Macrophage activation syndrome triggered by active systemic lupus erythematosus : Successful treatment by interleukin-1 inhibition (anakinra).

This article presents a case of fulminant macrophage activation syndrome (MAS) as a rare complication of active systemic lupus erythematosus in a 33-year-old female patient. Initial presentation showed severe lupus disease exacerbation with renal involvement, hemolytic anemia, and neuropsychiatric changes. Early therapy focused on broad immunosuppression (high-dose corticosteroids and cyclophosphamide); however, disease remission could not be achieved. After an additional inflammatory focus and underlying malignancy were excluded, the triplet of pancytopenia, fever, and high ferritin levels indicated MAS, a bone marrow biopsy confirmed secondary hemophagocytic histiocytosis. Treatment with an interleukin­1 antagonist (anakinra) induced a fast, effective therapeutic success.

Adherence and health literacy as related to outcome of patients treated for rheumatoid arthritis : Analyses of a large-scale observational study.

BACKGROUND: Disabilities in daily living and quality of life are key endpoints for evaluating the treatment outcome for rheumatoid arthritis (RA). Factors possibly contributing to good outcome are adherence and health literacy. METHODS: The survey included a representative nationwide sample of German rheumatologists and their patients with RA. The physician questionnaire included the disease activity score (DAS28) and medical prescriptions. The patient questionnaire included fatigue (EORTC QLQ-FA13), health assessment questionnaire (HAQ), quality of life (SF-12), health literacy (HELP), and patients' listings of their medications. Adherence was operationalized as follows: patient-reported (CQR5), behavioral (concordance between physicians' and patients' listings of medications), physician-assessed, and a combined measure of physician rating (1 = very adherent, 0 = less adherent) and the match between physicians' prescriptions and patients' accounts of their medications (1 = perfect match, 0 = no perfect match) that yielded three categories of adherence: high, medium, and low. Simple and multiple linear regressions (controlling for age, sex, smoking, drinking alcohol, and sport) were calculated using adherence and health literacy as predictor variables, and disease activity and patient-reported outcomes as dependent variables. RESULTS: 708 pairs of patient and physician questionnaires were analyzed. The mean patient age (73% women) was 60 years (SD = 12). Multiple regression analyses showed that high adherence was significantly associated with 5/7 outcome variables and health literacy with 7/7 outcome variables. CONCLUSION: Adherence and health literacy had weak but consistent effects on most outcomes. Thus, enhancing adherence and understanding of medical information could improve outcome, which should be investigated in future interventional studies.

[Therapy of ANCA-associated vasculitis with severe renal manifestation under routine conditions]. / Therapie der ANCA-assoziierten Vaskulitis mit schwerer renaler Beteiligung unter Routinebedingungen.

INTRODUCTION: In the MEPEX trial the poor prognosis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis with severe renal manifestation (AAVr) could be significantly improved in the first year by plasmapheresis. How and to what extent is this knowledge of AAVr therapy implemented into routine practice and what effectiveness and adverse events resulted? METHODS: This was a retrospective cohort study in which all patients who received remission induction therapy for AAVr under routine clinical conditions (RCC) in this hospital from 2009 to 2014 after publication of the MEPEX trial (n = 22) were compared with those in the plasmapheresis arm of the MEPEX trial (n = 70). Endpoints were dialysis-dependent chronic kidney disease and mortality after 3 and 12 months and severe life-threatening adverse events during the first 12 months. RESULTS: All patients with AAVr were treated by plasmapheresis under RCC. The two groups showed no differences with respect to the rate of dialysis dependency (after 3 months RCC 14 % versus MEPEX 16 %, P = 1.00 and after 12 months RCC 23 % versus MEPEX 14 %, P = 0.55) or mortality (after 3 months RCC 18 % versus MEPEX 16 %, P = 0.75 and after 12 months RCC 18 % versus MEPEX 27 %, P = 0.57). The rate of severe life-threatening adverse events was similar under RCC and under controlled study conditions (64 % versus 69 %, P = 0.87). CONCLUSION: Under RCC there is a high quality of medical treatment for AAVr. All patients received plasmapheresis for remission induction with comparable effectiveness and safety compared to controlled study conditions.

