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We provide an overview of recent articles which describe new thinking regarding HLA-B27-associated reactive arthritis (ReA), including those additional infection-related arthritides triggered by microbes that often are grouped under the term ReA.With the advent and continuation of the pandemic, an increasing number of cases and case series of post-COVID-19 arthritis have been reported and classified as ReA. Further, arthritis after COVID-19 vaccination is a new entity included within the spectrum of ReA. New causative microorganisms identified in case reports include Clostridium difficile, Mycoplasma pneumoniae, Giardia lamblia, Leptospira , and babesiosis. SARS-CoV-2 is emerging as a significant etiologic agent for apparent ReA.It is now clear that comprehensive clinical and laboratory investigations, synovial fluid analyses, and close follow-up of patients all are essential to differentiate ReA from diseases that may present with similar clinical attributes. Further, and importantly, additional research is required to define the wide diversity in causative agents, epidemiology, and rare case presentations of these arthritides. Finally, new classification and diagnostic criteria, and updated treatment recommendations, are essential to the advancement of our understanding of ReA.

Purpose of Review This article presents a comprehensive narrative review of reactive arthritis (ReA) with focus on articles published between 2018 and 2020. We discuss the entire spectrum of microbial agents known to be the main causative agents of ReA, those reported to be rare infective agents, and those reported to be new candidates causing the disease. The discussion is set within the context of changing disease terminology, definition, and classification over time. Further, we include reports that present at least a hint of effective antimicrobial therapy for ReA as documented in case reports or in double-blind controlled studies. Additional information is included on microbial products detected in the joint, as well as on the positivity of HLA-B27. Recent Findings Recent reports of ReA cover several rare causative microorganism such as Neisseria meningitides, Clostridium difficile, Escherichia coli, Hafnia alvei, Blastocytosis, Giardia lamblia, Cryptosporidium, Cyclospora cayetanensis, Entamoeba histolytica/dispar, Strongyloides stercoralis, β-haemolytic Streptococci, Mycobacterium tuberculosis, Mycoplasma pneumoniae, Mycobacterium bovis bacillus Calmette-Guerin, and Rickettsia rickettsii. The most prominent new infectious agents implicated as causative in ReA are Staphylococcus lugdunensis, placenta- and umbilical cord–derived Wharton’s jelly, Rothia mucilaginosa, and most importantly the SARS-CoV-2 virus. Summary In view of the increasingly large spectrum of causative agents, diagnostic consideration for the disease must include the entire panel of post-infectious arthritides termed ReA. Diagnostic procedures cannot be restricted to the well-known HLA-B27-associated group of ReA, but must also cover the large number of rare forms of arthritis following infections and vaccinations, as well as those elicited by the newly identified members of the ReA group summarized herein. Inclusion of these newly identified etiologic agents must necessitate increased research into the pathogenic mechanisms variously involved, which will engender important insights for treatment and management of ReA. Supplementary Information The online version contains supplementary material available at 10.1007/s11926-021-01018-6.

The coping with rheumatoid arthritis of the famous French impressionist painter Pierre-Auguste Renoir (1841-1919) is described in former publications. The heavily handicapped painter has in his last years created sculptures in cooperation with the sculptor Richard Guino (1890-1973). The extraordinary genesis of the sculptures through a masterful artistic cooperation, as well as the resulting legal issues and shameful copyright infringements, is reported. Renoir's decision to create sculptures with the help of Guido can be attributed to his remarkable artistic vision, vitality, optimistic nature, and strong will and is also a further testimonial of creative coping of an artist overcoming the physical handicap due to rheumatoid arthritis of his final years, so far not described in detail in the medical literature.

The recent paper from Sepriano et al provides an extremely important new insight on the concept of axial spondyloarthritis (axSpA).1 Clearly, the Gestalt of axSpA is heterogeneous, with three recognisable clinical entities labelled as: ‘pure axial SpA’, ‘axial SpA with peripheral signs’ and ‘axial SpA at risk’. The finding given in the paper suggests a larger overlap between axSpA and pSpA than anticipated at the time when the Assessment of SpondyloArthritis international Society (ASAS) criteria were developed. Thus, the question arises as to how accurately the three recognisable clinical entities of the ASAS classification criteria represent the diseases entities originally lumped together in the historical concept of SpA. The unifying historical concept of SpA lumps together an inter-related yet heterogeneous group of disorders which includes ankylosing spondylitis …

Recent studies regarding the frequency of Chlamydia-induced reactive arthritis (ReA) are reviewed, with a focus on the question of whether the entity is in fact disappearing or whether it is simply being underdiagnosed/underreported. Epidemiological reports indicate diversity in the frequency of Chlamydia-associated ReA in various parts of the world, with evidence of declining incidence in some regions. The hypothesis that early effective treatment with antibiotics prevents the manifestation of Chlamydia-associated ReA requires further investigation. For clinicians, it is important to remember that ReA secondary to Lymphogranuloma venereum (LGV) serovars L1–L3 of C. trachomatis is probably underestimated due to a limited awareness of this condition, the re-emergence in Western countries of LGV overall, and the present increasingly rare classical inguinal presentation.

With the market entry of biologics, the treatment of rheumatoid arthritis (RA) has changed fundamentally in terms of efficacy and costs.of this study is to analyse the treatment according the guideline of the German society of rheumatology for RA patients with disease-modifying anti-rheumatic drugs (DMARDs) using claims data from the statutory health insurance.The claims data of the Techniker Krankenkasse were analysed retrospectively for the years 2011 - 2014. Subgroup analyses were used to conduct prescription and treatment differences with respect to guideline-recommended conventional DMARDs and biologics.The study population included 55,538 RA patients (29.7 % incidence, 70.3 % prevalence, 22.3 % M05: Seropositive rheumatoid arthritis, 77.7 % M06: Other rheumatoid arthritis). Only 21,616 insured patients (38.9 %) were prescribed a guideline-recommended conventional DMARD or biologic at least once within one year of/after the first diagnosis. Among incident patients, the coverage rate with disease-modifying drugs was below the prevalence patients (31.5 % vs. 42.1 %). 60.9 % of M05 patients and only 29.7 % of M06 patients received a single DMARD after index diagnosis. If a DMARD has been prescribed, then it was prescribed, on average, within the first quarter of the initial diagnosis. The leading role in the prescription of basic therapies for index medication is provided by the rheumatologist. Nevertheless, 68.3 % of patients consulted a specialist in rheumatology at least once within a year of the first diagnosis.The results of this large sample show differences in the guideline recommended prescription of disease-modifying drugs for different subgroups of RA as well as an undersupply in patients not treated by the rheumatologist.Mit Einführung der Biologika hat sich die Therapie der rheumatoiden Arthritis (RA) hinsichtlich der Wirksamkeit und Kosten grundlegend gewandelt. Ziel dieser Studie ist es, die der S1-Leitlinie der DGRh entsprechende Versorgung von RA-Patienten mit krankheitsmodifizierenden Medikamenten (disease-modifying anti-rheumatic drugs; DMARDs) anhand von Routinedaten der gesetzlichen Krankenversicherung zu analysieren.Die Abrechnungsdaten der Techniker Krankenkasse wurden retrospektiv für die Jahre 2011 – 2014 analysiert. Im Rahmen von Subgruppenanalysen wurden Verschreibungs- und Versorgungsunterschiede einzelner in der Leitlinie empfohlener Wirkstoffe wie konventionelle DMARDs und Biologika analysiert.Die Studienpopulation umfasste 55 538 RA-Patienten (29,7 % inzidente, 70,3 % prävalente; 22,3 % M05: Seropositive chronische Polyarthritis, 77,7 % M06: Sonstige chronische Polyarthritis). Lediglich 21 616 Versicherte (38,9 %) bekamen mindestens einmal innerhalb eines Jahres nach der Erstdiagnose ein in der Leitlinie empfohlenes konventionelles DMARD oder Biologikum verordnet. Bei den inzidenten Patienten lag die Versorgungsquote mit krankheitsmodifizierenden Medikamenten unterhalb der prävalenten Patienten (31,5 vs. 42,1 %). 60,9 % der M05-Patienten und nur 29,7 % der M06-Patienten erhielten einen Einzelwirkstoff nach Index-Diagnose. Wenn ein Basistherapeutikum verordnet wurde, dann wurde dies durchschnittlich innerhalb eines Quartals nach Erstdiagnose verschrieben. Die führende Rolle in der Verschreibung von Basistherapeutika für die Indexmedikation übernimmt der Rheumatologe. Dennoch zeigte sich, dass nur 68,3 % der Patienten mindestens einmal innerhalb eines Jahres nach der Erstdiagnose einen rheumatologisch tätigen Facharzt konsultierten.Mittels einer großen Stichprobe konnten Unterschiede in der leitliniengerechten Verordnung von krankheitsmodifizierenden Arzneimitteln für verschiedene Subgruppen sowie eine Unterversorgung bei nicht vom internistischen Rheumatologen behandelten Patienten aufgezeigt werden.

