evaluation results of several models. The aim of this publication is to promote early detection of rheumatic and musculoskeletal diseases as one of the most important challenges in current rheumatology by encouraging further rheumatologic centers and practices to launch their own early recognition/screening consultation model on the basis of aspects presented herein.

[Interleukin-6 inhibition as a potential therapeutic target in rheumatic diseases]. / Interleukin-6-Blockade als potenzielles therapeutisches Target bei entzündlich-rheumatischen Erkrankungen.

As a pro-inflammatory cytokine, the 21-kDa glycoprotein interleukin-6 (IL-6) plays a crucial role in the initiation of acute inflammation, as well in the perpetuation of a chronic inflammatory immune response. Thus, IL-6 might be involved in the pathogenesis of various autoimmune diseases. So far, the IL-6-rezeptor-antibody tocilizumab (TCZ, RoActemtra®) is the only approved drug for the treatment of IL-6-mediated disease, including rheumatoid arthritis (RA), systemic juvenile idiopathic (sJIA) and polyarticular juvenile arthritis (pJiA), as well as Castleman's disease (in Japan only). In recent years, an emerging number of case reports and small uncontrolled case series have reported on the successful treatment of various other chronic inflammatory diseases, which has resulted in the idea of a broad therapeutic potential for IL-6 blockade. Numerous IL-6 targets are currently in phase II/III study programs for RA as well as for other indications. This review focuses on the development of tocilizumab and other IL-6 targets as a therapeutic option for various diseases in rheumatology.

Coexistence of antitopoisomerase I and anticentromere antibodies in patients with systemic sclerosis.

BACKGROUND: Antibodies targeting DNA topoisomerase I (ATA) or centromere proteins (ACA) are associated with clinical subsets of patients with systemic sclerosis (SSc). The occurrence of those autoantibodies is considered to be mutually exclusive. OBJECTIVE: To describe the clinical and immunogenetic data of three patients who are co-expressing both antibodies, and then review previous publications. METHODS: Both antibodies were detected by different methods, including indirect immunofluorescence technique, enzyme linked immunosorbent assay, immunodiffusion, and immunoblot. Patients were HLA typed by serological and molecular genetic methods. Data were extracted from published reports for comparison. The search for published studies was through Medline and other database research programmes. RESULTS: During routine laboratory diagnostics over several years three patients with scleroderma and coincidence of ATA and ACA were identified: patient 1 with diffuse SSc, Raynaud's phenomenon, puffy fingers and fingertip necrosis, contractures, and calcinosis; patient 2 with diffuse SSc, Raynaud's phenomenon, oedema of the hands, and interstitial calcinosis of hands, knees, and shoulders, and pulmonary fibrosis; patient 3 with scleroderma of hands, forearms, and face, Raynaud's phenomenon, puffy fingers, finger contractures, fingertip necrosis, and calcinosis. All three patients studied were carriers of HLA alleles known to be associated with these autoantibodies. In serial measurements the concentrations of the two antibodies showed independent or even reverse fluctuations. Screening of 100 patients with ACA for ATA and vice versa disclosed no further patients with coincidence of these antibodies. Twenty eight cases of ACA/ATA coexistence in 5423 patients (0.52%) with SSc or SSc associated symptoms were found in an analysis of published studies. CONCLUSION: The expression of ATA and ACA is not totally mutually exclusive, but coincidence is rare (<1% of patients with SSc). Patients with both autoantibodies often have diffuse scleroderma and show immunogenetic features of both antibody defined subsets of SSc.

Multiple mechanisms support oligoclonal T cell expansion in rheumatoid synovitis.