Optimized testing for C. trachomatis DNA in synovial fluid samples in clinical practice.

AIM: No standardized polymerase chain reaction (PCR) assay is available for detection of Chlamydia trachomatis (C. tr.) in synovial fluid (SF) for diagnostic use in clinical practice. This study tested the performance of two optimized molecular biology methods, to determine which is best suited for detecting C. tr. in SF clinical samples from patients with various rheumatologic diseases. METHODS: Two DNA extraction methods, i.e., (1) alkaline lysis and (2) QIAEX II Gel Extraction Kit® + cetyltrimethylammonium bromide (CTAB; Qiagen, Hilden, Germany), and C. tr.-omp1-152 bp PCR were tested in SF samples from a total of 329 patients with the following diagnoses: reactive arthritis (ReA; n = 10, 4 patients had posturethritic ReA), undifferentiated arthritis (UA; n = 66), rheumatoid arthritis (RA; n = 169), psoriatic arthritis (PSA; n = 12), and osteoarthritis (OA) n = 72. RESULTS: In SF samples, C. tr.-omp1-152 bp PCR in combination with alkaline lysis DNA extraction allowed detection of more C. tr.-positive samples: 3/10 (30%) ReA patients (all with posturethritic ReA) and 20/66 (38%) UA patients were positive, compared to the 0/10 (0%) patients with ReA and 1/66 (2%) with UA detected using the QIAEX II Gel Extraction Kit® + CTAB. Moreover, 2/12 (17%) SF samples from PSA patients tested positive with alkaline lysis. All samples from patients with OA and RA tested negative. CONCLUSION: Alkaline lysis in combination with C. tr.-omp1-152 bp PCR emerged as the most sensitive method for identification of C. tr. in clinical SF samples.

Use of clinical scores to guide therapeutic decisions in patients with rheumatoid arthritis in daily care.

OBJECTIVES: This study focuses on the application and impact of different clinical scores for treatment changes in daily practice in patients with rheumatoid arthritis (RA), as achieving remission is a feasible aim due to considerable improvements in therapeutic options. METHODS: In this prospective study, 1467 RA patients aged 15 to 88 years (72.5% female, 27.5% male) who had undergone treatment change or were treated with a disease-modifying antirheumatic drug (DMARD) for the first time were analysed. At three consecutive visits (T-1, T0, T1), scores were used to assess disease activity, loss of function, quality of life and imaging. In addition, the impact of the scores on treatment change was addressed (numerical rating scale, 1-10). RESULTS: The most commonly used scores were the DAS28 (65% of all visits), the Hanover functional ability questionnaire (FFbH, 36%) and the HAQ (11%). Other scores for evaluating RA are of little relevance in daily practice. No scores were calculated in only 10% of visits. Among the commonly used scores, the DAS28 had the highest influence on therapy decisions, followed by HAQ and FFbH (mean weight 6.62, 4.99 and 4.41, respectively). CONCLUSIONS: In daily practice, rheumatologists very often take scores for disease activity (especially DAS28) and loss of physical function into consideration when deciding on treatment for patients with RA. However, scores for measuring structural changes or quality of life, are not yet very well established with German rheumatologists.

[Reactive arthritis: from pathogenesis to novel strategies]. / Reaktive Arthritis: Von der Pathogenese zu neuen Therapiekonzepten.