Chlamydia trachomatis and Chlamydia pneumoniae together comprise the most frequent causative pathogens that elicit reactive arthritis (ReA). Advances in our understanding of the molecular biology/molecular genetics of these organisms have improved significantly the ability to detect chlamydiae in the joint for diagnostic purposes, as well as extending our current understanding of the pathogenic processes they elicit in the joint and elsewhere. An important aspect of the latter is that synovial chlamydiae infect the joint in an unusual but metabolically active state. While some standard treatments can provide a palliative effect on the ReA disease phenotype, many reports have indicated that standard antibiotic treatment does not provide a cure. Of critical importance, however, two recent reports of controlled clinical trials demonstrated that Chlamydia-ReA can be treated successfully using combination antibiotic therapy. These observations offer the opportunity of a cure for this disease, thereby increasing the practical importance of awareness and diagnosis of the spondyloarthritis caused by Chlamydia. In this viewpoint, we provide an overview of recent key findings in the epidemiology, pathophysiology, clinical manifestations, diagnosis and treatment of Chlamydia-induced arthritis. Our intention is for these insights to be translated rapidly into clinical practice to overcome misdiagnosis and underdiagnosis of the disease, and for them to stimulate the continued development of a cure.

Raoul Dufy (1877-1953) and Niki de Saint Phalle (1930-2002) were 2 famous artists who suffered from rheumatoid arthritis (RA). Both artists represent an additional outstanding example of successful coping with RA in former times when, for the first time, corticosteroids were available, but nevertheless treatment was very limited in the pre-biological era. Dufy was one of the earliest patients with RA who received corticosteroids and regained his creativity to paint for a few additional years, but finally he died of massive intestinal hemorrhages, the adverse event of the combination of corticosteroid plus aspirin. Niki de Saint Phalle, a self-taught French painter and sculptor, was one of the most significant and unconventional female artists of the 20th century. Her eventful life was full of emotional burdens and lifelong lung disease in addition to RA. Niki de Saint Phalle came out from each physical and emotional crisis with new forces and new artistic ideas. Interestingly, it has been suggested that the occupational exposure to colors contributed to the development of RA in artists, which used significantly more bright and clear colors based on toxic heavy metals such as Renoir and Dufy. Moreover, these 2 were cigarette smokers, a recently described risk factor for developing RA and increasing the severity once it does develop. Niki de Saint Phalle produced her sculptures made of plastic material without protection while she assumed that exposition to polyester and toxic fumes of polystyrene caused severe damage to her lungs, resulting in recurrent health problems.

Current molecular genetic understanding of the metabolically active persistent infection state of Chlamydia trachomatis and Chlamydia pneumoniae in the synovium in patients with arthritis and spondyloarthritis favors a causal relationship. Here, we examine how adequately the accepted criteria for that etiologic relationship are fulfilled, emphasizing the situation in which these microorganisms cannot be cultivated by standard or other means. We suggest that this unusual situation of causality by chlamydiae in rheumatic disease requires establishment of a consensus regarding microorganism-specific terminology as well as the development of new diagnostic and classification criteria. Recent studies demonstrate the value of molecular testing for diagnosis of reactive arthritis, undifferentiated spondyloarthritis, and undifferentiated arthritis caused by C. trachomatis and C. pneumoniae in clinical practice. Data regarding combination antibiotic therapy is consistent with the causative role of chlamydiae for these diseases. Observations of multiple intra-articular coinfections require more research to understand the implications and to respond to them.

The famous artists Pierre-Auguste Renoir (1841-1919) and Alexej von Jawlensky (1864-1941) had rheumatoid arthritis (RA). Both represent an outstanding example of successful coping with RA in former times when treatment was very limited, and these individuals took advantage of creative disease management. The most popular French impressionist painter Renoir used his creativity to develop his own exercises and assistive equipments for painting despite his disability. Thus, Renoir exemplifies an artistic life altered by RA over more than 25 years that he dedicated entirely to his art and the depiction of beauty and happiness testified by his own words: "The pain passes, but the beauty remains." Jawlensky, a Russian from origin, was one of the most important expressionist painter active in Germany and the first painter in the 20th century who created extensive series of paintings especially of human faces. From Jawlensky, we learned that his rapidly progressing, late-onset RA induced depression, disability, financial pressure, and social retreat. But the resulting artistic sublimation contributed to the change in his paintings, which we owe the more than 1000 series of the very unique, small-format "Meditations."For those interested in art, new insight will be opened into the life and work of the artists and increase the appreciation for their contribution to modern art.

Objective To assess prospectively the rates and to explore predictors of spinal radiographic progression over 2 years in a cohort of patients with early axial spondylarthritis (SpA). Methods Two hundred ten patients with axial SpA from the German Spondyloarthritis Inception Cohort were selected for this analysis based on the availability of radiographs at baseline and after 2 years of followup. Spinal radiographs were scored by 2 trained readers in a blinded, randomly selected order according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Spinal radiographic progression was defined as worsening of the mean mSASSS by ≥2 units over 2 years. Results Among the patients with axial SpA, 14.3% showed spinal radiographic progression after 2 years (20% of those with AS and 7.4% of those with nonradiographic axial SpA). The following parameters were independently associated with spinal radiographic progression: presence of syndesmophytes at baseline (odds ratio [OR] 6.29, P < 0.001), elevated levels of markers of systemic inflammation (for the erythrocyte sedimentation rate, OR 4.04, P = 0.001; for C-reactive protein level time-averaged over 2 years, OR 3.81, P = 0.001), and cigarette smoking (OR 2.75, P = 0.012). These associations were confirmed by multivariate logistic regression analysis. No clear association with spinal radiographic progression was observed for HLA–B27 status, sex, age, disease duration, Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, presence of peripheral arthritis, enthesitis, psoriasis, treatment with nonsteroidal antiinflammatory drugs, or treatment with disease-modifying antirheumatic drugs at baseline. Conclusion The presence of radiographic damage at baseline (syndesmophytes), elevated levels of acute-phase reactants, and cigarette smoking were all independently associated with spinal radiographic progression in patients with early axial SpA.