BACKGROUND: The synovial T cell infiltrate in rheumatoid arthritis (RA) is diverse but contains clonally expanded CD4+ populations. Recent reports have emphasized that RA patients have a tendency to develop CD4+ T cell oligoclonality which also manifests in the peripheral blood. Clonal dominance in the tissue may thus result from antigen specific stimulation in the synovial membrane or may reflect the infiltration of expanded clonotypes present throughout the lymphoid system. We have explored to what extent clonal populations amongst tissue CD4+ T cells display joint specificity as defined by their restriction to the joint, their persistence over time, and their expression of markers indicative for local activation. MATERIALS AND METHODS: Matched samples of peripheral blood and synovial fluid or synovial tissue were collected from 14 patients with active RA and CD4+ IL-2R+ and CD4+ IL-2R- T cells from both compartments were purified. Clonal populations of CD4+ T cells were detected by RT-PCR amplification of T cell receptor (TCR) transcripts with BV and BJ specific primers followed by size fractionation and direct sequencing of dominant size classes of TCR transcripts. RESULTS: Clonal CD4+ T cells were detected in the synovial fluid and synovial tissue of all patients. All patients carried synovial clonotypes that were undetectable in the blood but were present in independent joints or at several non-adjacent areas of the same joint. These joint restricted CD4+ clonotypes were generally small in size, were preferentially found in the IL-2R+ subpopulation, and persisted over time. A second type of clonogenic T cells in the synovial infiltrate had an unrestricted tissue distribution and was present at similar frequencies amongst activated and nonactivated T cells in the blood and affected joints. Ubiquitous clonotypes isolated from two different patients expressed sequence homologies of the TCR beta chain. CONCLUSIONS: Two types of expanded CD4+ clonotypes contribute to the T cell infiltrate in rheumatoid synovitis. Differences in the distribution pattern and in molecular features suggest that distinct mechanisms are supporting the clonal outgrowth of these two groups of clonotypes. Clonally expanded T cells restricted to the joint but present in several independent joints appear to respond to locally residing antigens. Clonogenic cells with an unrestricted distribution pattern and widespread activation in the blood and tissue may react to a different class of antigens which appear to be shared by multiple patients. T cell recognition in RA may be involved at several different levels and may be related to more than one pathomechanism.

[Diffuse fasciitis after Borrelia infection--a case report]. / Diffuse Fasziitis nach einer Borrelien-Infektion--ein kasuistischer Beitrag.

Diffuse fasciitis (DF) [diffuse fasciitis with eosinophilia-Shulman's syndrome] has occasionally been linked to a precedent infection with Borrelia burgdorferi. Here, we report on another case of DF in a 25 year old male, in whom Borrelia burgdorferi infection as possible inciting agent could be identified based on the patient's history and laboratory data. Efforts to microscopically demonstrate spirochetes or to amplify Borrelia-DNA by nested PCR in lesional tissue failed after antibiotic treatment had already been initiated. Although only a few cases of Borrelia associated diffuse fasciitis have been reported in the literature, the link between typical signs and symptoms as well as laboratory findings of Borrelia infection and the onset of diffuse fasciitis, starting at the primary site of EM, provide indirect evidence for a causative role of Borrelia burgdorferi as a potential infectious agent for DF.

Strong association of dermatomyositis-specific Mi-2 autoantibodies with a tryptophan at position 9 of the HLA-DR beta chain.

OBJECTIVE: To characterize the clinical and immunogenetic features of patients with Mi-2 autoantibodies. METHODS: Eighteen adult white patients with Mi-2 antibodies were clinically characterized and compared with 41 Mi-2-negative dermatomyositis (DM) patients. HLA class I and class II typing for DRB alleles was done by microcytotoxicity assay and for DQA and DQB alleles by polymerase chain reaction-based oligotyping. RESULTS: Seventeen of the 18 Mi-2-positive patients had DM. Symptoms of scleroderma, lung involvement, and arthritis were less common in this group than in the Mi-2-negative DM patients; the V-sign rash and nailfold involvement were found more frequently. Mi-2 antibodies were strongly associated with HLA-DR7 (88% versus 24% in healthy controls), HLA-DQA1*0201 (86% versus 23%), and DR7 "homozygosity" (31% versus 0%). A tryptophan residue at position 9 of the HLA-DR beta chain was present in all Mi-2-positive patients (100% versus 62%; homozygous in 81% versus 15%). CONCLUSION: Our results reemphasize the specificity of Mi-2 antibodies for DM, and extend previous reports that Mi-2 antibody production is associated with certain HLA class II antigens. We propose beta 9-Trp as a candidate epitope on the HLA-DR beta chain as a prerequisite for this type of autoimmune response.