Reactive arthritis (ReA) was first described 100 years ago. It is defined as a sterile joint inflammation following a primary, extra-articular infection often in the form of urethritis or enteritis and less frequently respiratory infection and is characterized by the presence of bacterial antigens or non-culturable bacteria in the joint,. The prevalence is estimated to be 40/100,000 adults, while the incidence is 4-5/100,000. The classic HLA-B27-associated form with asymmetric involvement of the lower extremities and/or the spine is part of the spondyloarthritis concept. The phenomenon of persistence, which will be discussed in detail herein, plays an important role in the pathogenesis of ReA. Up to 30% of patients develop chronic symptoms posing a therapeutic challenge. Combination antibiotic treatment showing a response in up to 63% of patients has recently been proposed. Biologics could represent an alternative therapeutic option for patients showing a severe and highly active disease course.

Reactive and undifferentiated arthritis in North Africa: use of PCR for detection of Chlamydia trachomatis.

Little is known about the possible role of Chlamydia in patients with reactive or unclassified arthritis in North Africa. This study used polymerase chain reaction (PCR) to survey this population. In addition, we compared the results in three different laboratories for PCR analyses for Chlamydia trachomatis (Ct) in synovial fluid (SF) and tissue (ST) from these North African patients with reactive arthritis (ReA), undifferentiated arthritis (UA), and in rheumatoid arthritis (RA) and osteoarthritis (OA). Eight ReA (six posturethritic, two postenteritic), 23 UA, 13 OA, and 12 RA patients were studied in Algeria, Morocco, and Tunisia. Serum, SF, and ST were obtained from each patient. Ct-PCR was performed in the three different laboratories and compared to Ct-serology [microimmunofluorescence (MIF) and anti-hsp60 enzyme-linked immunosorbent assay (ELISA)] performed in one laboratory. The rate of Ct-PCR positivity in SF/ST was low: none out of the eight ReA and three out of 23 UA patients. In the controls, Ct DNA was detected in two OA SF and in one RA SF. There was no concordance for Ct-PCR positivity between the three laboratories. MIF suggested previous Ct infection (IgG-positive) in two out of five posturethritic ReA, none out of one postenteritic ReA, one out of 17 UA, and nine out of 21 RA/OA patients tested. No MIF-positive patient was PCR-positive from SF or ST. However, anti-hsp60 IgG was detected in all four out of four patients positive by PCR and in 11 out of 44 PCR-negative patients (p = 0.002). In this multinational comparative study, the rate of Ct-PCR-positive synovial specimens in North African ReA/UA patients was low. Concordance among the three PCR testing laboratories was poor indicating the need for test standardization. All Ct-PCR-positive patients were found positive by anti-hsp60 IgG serology.

[Laboratory diagnosis of rheumatic diseases. Part 3: arthritides caused by infection]. / Labordiagnostik rheumatischer Erkrankungen: Teil 3: Infektbedingte Arthritiden.

This third part of this series of articles on laboratory diagnostics of rheumatic diseases considers the rheumatic diseases caused by infection by microorganisms, or reactive arthritides. The basis for laboratory diagnostics of infection-reactive arthritides is the investigation of anti-infection antibodies. In some situations, DNA amplification methods may be helpful. Bacterially infected joints should be immediately examined by arthrocentesis and microscopic examination and laboratory culture of the synovial fluid.

Comparing 10-day and 4-month doxycycline courses for treatment of Chlamydia trachomatis-reactive arthritis: a prospective, double-blind trial.

OBJECTIVE: To compare the efficacy of a 10-day and a 4-month doxycylcine course for the treatment of Chlamydia trachomatis-reactive arthritis (Ct-ReA). METHODS: Patients with active Ct-ReA were enrolled in a prospective, multicentre, double-blind, controlled clinical trial and randomised to receive doxycycline 100 mg twice daily for 10 days followed either by placebo or by continued doxycycline 100 mg twice daily over 4 months. Various clinical and laboratory parameters referring to disease activity were recorded in the beginning and at the end of treatment. RESULTS: 32 of 37 patients included (15 men and 17 women; mean (standard deviation) disease duration 17 (13) months completed the study; 17 were randomised to short-term doxycycline and placebo (placebo group) and 15 to prolonged treatment with doxycycline (doxycycline group) over the 4-month study period. After this time, only two patients from each group went into remission. There were no drop-outs owing to adverse events or treatment failures. CONCLUSIONS: The results of this study suggest that prolonged treatment with a 4-month course of doxycycline is not superior to short-term treatment over 10 days in patients with Ct-ReA.