Interferon-gamma (IFNgamma)-mediated indoleamine 2,3-dioxygenase (IDO) expression, important in innate immunity, immune suppression, and tolerance, can be counteracted by ferrous iron (FeSO(4)). Elevation of intracellular iron levels during stimulation with IFNgamma impeded IFNgamma-induced IDO mRNA and protein expression in HEp-2 cells. Decreased IDO expression was accompanied by decreased tryptophan degradation. Accordingly, IFNgamma-mediated suppressing effects on Chlamydia trachomatis (CT) infection were reduced or even abolished in the presence of FeSO(4). Conversely, lowering intracellular iron levels by deferoxamine (DFO) did not increase IFNgamma-induced IDO expression but potentiated Chlamydia-suppressing effects by lowering intracellular iron availability. Additionally, DFO led to a CT-induced IDO expression in HEp-2 cells not treated with IFNgamma. In summary, this study demonstrates that iron acts as a regulatory element for modulating IDO expression, in addition to its function as an essential element for chlamydial growth. This may represent an important control mechanism of IDO expression at the transcriptional level.

Objective Understanding of the molecular pathophysiology of spondylarthritis (SpA) remains largely elusive. This is related both to the complexity of the disease (axial versus peripheral disease, inflammation versus tissue remodeling) and to the difficulty in obtaining samples from primary disease sites. This study was undertaken to explore a gene expression approach for identifying novel candidate mediators of SpA. Methods Sacroiliac joint fluid aspirates from 3 SpA patients with active sacroiliitis were studied by microarray analysis. The expression of selected candidate molecules in peripheral synovitis was confirmed by reverse transcriptase–polymerase chain reaction and enzyme-linked immunosorbent assay. Results Microarray analysis identified 4 sacroiliitis gene clusters, containing a total of 47 messenger RNA (mRNA) transcripts. Two clusters contained genes expressed in all sacroiliitis samples, corresponding to both known and unsuspected candidate mediators of SpA pathology. These included proinflammatory molecules as well as molecules involved in tissue remodeling, such as transforming growth factor β2. Of the novel candidate genes selected for confirmation, interleukin-7 (IL-7) mRNA expression was higher in SpA peripheral synovial fluid and synovial tissue samples than in osteoarthritis samples, and similar to expression in rheumatoid arthritis (RA) samples. At the protein level, synovial fluid IL-7 levels were even higher in SpA than in RA, despite lower levels of tumor necrosis factor α and IL-1β. Conclusion In the present study, both known and unsuspected candidate mediators of SpA pathogenesis were identified, including IL-7. The specific overexpression of IL-7 at sites of peripheral synovitis in SpA suggests that further functional investigations of the role of this cytokine in SpA pathogenesis are warranted.

An international study was performed to investigate the discrepancy between physician and population perception of the management of musculoskeletal pain (MP). One thousand, one hundred and fifty-four people with MP and 604 primary care physicians randomly selected from six countries (UK, Germany, Italy, France, Australia and Mexico) were interviewed by telephone. The interviews were based on structured questionnaires that captured: the management of pain, knowledge about the condition, sources of information, information communicated within the consultation, and patient roles in pain management. People with MP are confused about the different treatment options available (up to 63% out of N = 1,154) to them and their relative benefits and risks (33-51%). Doctors are the most valued and appropriate source of information (by up to 80% of people, N = 1,154) but are difficult to access. When people do have a clinical consultation, there may be a disparity between the information doctors convey and patient recall of the information provided. For example, most doctors tell patients the number of tablets they will need to take to achieve optimal pain relief, but only 34-63% of people with MP recall being given this information. Lack of information may partially explain why so few people (7-36%) return to their doctor when their prescribed medication is ineffective. This survey identified lack of information as a potential barrier to effective treatment. Physicians' perceptions that people with MP are not able to appraise all the information and may prefer a passive role in their care need to be challenged if patients are to be participants in the management of their condition.

Peptidomic analysis using Differential Peptide Display (DPD) of human peripheral blood mononuclear cells (PBMC) mock-infected or persistently infected by Chlamydia trachomatis (CT) revealed 10 peptides, expressed upon CT infection. Analysis of these 10 candidates by tandem mass spectrometry enabled the determination of seven candidates as fragments from the precursors (I) ferritin heavy chain subunit, (II) HLA class II histocompatibility antigen, (III) vimentin, (IV) indoleamine 2,3-dioxygenase, (V and VI) pre-B cell enhancing factor (PBEF), and (VII) Interleukin-8 (CXCL8). The identified candidates proved the presence of anti-bacterial and immunologically active monocytic proteins after CT infection.

Unravelling the molecular mechanisms A number of bacteria have been implicated as causing reactive arthritis. In epidemiological studies Chlamydia have been identified as the most common bacteria triggering reactive arthritis in Western countries.1 Only 1–3% of patients acquiring infection at the urogenital tract as the primary site of infection develop Chlamydia -induced arthritis. It has been shown that C trachomatis reaches the joint from the urogenital system through circulating monocytes and that monocytes/macrophages are the common host cells for persistent organisms during long term infection, with a major role in the induction of inflammation (fig 1). Most patients will achieve clinical remission within 6 months after infection. However, a chronic disease course occurs with intermittent relapses and periods of remission despite the presence of persistent bacteria in the joint. To date, there is no explanation for this clinical heterogeneity, but it is probably related to the genetic background of the host as well as to bacterial factors, such as the ability of C trachomatis to modify its life cycle. Figure 1 Pathogenetic concept of Chlamydia -induced arthritis. (1) Primary urogenital infection; (2) dissemination of the bacteria into the joint; (3) intracellular persistence of the bacteria (a) and subsequent synthesis of antigens (AG) out of phagosomes or antigens (b) detected by T cells, which in turn activate monocytes through multiple cytokines; (4) production and release of proinflammatory mediators by the activated monocytes establishing and sustaining the actual inflammation. During the past decade, significant progress has been made in understanding the aetiopathogenesis of reactive arthritis. Convincing evidence suggests that bacteria and microbial antigens triggering reactive arthritis persist in the joints and other reservoirs such as the entry site of the infection. Owing to intensive immunological and immunogenetic research into reactive arthritis over past decades, the present view of the disease mechanisms is mainly …

Earlier studies from this group demonstrated that Chlamydophila pneumoniae co-localized with dendritic cells (DC) in temporal artery biopsies from patients with giant cell arteritis (GCA). To investigate the interaction of DC with C. pneumoniae we employed an in vitro cell culture system of human monocyte derived DC. These DC were infected with C. pneumoniae and observed at regular time intervals up to 25 days post infection. Chlamydiae were visualized inside DC by both confocal and electron microscopy. Statistical analysis showed an increase in the number of chlamydial antigen during that period (p < 0.00005, chi2-test). Titration of DC lysates on HEp-2 cells showed that infectious progeny was recovered at various intervals but showed no exponential growth. Additionally, RT-PCR analyses of infected DC identified transcripts from dnaA, ftsK and tal throughout a period of 14 days, indicating viable chlamydiae. Thus, human monocyte-derived DC are susceptible to C. pneumoniae infection. These results indicate that C. pneumoniae-infected DC can play an important role in the transmission of these bacteria in GCA and other chlamydial diseases.

The objective of this study is to review the concept of the 'Hannover Costing Study' and to present and discuss the major insights generated during the course of the project. The costing study was performed in conjunction with a randomized controlled prospective trial assessing the effectiveness of a disease management module in rheumatoid arthritis (RA). A full set of clinical and cost data both from patient-reported and payer-derived cost data was developed. In particular the study included (1) the development of a matrix of cost domains which might be used as a common taxonomy in costing studies, (2) the descriptive analysis of payer derived cost data, (3) the analysis of cost data in patients with uncertain diagnosis; (4) the development and validation of a patient-reported costing instrument, and (5) an assessment of productivity costs. The following are the results (1) the developed matrix of cost domains included 16 separate cost domains: 7 outpatient, 3 inpatient, 4 other disease related, and 2 productivity domains; (2) the micro-costing analysis showed total direct costs ofeuro3,815 per patient-year (standard error of mean, SEM:euro267) and RA-related direct costs wereeuro2,312 per patient-year; (3) in patients with uncertain diagnosis of RA and no treatment with 'Disease Modifying Antirheumatic Drugs' (DMARD) costs were significantly lower; (4) the comparison of patient-reported with payer-reported cost data generally supports the use of highly aggregated items to assess health care utilization in RA; (5) productivity costs in patients that are gainfully employed and in patients who receive RA-related retirement payments exceed RA-related direct costs. Furthermore, RA-patients reported their productivity losses adequately. The study added some additional insights to the following questions: What costs should be collected, what level of detail is required for that task, what patients should by analyzed, and what data sources should be used in further studies in RA.