Dominant clonotypes in the repertoire of peripheral CD4+ T cells in rheumatoid arthritis.

Clonal expansion of T cell specificities in the synovial fluid of patients has been taken as evidence for a local stimulation of T cells. By studying the T cell receptor (TCR) repertoire of CD4+ T cells in the synovial and peripheral blood compartments of patients with early rheumatoid arthritis (RA), we have identified clonally expanded CD4+ populations. Expanded clonotypes were present in the peripheral blood and the synovial fluid but were not preferentially accumulated in the joint. Dominant single clonotypes could not be isolated from CD4+ cells of HLA-DRB1*04+ normal individuals. Clonal expansion involved several distinct clonotypes with a preference for V beta 3+, V beta 14+, and V beta 17+CD4+ T cells. A fraction of clonally related T cells expressed IL-2 receptors, indicating recent activation. The frequencies of clonally expanded V beta 17+CD4+ T cells fluctuated widely over a period of one year. Independent variations in the frequencies of two distinct clonotypes in the same patient indicated that different mechanisms, and not stimulation by a single arthritogenic antigen, were involved in clonal proliferation. These data support the concept that RA patients have a grossly imbalanced TCR repertoire. Clonal expansion may result from intrinsic defects in T cell generation and regulation. The dominance of expanded clonotypes in the periphery emphasizes the systemic nature of RA and suggests that T cell proliferation occurs outside of the joint.

[Eosinophilia-myalgia syndrome with fasciitis and interstitial myositis after L-tryptophan administration]. / Eosinophilie-Myalgie-Syndrom mit Fasziitis und interstitieller Myositis nach L-Tryptophan-Einnahme.

We describe a 53-year-old women with eosinophilia-myalgia syndrome who suddenly developed severe persistent myalgias of her arms, legs, back, and shoulder after a 5-month period of daily L-tryptophan ingestion, associated with fever, progressive stenocardia and left-sided congestive heart failure. Laboratory tests showed a leukocytosis of 11.2/nl with 3.14/nl eosinophils and an elevated erythrocyte sedimentation rate. There was a marked, predominantly proximal sclerosis of her arms, legs and trunk with a brownish discoloration. The skin of her arms and legs appeared dimpled (peau d'orange). Findings of the electrophysiological examinations were consistent with sensory neuropathy and myositis. Remarkable fasciitis and interstitial myositis were present in a biopsy specimen (from skin to muscle) taken from her thigh. However, eosinophilic infiltrates were rare. Angiography revealed an apical obstructive cardiomyopathy. In this paper, we describe the clinical findings, the course over 2 years, as well as the therapeutic management. Furthermore, the most important differential diagnoses are discussed and the literature is reviewed with special attention given to more recent pathogenic insights into this newly recognized multisystem disease.

Determination of left atrial area and volume by cross-sectional echocardiography in healthy infants and children.

Part 1 of the study measured the end-systolic and end-diastolic left atrial (LA) areas and volumes in 30 children through sector echocardiography, and compared these values with those obtained with biplane angiocardiography. A strong correlation exists between the LA area in the frontal plane as determined by apical (r greater than 0.91) and subcostal (r greater than 0.98) echocardiography on the one hand and by angiocardiography on the other. However, there is a slight underestimation of the LA area by the apical 4-chamber view. LA volume as determined by subcostal sector echocardiography in the frontal and sagittal plane also correlated well with LA volume calculated with biplane angiocardiography (r greater than 0.97). Part 2 of the study determined LA areas and volumes in 74 healthy newborns and infants by echocardiography and related them to body weight and body surface area, thus obtaining normal values for this age group. The relation of the LA area and volume measurements in newborns and infants to body weight or surface area was best described by a linear function. The mean of the percentage of systolic-diastolic area diminution was 53 +/- 6% for the apical 4-chamber view and 50 +/- 4% for the subcostal 4-chamber view. LA ejection fraction determined by the subcostal biplane volume measurements was 62 +/- 7% (mean +/- standard deviation). These values were independent of body weight or surface area.