Involvement of neurotrophins and their receptors in spondyloarthritis synovitis: relation to inflammation and response to treatment.

OBJECTIVE: To investigate whether expression of the four members of the neurotrophin (NT) family and their four corresponding receptors is related to synovial inflammation in patients with spondyloarthritis (SpA). MATERIAL AND METHODS: Synovial fluid (SF) and serum NTs and their receptors were measured by ELISA. Immunohistochemistry was used for synovial tissue biopsy specimens from patients with SpA, rheumatoid arthritis, and osteoarthritis (OA). In SpA synovium, immunoreactivity of the receptors trkA and NGFRp75 was also assessed before and after 12 weeks of treatment with the monoclonal anti-tumour necrosis factor alpha antibody, infliximab. RESULTS: mRNA transcripts of all NTs and receptors were expressed in the inflamed synovium. At the protein level, brain derived neurotrophic factor and NT-3 were significantly higher in the SF of patients with SpA than in those with OA. In contrast, ELISA of serum samples showed that the highest member in SpA was NT-4. Immunohistochemistry demonstrated that the NT receptors trkA and NGFRp75 were highly expressed in the inflamed synovium of patients with SpA, correlating with vascularity and lymphoid aggregates, respectively. Additionally, immunoreactivity of both receptors was significantly decreased after infliximab treatment. CONCLUSIONS: NTs and their receptors are expressed in inflamed peripheral joints of patients with SpA. Their expression is not constitutive but related to inflammation and they may be involved in the local disease processes.

Standardised work-up programme for fever of unknown origin and contribution of magnetic resonance imaging for the diagnosis of hidden systemic vasculitis.

BACKGROUND: Fever of unknown origin (FUO) is a diagnostic challenge. Rheumatologists are often in charge of patients with FUO because the vasculitides, especially, are potential and common causes of FUO. OBJECTIVE: To evaluate the value of a standardised investigation to identify the cause of FUO. METHODS: A standardised work-up programme for patients with FUO was started at the beginning of September 1999. The rate of identified causes of FUO was compared between all patients with FUO admitted to a tertiary care centre of rheumatology between January 1996 and August 1999 (control group) and September 1999 and January 2003 (work-up group). In January 2002 magnetic resonance imaging (MRI) was added to the investigation. RESULTS: 67 patients with FUO were identified--32 before and 35 after institution of the work-up programme. Before implementation 25% of all patients with FUO remained undiagnosed, after implementation 37%. After institution of the investigation the percentage of patients with vasculitides increased significantly from 6% (n = 2) to 26% (n = 9, p = 0.047, Fisher's exact test). This increase could be attributed to the addition of MRI in 2002. When all patients with FUO before 2002 (n = 55) and thereafter (n = 12) were compared the prevalence of systemic vasculitis increased from 11% (n = 6) to 42% (n = 5, p = 0.021). CONCLUSION: Implementation of a standardised work-up programme for FUO did not improve the overall rate of diagnosis. Addition of MRI significantly increased the diagnosis of systemic vasculitis as the underlying cause of FUO. MRI should be included in the investigation of patients with FUO when vasculitis is suspected.

Alpha beta but not gamma delta T cell clones in synovial fluids of patients with reactive arthritis show active transcription of tumour necrosis factor alpha and interferon gamma.