Objective: To determine rheumatoid arthritis related out of pocket expenditure (OOPE) in Germany and to disaggregate the total OOPE into contributing cost domains. Methods: Data for the cost analysis were drawn from a multicentre randomised controlled prospective trial to assess the effectiveness of clinical quality management in patients with rheumatoid arthritis. Both payer sources and patient cost questionnaires were used to generate health care utilisation data. All cost domains of a recently published matrix were reviewed and potential sources of OOPE were determined. Health care utilisation data were developed throughout 2001. Co-payment regulations as per January 2004 were applied in order to indicate the most recent level of OOPE in Germany. Data were analysed in both physical and monetary units using descriptive statistics. Results: In all, 136 patients with rheumatoid arthritis were included. Mean total OOPE per patient and year was €417.20 (SEM 38.8, median 271.2). OOPE accounted for 15.3% of the total direct costs of rheumatoid arthritis. Total OOPE were further subdivided into cost domains: “non-physician service utilisation”’ (€194.40 per patient and year; SEM 24.2), “medication” (€99.00; 6.1), “transportation” (€56.20; 17.4), “visits to physicians” (€38.40; 0.6), “hospital facilities” (€24.00; 5.6), and “devices and aids” (€5.10; 0.8). Conclusions: Rheumatoid arthritis is associated with substantial OOPE, imposing a considerable economic burden for patients. OOPE contribute significantly to the total health care expenditure in rheumatoid arthritis. The patient perspective has to be taken into account when calculating the overall direct costs of rheumatoid arthritis from a societal point of view.

Antibiotic treatment of all disease manifestations after infection with Borrelia sensu lato spp aims at resolving the presenting disease manifestation and preventing late stage disease. The goals are resolution of the preventing manifestation and prevention of the spread of bacteria to prevent late disease like arthritis. Different borrelial species prevail in Europe. The natural disease course of European borreliosis is not well defined and the effect of antibiotic treatment is unclear.

Objective: To estimate the 3-year incremental cost effectiveness and cost utility of introducing leflunomide into sequential therapy, consisting of the most frequently used disease-modifying antirheumatic drugs (DMARDs), for patients with rheumatoid arthritis in specialised, i.e. rheumatological, care in Germany. Design and setting: The analysis was conducted from the societal perspective in Germany using an existing 3-year simulation model, which was adapted to the German healthcare system after secondary analysis of relevant publications and data. DMARD sequences including leflunomide were compared with those excluding leflunomide. Costs comprised direct costs incurred by treatment and indirect costs incurred by loss of productivity (sick leave and premature retirement) of rheumatoid arthritis patients. Effectiveness parameters were given by response years gained (RYGs) according to the American College of Rheumatology (ACR) criteria for 20%, 50% and 70% improvement (ACR20/50/70RYGs) and by QALYs gained (QALYGs). Costs, effects and QALYs were discounted by 5% per annum. In the base-case analysis, average values of costs, response years and QALYs were applied. Costs were in 1998–2001 values (€1 ≈ $US0.91, average of the period from the year 2000 through 2001). Main outcome measures and results: After 3 years, adding leflunomide was less costly and more effective than the strategy excluding leflunomide when total (direct and indirect) costs were considered. There were savings of €271 777 and 8.1, 4.3, 5.1 and 4.9 ACR20RYGs, ACR50RYGs, ACR70RYGs and QALYGs per 100 patients, respectively, obtained through adding leflunomide. Focusing on direct costs, adding leflunomide was more costly and more effective compared with excluding leflunomide, with an incremental cost effectiveness of €5004 per ACR20RYG, €9535 per ACR50RYG, €7996 per ACR70RYG, and an incremental cost utility of €8301 per QALYG, after 3 years. The robustness of the results was shown in comprehensive sensitivity analyses. In the analysis of extremes, different combinations of the limits of cost, effectiveness and utility parameters were investigated. Adding leflunomide to sequential DMARD therapy remained dominant in 79% of the possible cases, i.e. was less costly and more effective than the strategy excluding leflunomide. Focusing on direct costs, adding leflunomide became dominant in 29% and remained more costly and more effective in 50% of possible cases. Conclusions: Our analysis suggests, with its underlying data and assumptions, that having leflunomide as an additional option in a DMARD treatment sequence extends the time patients benefit from DMARD therapy at reasonable additional direct costs. Adding leflunomide may even be cost saving when total (direct and indirect) costs are considered. As data on DMARD effectiveness were extracted from the results of clinical trials, real-world data from observational studies would be needed to corroborate the findings of the present analysis.

Objective. Infliximab, a monoclonal antibody against tumour necrosis factor a (TNF-a), is approved in Europe for the treatment of patients with active ankylosing spondylitis (AS) who have responded inadequately to conventional therapy. This report provides analyses from a 3-yr extension study, as a follow-up to both the 1- and 2-yr open label extensions of the original 3-month randomized controlled trial of infliximab in patients with AS. Methods. Of the 49 patients with AS who completed the second year of the study, 46 continued treatment with infliximab 5 mg/kg every 6 weeks up to week 156. The Bath AS Disease Activity Index (BASDAI), the Bath AS Functional Index, the Bath AS Metrology Index, patient’s and physician’s global assessments, quality of life (Short Form-36), C-reactive protein (CRP) and erythrocyte sedimentation rate were assessed throughout the study period. Results. The improvement of signs and symptoms observed in the majority of the patients during the first and second year was sustained throughout the third year of the study. Forty-three patients (62% of the 69 patients enrolled at baseline and 93% of the patients who started the third year) completed week 156. In the intention-to-treat analysis, an ASAS ‘5 out of 6’ and ASAS 40% response was seen by 46% and 50% of the patients, respectively. The scores for other efficacy assessments were similar to the values observed at weeks 54 and 102. Median CRP levels remained low (1.5 mg/l at week 156). There were no relevant side-effects and no discontinuation because of drug-related adverse events during the third year of the study. Conclusions. Patients with AS receiving infliximab for 3 yr showed a durable clinical response without loss of efficacy. Long-term infliximab treatment was well tolerated by patients in this study.

Objective: To obtain results of the second year extension of an original 3 month randomised, placebo controlled trial (and the 1 year extension study) assessing the use of infliximab, a monoclonal antibody to tumour necrosis factor α, for the treatment of patients with ankylosing spondylitis (AS). Methods: Of the 54 patients with AS who completed the first year of the study, 52 continued to receive infliximab 5 mg/kg every 6 weeks up to week 102. The primary end point was the proportion of patients achieving at least 50% improvement from baseline in the Bath AS Disease Activity Index (BASDAI) at week 102. Other assessments included patient and physician global assessments, quality of life as assessed by Short Form-36, Bath AS Functional Index, Bath AS Metrology Index, and C reactive protein (CRP). Results: Improvement in signs and symptoms of AS seen during the first year of the study was sustained during the second year. Forty nine patients (71% of 69 enrolled patients and 49/52 (94%) patients who started year 2) completed the study up to week 102. Thirty (58%) patients achieved at least 50% improvement from baseline in the BASDAI score at week 102. Scores for other efficacy assessments were similar at weeks 54 and 102. Median CRP levels remained low at weeks 54 and 102 (3.9 and 4.3 mg/l, respectively). Side effects during the second year of the study were similar to those of the first year of treatment with infliximab. Conclusions: Patients with AS treated for 2 years with infliximab 5 mg/kg exhibited a good and durable clinical response.

To quantify direct costs of medication and cost of illness (according to functional capacity) for patients with rheumatoid arthritis (RA) in Germany, allowing further use in a health economic evaluation of sequential therapy with disease-modifying antirheumatic drugs (DMARDs) in specialised, i.e. rheumatological, care in Germany.The analysis was conducted from the societal perspective in Germany using a modelling approach, which was based on secondary analysis of existing data and on data from a sample of 583 patients from the German rheumatological database of 1998. Functional capacity was defined by the Hannover Functional Ability Questionnaire (HFAQ) scores. Costs were calculated from resources utilised and patients' work capacity. Direct costs consisted of outpatient medical services, inpatient treatment, long-term care and rehabilitation treatment. Indirect costs incurred by sick leave and premature retirement were quantified according to the human-capital approach.Average total direct costs (year 1998-2001 values) per patient per year for continuous treatment with the selected DMARDs comprising costs for drugs, monitoring and treatment of adverse drug reactions (ADRs) were highest for intramuscular gold (sodium aurothiomalate) [euro 2106 (euro 1 approximately equal to $US 0.91; average of the period from 2000 through 2001)] followed by leflunomide (euro 2010), azathioprine (euro 1878), sulfasalazine (euro 1190), oral methotrexate (euro 708), and lowest for the antimalarials chloroquine/hydroxychloroquine (euro 684). There were additional yearly costs for RA-related non-DMARD medication of euro 554 per patient, including management of ADRs. Mean cost of illness (year 1998 values) excluding medication cost amounted to euro 17,868 per RA patient per year. Annual costs increased with increasing disability, i.e. decreasing functional capacity, of RA patients from euro 6029 per patient with more than 94% of functional capacity to euro 28,509 per patient with20% of functional capacity. In general, there was a predominance of indirect costs in each of the categories of functional capacity, ranging between 74% and 87% of total (direct and indirect) annual costs per RA patient. Annual direct costs increased from euro 811 to euro 7438 per patient with increasing disability. Inpatient treatment was the predominant component of direct costs. Patients in the worst category (20%) of function experienced hospital costs that were 6.5 times higher than those of patients in the best category (94%).On the basis of the data presented it can be concluded that the results of this investigation are typical for patients in rheumatological care in Germany and can therefore be used in a health economic analysis of different DMARD sequences aimed at changing disease progression over time.

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.

Objective To assess the effect of 5 mg/day prednisolone on disease progression in patients with early rheumatoid arthritis (RA) receiving standardized disease-modifying antirheumatic drug (DMARD) therapy. Methods Patients with active RA of

Objective To render information on the accuracy of patient-reported indirect cost data compared with payer-derived data of the real indirect costs on a patient-by-patient basis concerning disease-related productivity losses in rheumatoid arthritis (RA). Methods The assessment of indirect cost data was part of a clinical, multicenter, randomized RA trial. A total of 234 patients of working age with a diagnosis of RA (according to 1987 American College of Rheumatology criteria) were recruited. Demographics of the cohort were mean age 53 years, mean disease duration 8 years, 76% were women, and all had membership in the regional statutory health insurance plan. Every 3 months corresponding indirect cost data were derived for the cohort from a health economic questionnaire for cost assessment in patients with RA and the payer's database over a period of 18 months. Comparative statistical analyses were performed between patient-reported and insurance claims data. Results The mean annual productivity losses due to sick leave amounted to 14 and 17 days per patient (questionnaire versus payer data), and productivity losses due to work disability amounted to 3 days (both); monetary valuation renders overall costs of €1,240 and €1,590, respectively. The difference of 17% in overall productivity losses is not significant. Comparison of productivity losses reveals a strong correlation of r = 0.83 in those due to sick leave and of κ = 0.84 in those due to work disability between questionnaire and payer data. Conclusion The comparison of questionnaire and payer data shows that RA patients report their productivity losses adequately. Indirect cost assessment should therefore be included in further RA trials and observational studies.

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

The current literature covering cost-effectiveness and cost-utility analyses of biological treatments in patients with rheumatoid arthritis (RA) are reviewed in order to discuss options and limitations for future application of these highly priced drugs in routine clinical practice. The cost-effectiveness and cost-utility ratios of the studies analysed are converted into the corresponding Euros of the publication year. Etanercept treatment achieved a cost-effectiveness ratio of 44,300 Euros (2002)/ACR 20 (20% response according to American College of Rheumatology criteria) and 43,100 Euros (2002)/ACR 70WR (ACR 70 weighted response) compared with sulfasalazine and methotrexate, respectively, in methotrexate-naive RA. In methotrexate-resistant RA, the combination of etanercept and methotrexate is compared to a combination therapy of methotrexate, sulfasalazine and hydroxychloroquine revealing costs of 46,100 Euros (2000)/ACR 20, and 37,700 Euros/ACR 70WR. The cost-utility ratios for infliximab treatment range from 16,000 Euros to almost 166,000/QALY (quality adjusted life-year) gained, the studies investigating etanercept treatment show a ratio of approximately 25,000 Euros and 120,000/QALY gained. No substantial differences of cost-utilities of infliximab and etanercept were found. The administration of these drugs as third-line therapy is regarded cost-effective compared to other well-accepted therapies with comparable cost-utility ratios of50,000 Euros/QALY gained. Still, data on economic outcomes of RA trials are sparse and further cost-effectiveness and cost-utility evaluations are needed.

Chlamydia trachomatis (CT) as well as Chlamydophila pneumoniae (CP) cause chronic inflammatory diseases in humans. Persistently infected monocytes are involved in the pathogenesis by inducing mediators of inflammation. An in vitro system of chlamydial persistence in human peripheral blood monocytes (HPBM) was used to investigate prostaglandin E(2) (PGE(2)) production and the expression of the key enzyme for prostaglandin production, cyclooxygenase-2 (COX-2). PGE(2) production was determined by PGE(2)-ELISA of HPBM-culture supernatants. Cox-2 mRNA expression was measured by real-time RT-PCR of total RNA isolated from HPBM. Both, CT and CP, stimulated PGE(2) production of HPBM in vitro. Equivalent numbers of CT per host cell induced a higher PGE(2)-response compared to CP. The amount of synthesized PGE(2) depended on the chlamydial multiplicity of infection (MOI). Even at an MOI of 10 the amount of CT- and CP-induced prostaglandin, respectively, was lower than the amount of prostaglandin induced by E. coli lipopolysaccharide (LPS) at a concentration of 10microg/ml. In contrast to stimulation with LPS, Chlamydia-induced PGE(2) production as well as cox-2 mRNA decreased after day 1 post infection (p.i.). These data indicate that Chlamydia stimulate PGE(2) production in human monocytes. Since Chlamydia are often contaminated by mycoplasma, the influence of mycoplasma on the prostaglandin production was investigated additionally. Mycoplasma fermentans (MF) also stimulated PGE(2) production. The co-infection of mycoplasma and Chlamydia resulted in an additive effect in the production of PGE(2). Thus it is important to use host cells and Chlamydia free of mycoplasma contamination for the analysis of Chlamydia-induced prostaglandin production.