OBJECTIVE: To compare the cytokine expression profile of three CD8+, three CD4+, and three gammadelta+ T cell clones all derived from the synovial fluids of three patients with reactive arthritis (ReA). METHODS: Complementary DNA based microarrays containing the specific sequence of 56 cytokine transcripts were used for screening. Selected genes were confirmed by reverse transcriptase-polymerase chain reaction assay. RESULTS: Microarray showed that transcripts encoding for interferon gamma and tumour necrosis factor alpha were expressed by all CD8+ and CD4+ T cell clones. However, gammadelta+ T cells predominantly expressed transforming growth factor beta2 and granulocyte monocyte-colony stimulating factor. CONCLUSION: T lymphocyte clones from the joint of patients with ReA exhibit differential cytokine expression profiles. CD8+ and CD4+ T cells demonstrate a Th1 mediated profile, whereas gammadelta+ T cells show a more heterogeneous and less proinflammatory Th3 driven pattern.

[Diagnosis of reactive arthritis]. / Diagnostik der reaktiven Arthritis.

For the diagnosis of reactive arthritis, there is no single test. A combination of different parameters such as clinical presentation and laboratory parameters is necessary. Here we suggest a procedure for clinical practice of which tests should be performed when, based on the individual situation. To assess the clinical value of a test, it is not only necessary to know the specificity and sensitivity of a test but also the assumed likelihood of the disease (pretest probability).

Technical validation of cDNA based microarray as screening technique to identify candidate genes in synovial tissue biopsy specimens from patients with spondyloarthropathy.

OBJECTIVES: To validate the use of cDNA based microarray on synovial biopsies by analysing the experimental variability due to amplification of RNA, reproducibility of the assay, heterogeneity of the tissue, and statistical analysis. METHODS: Total RNA was extracted from three spondyloarthropathy (SpA) and three osteoarthritis (OA) synovial tissue biopsy specimens and from the peripheral blood mononuclear cells (PBMC) of four healthy donors. Exponential RNA amplification by SMART-PCR was compared with linear amplification. Reproducibility was tested by comparing different microarray systems and by performing duplicate experiments. Sample heterogeneity was assessed by comparing overall gene expression profiles, histopathology, and analysis of genes expressed in the synovium and normal PBMC. Statistical analysis using t test and Bonferroni adjustment was verified by permutation of class labels. RESULTS: Gene expression was concordant in 12/14 (86%) cytokine/chemokine genes between both microarrays and different RNA amplification systems. When one microarray system was used, expressed genes were 78-95% concordant in duplicate experiments. Gene expression profiles had a higher degree of similarity between SpA synovium than between PBMC or OA synovium despite clear histopathological differences between synovial samples. Comparison of SpA synovium with OA synovium and with PBMC yielded 11 and 18 expressed transcripts, respectively; six were shared in both comparisons. Permutations of SpA and OA samples yielded only one expressed gene in 19 comparisons. CONCLUSIONS: These data provide evidence that microarrays can be used for analysis of synovial tissue biopsies with high reproducibility and low variability of the generated gene expression profiles.

Anti-tumour necrosis factor (TNF)-alpha therapy in undifferentiated spondyloarthropathy.

The cytokine tumour necrosis factor (TNF)-alpha plays a major role in the spinal inflammatory process of spondyloarthropathy. In contrast to rheumatoid arthritis, disease modifying antirheumatic drugs have not been proved effective against inflammation and progressive ankylosis. Initial studies on TNFalpha inhibitors in ankylosing spondylitis are promising and raise the question as to whether early stages of the disease, mostly classified as "undifferentiated spondyloarthropathy" (uSpA), should also be treated with TNFalpha inhibitors. This article summarises the preliminary results of 11 uSpA patients in 4 different trials treated with TNFalpha inhibitors.

[Diagnostics]. / Diagnostik.

The round-table group "diagnostic" discussed the laboratory-based diagnosis of rheumatic diseases under the following three main questions: "What is necessary?"; "What is possible?" and "What has been achieved?".

[New aspects of bacteriological pathogen diagnosis in rheumatic diseases]. / Neue Aspekte bakteriologischer Errergerdiagnostik bei rheumatischen Erkrankungen.