Objectives: To describe the impact of musculoskeletal pain (MP); to compare management of MP by the population and by primary care physicians; and to identify misconceptions about treatment. Methods: 5803 people with MP and 1483 primary care physicians, randomly selected, in eight European countries were interviewed by telephone. A structured questionnaire was used to ask about usual management of MP and perceived benefits and risks of treatment. Current health status (SF-12) was also assessed. Results: From primary care physicians’ perceptions, MP appears to be well managed. All presenting patients are offered some form of treatment, 90% or more doctors are trying to improve patients’ quality of life, and most are aware and concerned about the risks of treatment with NSAIDs. From a population perspective, up to 27% of people with pain do not seek medical help and of those who do, several wait months/years before seeing a doctor. 55% or fewer patients who have seen a doctor are currently receiving prescription treatment for their pain. Communication between doctors and patients is poor; few patients are given information about their condition; and many have misconceptions about treatment. Conclusions: Management of MP is similar across eight European countries, but there is discordance between physician and patient perspectives of care. Some people with pain have never sought medical help despite being in constant/daily pain. Those who do seek help receive little written information or explanation and many have misperceptions about the benefits and risks of treatment that limit their ability to actively participate in decisions about their care.

Chlamydia trachomatis-infected macrophages induce T cell apoptosis. This ability might promote intracellular survival of Chlamydia and perpetuate chronic chlamydial infection. The purpose of this study was to examine the molecular mechanisms by which C. trachomatis-infected macrophages induce T cell apoptosis. Monocytes and T cells were isolated from the peripheral blood of healthy donors. Macrophages were infected with C. trachomatis, and autologous T cells were stimulated by mitogen. After 6 days, both populations were cultured together using a two-chamber transwell membrane system to differentiate between mechanisms involving either cell-to-cell contact or secretion of apoptotic factors. Apoptotic T cells were identified by propidium iodide through-flow cytometry, and tumor necrosis factor-alpha (TNF-alpha) concentrations were measured by enzyme-linked immunosorbent assay. Antagonists of TNF-alpha, the Fas (CD95) molecule, TNF-related apoptosis-inducing ligand (TRAIL), and catalase were added to differentiate between the pathways of apoptosis. C. trachomatis-infected macrophages significantly induced T cell apoptosis by cell-to-cell contact (mean +/- standard deviation, 30+/-4%; P

Chlamydia trachomatis (Ct)-induced arthritis (CtIA) is characterized by persistent Ct infection, which stimulates secretion of cytokines in vitro. We therefore investigated whether CtIA patients have a unique cytokine profile in synovial fluid or serum in vivo. Because underlying Ct infection is overlooked in a high percentage of patients with initially diagnosed undifferentiated oligoarthritis (UOA), we examined whether determination of cytokines might also be of diagnostic relevance for this arthritis form. Matched serum and synovial fluid specimens from 26 patients with CtIA were analyzed and compared to those from 34 patients with UOA in whom Ct infection was excluded and those of nine patients with rheumatoid arthritis (RA). In 15 CtIA patients, Ct DNA from synovial fluid could be amplified by polymerase chain reaction. The following cytokine or cytokine antagonists were measured by enzyme-linked immunosorbent assay: interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, IL-6, IL-1 receptor antagonist, and soluble TNF receptor p75. No statistically significant differences in cytokine levels between patients with CtIA or the other arthritis forms were detected. Also, comparison between CtIA patients with (n = 17) and without Chlamydia DNA (n = 9) in synovial fluid revealed no significant differences for these cytokines. Cytokine levels in serum and synovial fluid were not different between CtIA, UOA without Ct infection, and RA patients. The intracellular presence of Ct was not associated with a specific profile of these cytokines in vivo.

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

Objective: To compare the three year safety and efficacy of cyclosporin and parenteral gold in the treatment of early, active, severe rheumatoid arthritis (RA), and to study the reversibility of cyclosporin associated renal dysfunction in patients who discontinued cyclosporin treatment. Methods: The patients continued to receive cyclosporin or parenteral gold in an 18 month open extension to an 18 month randomised, parallel group study. The main efficacy variable was blinded evaluation of radiographic progression of joint damage. Safety variables included serum creatinine, calculated creatinine clearance, and blood pressure. Results: Radiographic progression during follow up was similar in both groups. About 60% of the patients in the intention to treat groups (n=272) and about half of the patients in the completer groups (n=114) had definite radiographic progression in joint damage (increases >6 in the Larsen-Dale score), and about one in three also had substantial progression (>18 increase in Larsen-Dale score). Both systolic and diastolic blood pressure were significantly increased in the cyclosporin group compared with the gold group, and 12/139 (9%) versus 3/139 (2%) (p=0.03) had notably raised blood pressure. The mean serum creatinine increased by 28% at the treatment end point in the cyclosporin group as compared with 7% in the gold group. The mean calculated creatinine clearance was reduced by 16% and increased by 1% in the cyclosporin and gold groups, respectively, at the end of the study. At the final follow up visit after discontinuation of cyclosporin (at least three months after treatment was stopped) the mean serum creatinine was increased by 15% and creatinine clearance reduced by 16%. Sustained increases in serum creatinine at this post-treatment end point were mostly seen in patients with a raised serum creatinine during treatment of at least 50%. Conclusion: Three year changes in radiographic damage during cyclosporin and parenteral gold were similar in patients with early, active RA. Abnormal renal function and raised blood pressure were often seen in the cyclosporin treated patients.

BACKGROUND Treatment options for patients with ankylosing spondylitis are few. We aimed to assess the effectiveness of infliximab, an antibody to tumour necrosis factor (TNF)-alpha, in treatment of such patients.In this 12-week placebo-controlled multicentre study, we randomly assigned 35 patients with active ankylosing spondylitis to intravenous infliximab (5 mg/kg) and 35 to placebo at weeks 0, 2, and 6. One patient in the infliximab group was withdrawn from the study. Our primary outcome was regression of disease activity of at least 50%. To assess response, we used validated clinical criteria from the ankylosing spondylitis assessment working group, including disease activity (BASDAI), functional indices (BASFI), metrology (BASMI), and quality of life (short form 36). Analyses were done by intention to treat.18 (53%) of 34 patients on infliximab had a regression of disease activity at week 12 of at least 50% compared with three (9%) of 35 on placebo (difference 44% [95% CI 23-61], p0.0001). Function and quality of life also improved significantly on infliximab but not on placebo (p0.0001 and p0.0001, respectively). Treatment with infliximab was generally well tolerated, but three patients had to stop treatment because of systemic tuberculosis, allergic granulomatosis of the lung, or mild leucopenia.Our results show that treatment with infliximab is effective in patients with active ankylosing spondylitis. Since there are some potentially serious adverse effects, we recommend that this treatment mainly be used in co-operation with rheumatological centres.

The Chlamydia trachomatis genome encodes glycolysis and pentose phosphate pathway enzymes, two ATP/ADP exchange proteins, and other energy transduction-related components. We asked if and when chlamydial genes specifying products related to energy transduction are expressed during active vs. persistent infection in in vitro models and in synovia from Chlamydia-associated arthritis patients. Hep-2 cells infected with K serovar were harvested from 0-48 h post-infection (active infection). Human monocytes identically infected were harvested at 1, 2, 3, 5 days post-infection (persistent). RNA from each preparation and from synovial samples PCR-positive/-negative for Chlamydia DNA was subjected to RT-PCR targeting (a) chlamydial primary rRNA transcripts and adt1 mRNA, (b) chlamydial mRNA encoding enzymes of the glycolysis (pyk, gap, pgk) and pentose phosphate (gnd, tal) pathways, the TCA cycle (mdhC, fumC), electron transport system (cydA, cydB), and sigma factors (rpoD, rpsD, rpoN). Primary rRNA transcripts and adt1 mRNA were present in each infected preparation and patient sample; controls were negative for chlamydial RNA. In infected Hep-2 cells, all energy transduction-related genes were expressed by approximately 11 h post-infection. In monocytes, pyk, gap, pgk, gnd, tal, cydA mRNA were present in 1-2-day-infected cells but absent at 3 days and after; cydB, mdhC, fumC were expressed through 5 days post-infection. RT-PCR targeting mRNA from sigma factor genes indicated that lack of these gene products cannot explain selective transcriptional down-regulation during persistence. Analyses of RNA from synovial tissues mirrored those from the monocyte system. These data suggest that in the first phase of active chlamydial infection, ADP/ATP exchange provides energy required for metabolism; in active growth, glycolysis supplements host ATP. In persistence host, rather than bacterially produced, ATP is the primary energy source. Metabolic rate in persistent C. trachomatis is lower than in actively growing cells, as judged from assays for relative chlamydial primary rRNA transcript levels in persistent vs. actively growing cells.

An in vitro cell culture model was used to investigate the long-term effects of azithromycin, rifampin, and the combination of azithromycin and rifampin onChlamydia trachomatisinfection. Although standard in vitro susceptibility testing indicated efficient inhibition by azithromycin, prolonged treatment did not reveal a clear elimination of chlamydia from host cells. Chlamydia were temporarily arrested in a persistent state, characterized by culture-negative, but viable, metabolically active chlamydia, as demonstrated by the presence of short-lived rRNA transcripts. Additionally, azithromycin induced generation of aberrant inclusions and an altered steady-state level of chlamydial antigens, with the predominance of Hsp60 protein compared to the level of the major outer membrane protein. Treatment with azithromycin finally resulted in suppression of rRNA synthesis. Chlamydial lipopolysaccharide and processed, functional rRNA were detectable throughout the entire incubation period. These in vitro data show a good correlation to those from some recent clinical investigations that have reported on the persistence of chlamydia, despite appropriate antibiotic treatment with azithromycin. Rifampin was highly active by in vitro susceptibility testing, but prolonged exposure to rifampin alone for up to 20 days resulted in the emergence of resistance. No development of resistance to rifampin was observed when chlamydia-infected cells were incubated with a combination of azithromycin and rifampin. This combination was shown to be more efficient than azithromycin alone, in that suppression of rRNA synthesis occurred earlier. Thus, such a combination may prove more useful than azithromycin alone.

Objective—To describe current treatment of patients with rheumatoid arthritis (RA) in German rheumatology. Methods—Data from the German rheumatological database of 1998, comprising clinical and patient questionnaire data of 12 992 outpatients with RA seen at 24 collaborative arthritis centres in Germany, were analysed. Results—At the time of documentation, 88% of the patients with RA were undergoing disease modifying antirheumatic drug (DMARD) treatment. Methotrexate (MTX) was prescribed to 56% of the patients (61% with seropositive and 45% with seronegative RA). Combination treatment was used in 15%. MTX was the drug of first choice even in patients with up to one year’s disease duration (49%), followed by antimalarial drugs (21%). Patients treated by non-rheumatologists within the previous year had received DMARD treatment in only 33% of the cases. In steroid treatment, low doses (

OBJECTIVE To describe the aims, principles, and content of the German rheumatological database and to present data on patient mix and healthcare provision for the year 1998. METHODS The German rheumatological database contains clinical and patient derived data of the outpatients with inflammatory rheumatic diseases seen at one of the 24 collaborative arthritis centres. The case mix, institutional context, and demographic features of 25 653 patients from the year 1998 were analysed. RESULTS 51% of the patients had rheumatoid arthritis, 23% seronegative spondyloarthropathies, including ankylosing spondylitis, psoriatic arthritis, and reactive arthritis, and 19% had vasculitis, including SLE (5%). The distribution of the age at onset of patients with RA with ⩽2 years9 disease duration was comparable with recent incidence data from population studies. The case mix differed between university departments and rheumatology hospitals as well as individual practices. 65% of the male and 46% of the female patients at ages 18–60 were still in gainful employment, the rates of employment were 14% below the population rates for women, and 11% below those for men. 62% of all patients had seen a rheumatologist within the first year of disease, 73% within the first two years. Ankylosing spondylitis was seen in rheumatological care much later than all other diseases (only 39% within the first year). The mean number of contacts with a rheumatologist was five a year; rheumatologists in individual practices saw their patients seven times a year on the average. Together with visits to the non-specialist doctor mainly treating the patient, the mean number of visits to the doctor for a rheumatic condition was 20 a year. CONCLUSION Large databases like this one give information about the patient case mix in different healthcare settings, about treatment practice, and about the consequences of disease. Patients treated in specialised rheumatology units in Germany are referred earlier than in the past, which probably reflects better regional cooperation due to the implementation of arthritis centres. University departments and outpatient clinics of rheumatology hospitals contribute considerably to the specialised care of patients with arthritis and connective tissue diseases.

Objective To evaluate the short-term efficacy of celecoxib, a cyclooxygenase 2–specific inhibitor, in the treatment of ankylosing spondylitis (AS). Methods The study was a 6-week randomized, double-blind, placebo-controlled trial with 3 treatment arms: placebo, ketoprofen 100 mg twice daily, and celecoxib 100 mg twice daily. Patients who had AS according to the modified New York criteria, without peripheral synovitis and with active disease (pain ≥40 mm on a 100-mm visual analog scale [VAS] and an increase in pain of at least 30% after nonsteroidal antiinflammatory drug withdrawal) were eligible for study. Primary outcome measures were change in pain intensity (VAS) and change in functional impairment (Bath Ankylosing Spondylitis Functional Index [BASFI]). Results Of the 246 randomized patients, 76 were allocated to receive placebo, 90 ketoprofen, and 80 celecoxib. There were no statistically significant differences between treatment groups at study entry. During the 6 weeks of the study, the decrease in pain and functional impairment was greater in the active treatment groups than in the placebo group, with a trend in favor of celecoxib when the 2 active treatments were compared. The mean changes were −13 mm, −21 mm, and −27 mm (P = 0.006) for pain and 1, −6, and −12 (P = 0.0008) for BASFI score in the placebo, ketoprofen, and celecoxib groups, respectively. During treatment, the number of patients reporting epigastric pain was 6 (8%), 13 (14%), and 10 (13%) in the placebo, ketoprofen, and celecoxib groups, respectively. Conclusion The results of this study confirm the clinically relevant antiinflammatory effect of celecoxib at a 200-mg daily dosage, with significant improvement of both pain and function in patients with AS.

Objective More than 50% of patients with synovitis involving 1–4 joints remain classified as having undifferentiated oligoarthritis (UOA) after 1 year of disease. The clinical presentation is often similar to that of reactive arthritis (ReA) and other spondylarthropathies or to Lyme arthritis. We therefore determined how often Chlamydia trachomatis (Ct) and Borrelia burgdorferi (Bb) can be identified in patients with UOA, by using an extensive laboratory approach. Methods We prospectively studied 52 patients with UOA who presented at an early synovitis clinic in a region highly endemic for Lyme disease. Patients were examined by standardized clinical and immunoserologic procedures. Synovial fluid was screened for the presence of Ct and Bb DNA by polymerase chain reaction (PCR). Urine was tested for Ct DNA by ligase chain reaction, and serum was tested for Ct antibodies by enzyme-linked immunosorbent assay and Bb antibodies by hemagglutination test and Western blotting. PCR results in the UOA patients were compared with the results in cohorts of patients with definite rheumatoid arthritis (RA), Lyme arthritis, and Chlamydia-induced arthritis (CIA). Results In the synovial fluid of 9 of 52 patients with UOA (17%), we found Ct DNA, and in 6 of the 52 patients (12%), Bb DNA was found. The frequency of bacteria-specific DNA was 50% (7 of 14) in CIA patients and 69% (11 of 16) in patients with Lyme arthritis. No Bb or Ct DNA was found in the synovial fluid of the 31 RA patients. Conclusion With optimized PCR protocols, it is possible to detect considerable levels of Bb and Ct DNA in the synovial fluid of patients with UOA. Although the presence of bacterial DNA does not unequivocally prove its etiologic significance, we suggest that at least one-third of patients with UOA may have a form of ReA that involves asymptomatic primary infection.