Microbiological diagnosis for rheumatic diseases is increasingly used as part of the diagnostic work-up in rheumatological practice due to growing knowledge about bacteria-induced rheumatic diseases. This review's focus lies on rheumatic diseases, which in contrast to septic-infectious arthritis, are characterized by the inability to culture bacteria from the inflammed joint. These reactive arthritides occur after primary extraarticular bacterial infection. The etiological diagnosis of reactive arthritis is based on the detection of a previous or ongoing bacterial infection. Diagnosis is performed by serology or direct detection of the bacterial organism or parts thereof at the site of entry and recently by molecularbiology-based detection of the bacteria in the inflamed joint. This review reflects the current diagnostic approaches and formulates diagnostic algorithms for specific and well-directed microbiological diagnosis.

The genetically-engineered secretory B27/Q10 chimeric molecule inhibits HLA-B27 restricted alloreactive T-lymphocytes.

OBJECTIVES: Intracellularly persisting bacterial infections and high association with HLA-B27 are the hallmarks of reactive arthritis. Soluble HLA-B27 molecules are induced by bacterial infection; however their biological role in arthritis is unknown. It was the aim of this study to generate soluble HLA-B27 molecule and to analyze its effect on cytotoxic HLA-B27 alloreactive CD8+ T-lymphocytes in order to better understand potential functional links between persistent infection and HLA-B27 association. METHODS: Using PCR Exons 1 through 4 of HLA-B*2705 were fused to Exon 5 of the soluble murine MHC class I variant Q10 and stably transfected into Hela-cells. Transfectants were analyzed using specific PCR, RT-PCR and intracellular and extracellular staining with anti-HLA-B27 monoclonal antibody ME1. Secretion of B27Q10 in the supernatant was examined by isoelectric focusing (IEF). The effect of B27Q10 on T-cells was analyzed using either HLA-B27- or HLA-A2-restricted alloreactive T-cells in a standard 51Cr-release assay. RESULTS: PCR and RT-PCR demonstrated the DNA and mRNA of B27Q10 in the transfectants. By intracellular and extracellular staining with ME1 B27Q10-molecule was detected intracellularly but was not expressed in the cell membrane. Using IEF soluble B27Q10-molecules were found in supernatants of transfectants in a concentration of up to 1.342 microg/ml. Soluble B27QJO-molecule inhibited specifically the cytotoxicity of HLA-B27-restricted alloreactive T-cells by about 30%. CONCLUSION: The secretory non-membrane-expressed molecule B27Q10 inhibits HLA-B27 specific T-cells. The inhibition of cytotoxic T-cells by bacteria induced soluble HLA-B27 may thus enable bacterial persistence.

A 588-gene microarray analysis of the peripheral blood mononuclear cells of spondyloarthropathy patients.

OBJECTIVES: To identify genes which are more highly expressed in the peripheral blood mononuclear cells (PBMC) of patients with spondyloarthropathy (SpA), rheumatoid arthritis (RA) and psoriatic arthritis (PsA), in comparison to normal subjects. METHODS: A 588-gene microarray was used as a screening tool to select a panel of such genes from PBMC of these subjects and of normal subjects. Results were then validated by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: The following genes were more highly expressed in arthritis patients than in normal subjects: macrophage differentiation marker MNDA (myeloid nuclear differentiation antigen), MRP8 and MRP14 (migratory inhibitory factor-related proteins); signalling molecules JAK3 (janus kinase 3) and MAP kinase p38 (mitogen-activated protein kinase); receptors TNFR2/p75, C-C-chemokine receptor type 1 (CCR1), C-X-C-chemokine receptor type 4 (CXCR4) and integrin beta1; and the cytokines/chemokines interleukin (IL) 1beta and IL-8. Expression of CXCR4 was unexpectedly high among all arthritis subjects. Using RT-PCR, ELISA and immunohistology, expression of stromal cell-derived factor 1 (SDF-1) was demonstrated in arthritis joints. CONCLUSIONS: The CXCR4/SDF-1 is a potential pro-inflammatory axis for RA, PsA and SpA.