Viruses can escape T-cell surveillance by infecting macrophages and thereby induce apoptosis of noninfected T cells. This ability had not been demonstrated for bacteria. We investigated whether infection of macrophages with the important human pathogenChlamydia trachomatiscan induce T-cell apoptosis. BecauseChlamydia-Mycoplasmacoinfection is a frequent event, the ability ofMycoplasma fermentans-infected macrophages to induce T-cell apoptosis was also studied. Infected macrophages were cocultivated with autologous T cells in different activation states. Propidium iodide-based fluorescence-activated cell sorter analysis demonstrated that macrophages infected with viable chlamydiae induced T-cell death. Apoptosis was identified as the mode of death induction by using a terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling assay. Induction of T-cell death was macrophage dependent. Incubation of T cells with infectious chlamydiae in the absence of macrophages did not lead to T-cell apoptosis. UV irradiation of chlamydiae diminished the ability to induce death. T-cell death was induced by a cell-free supernatant of infected macrophages. Not only phytohemagglutinin-preactivated T cells but also non-mitogen-preactivated T cells were susceptible toC. trachomatis-induced apoptosis. In contrast,M. fermentansinfection of macrophages did not induce T-cell death. Coinfection had no additional effect. In summary, intracellular chlamydial infection of macrophages can induce T-cell apoptosis. Apoptosis induction by chlamydiae possibly explains how persistently infected macrophages escape T-cell surveillance and why theChlamydia-specific T-cell response is diminished during persistent chlamydial infection.

Several strains of Chlamydia trachomatis (CT) and C. pneumoniae (CP) from different sources were screened for mycoplasma contamination using a sensitive nested 16S rDNA polymerase chain reaction-specific for a broad range of mycoplasma species. Five of nine CT and 5/16 CP isolates were contaminated by mycoplasma. Mycoplasma fermentans, M. hyorhinis and M. hominis were found as contaminating agents. To our knowledge no data are available on whether coinfection of chlamydia with mycoplasma alters the biological behavior of chlamydia. Analysis of the biological effect of mycoplasma on chlamydial infection showed a profound mycoplasma-induced reduction of chlamydial growth. Mycoplasma were efficiently eliminated from chlamydial cultures in HEp-2 cells by treatment with mupirocin without affecting chlamydial replication or host cell growth. Two chlamydial strains, C. trachomatis serovar K and one clinical isolate of C. pneumoniae were purged by this method.

by Moll et al. [2] the school of ‘lumpers’, who preferred Infection of the urogenital or gastrointestinal tract to group the so-called ‘variants of rheumatoid arthritis’ Alteration of the skin (psoriasiform skin or nail lesion, with rheumatoid arthritis itself, were overcome by the erythema nodosum) school of ‘splitters’, prompted by the idea that these Buccal ulceration of the mouth, small or large intestine and seronegative arthritides were, in fact, entirely separate urogenital tract Thrombophlebitis entities. This change was mirrored by the Nomenclature Pyoderma gangraenosum and Classification of the Rheumatic Diseases proposed Familial aggregation by the American Rheumatism Association in 1963 [1]. Association with HLA-B27 Rheumatoid arthritis, juvenile Still’s disease, ankylosing spondylitis, psoriatic arthritis, and Reiter’s syndrome 1. The term seronegative arthritis still survives and is were then classified under separate headings with the not completely out of use, which may be illustrated common denominator ‘polyarthritis of unknown origin’. by the fact that the Editor of this journal initially

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclo-oxygenase (COX), which leads to suppression of COX-1-mediated production of gastrointestinal-protective prostaglandins. Gastrointestinal injury is a common outcome. We compared the efficacy, safety, and tolerability of long-term therapy with celecoxib, a COX-1 sparing inhibitor of COX-2, with diclofenac, a non-specific COX inhibitor.655 patients with adult-onset rheumatoid arthritis of at least 6 months' duration were randomly assigned oral celecoxib 200 mg twice daily or diclofenac SR 75 mg twice daily for 24 weeks. Anti-inflammatory and analgesic activity and tolerability were assessed at baseline, every 4 weeks, and at week 24. We assessed gastrointestinal safety by upper-gastrointestinal endoscopy within 7 days of the last treatment dose at centres where the procedure was available. Analysis was by intention-to-treat.430 patients underwent endoscopy (celecoxib n=212, diclofenac n=218). The two drugs were similar in management of rheumatoid arthritis pain and inflammation. Gastroduodenal ulcers were detected endoscopically in 33 (15%) patients treated with diclofenac and in eight (4%) in the celecoxib group (p0.001). The rate of withdrawal for any gastrointestinal-related adverse event, most commonly abdominal pain, diarrhoea, and dyspepsia, was nearly three times higher in the diclofenac-treated group than in the celecoxib group (16 vs 6%; p0.001).Celecoxib showed sustained anti-inflammatory and analgesic activity similar to diclofenac, with a lower frequency of upper gastrointestinal ulceration or gastrointestinal adverse events, and tolerability was better.

A role for bacterial infection in the aetiology of inflammatory arthritis has been suspected for many years. Yet over that relatively long period of time only a few acute or chronic arthritides have been unequivocally linked to an infectious agent; these include septic arthritis, rheumatic fever, and, more recently, Lyme arthritis. The term reactive arthritis was first introduced to describe the association between Yersinia enterocolitica infection and arthritis, and it was intended to differentiate this form of acute, non-suppurative arthritis, which is characterised by negative joint culture, from infectious, purulent arthritis; the differentiation was meant to suggest an underlying sterile immune mediated pathomechanism.1 A few years later, immediately after discovery of the association between HLA-B27 and ankylosing spondylitis and Reiter’s syndrome, the term reactive arthritis was also related to this genetic marker; at this time the term was more strictly applied to the HLA-B27 associated reactive arthritides, following infections with enterobacteria and chlamydia.2 This concept has been widely recognised and accepted. However, non-HLA-B27 associated arthritides, such as Lyme disease induced by Borrelia burgdorferi , Neisseria gonorrhoeae induced reactive arthritis, post-streptococcal reactive arthritis, and rheumatic fever are viewed presently as reactive arthritides (see table1 for the spectrum of bacterial species triggering reactive arthritis). This inclusion is based on the observation that these arthritides also develop after a primary extra-articular infection, and that despite negative culture results, the organisms can be detected in the joint (for example, Borrelia ,7 Neisseria 9). View this table: Table 1 Bacteria triggering reactive arthritis–manifestations at the entry site (see references3–11,23,29,34) This brief historical outline demonstrates not only the changing definition of “reactive arthritis” over time, but also illuminates the lack of general consensus concerning the precise clinical and scientific conditions to which this term should be …

Objective Disease activity has been defined using a self-administered instrument, focusing on fatigue, axial pain, peripheral pain, enthesopathy and morning stiffness [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)]. This validated instrument is simple and takes 40 s to complete, but whether the index is an accurate expression of the component parts, or whether additional weighting would enhance its efficacy, is unclear. Methods Four hundred and seventy-three patients with ankylosing spondylitis received placebo or active non-steroidal anti-inflammatory drug (NSAID) for 6 weeks, and changes between entry and completion were captured by BASDAI and the individual components. Principle component analysis (PCA) was used to explore the best combinations of variables in decreasing order of explained total dispersion and to assess whether a single sum (or algebraic expression) best defined disease activity status. Results At entry, the correlation between BASDAI and the first axis was 0.99, 0.11 with the second, and zero thereafter. Data at study end and relating to change revealed a 100% correlation (R = 1) between the first axis and the sum, with zero for the remainder. Conclusions The data support BASDAI as being a valid and appropriate composite to define disease activity in ankylosing spondylitis. Developed as a simple sum of its components, BASDAI has excellent content validity.