[Tight control-Demand for short term control of rheumatoid arthritis]. / "Tight control" ­ Forderung nach engmaschiger Kontrolle der rheumatoiden Arthritis.

The prognosis of rheumatoid arthritis (RA) has been significantly improved in recent decades. This is mainly due to earlier detection, better diagnostics and new treatment options, such as the optimized use of classical disease-modifying antirheumatic drugs (DMARD) and biologicals. Other factors involved were earlier intervention, improved availability of information and analyses and certainly also standardization of care (e.g. guidelines). An additional important component is close monitoring of disease activity in order to be able to adapt the treatment in a timely manner and thus prevent damage. The demand for tight control is the subject of this article.

[Higher prevalence of depressive and anxiety symptoms in early arthritis patients in comparison to the normal population]. / Höhere Prävalenz von depressiven und ängstlichen Symptomen bei Früharthritispatienten im Vergleich zur Normalbevölkerung.

BACKGROUND: Many studies and registry data confirm that depression, often associated with anxiety disorders is very often found in patients with rheumatoid arthritis (RA). To what extent these psychiatric disorders are already relevant at a very early stage of the disease, has currently not been adequately investigated. METHODS: In this study 176 patients with early joint symptoms (<1 year) were surveyed in an early arthritis consultation (EAC). The hospital anxiety and depression scale (HADS) was completed by the patients to examine the prevalence of depressive and anxiety symptoms. The results were compared to normative data of the general German population and between the diagnosis groups. RESULTS: With 47.7% the prevalence of global distress for EA patients was almost twice as high compared to the corresponding group from the general population. This was also confirmed for depressive and anxiety symptoms. The EA patients without confirmed evidence of musculoskeletal inflammatory rheumatic disease (RD) showed nearly the same point prevalence as patients with confirmed RD. In multiple logistic regression the health assessment questionnaire (HAQ) was positively associated with global distress (odds ratio, OR 3.63) while the visual analogue scale (VAS) for global disease activity was positively associated with symptoms of depression (OR 1.03). Female EA patients (OR 5.45) appear to have a higher probability for experiencing corresponding symptoms, whereas patients over 60 years old appear to have less anxiety than younger patients (OR 0.11). CONCLUSION: The high prevalence of symptoms of depression and anxiety in EA patients compared to the general population is a challenge for rheumatologists, orthopedists and general practitioners, particularly with respect to the differentiation of possible psychosomatic components in noninflammatory joint complaints. The results suggest that screening for psychiatric problems in patients with rheumatism should be evaluated as soon as possible as these can have a great impact on the perception of pain and physical functional status from the very beginning.

[Tips and tricks in court-Practical experience from a medical viewpoint]. / Tipps und Tricks vor Gericht ­ Praktische Erfahrungen aus ärztlicher Sicht.

When it comes to legal aspects and doctors have to go to court, most likely they will serve as an expert or regular witness or as a defendant in a civil litigation in case of recourse claims and only rarely as defendants in a criminal case. With the exception of expert testimonies by seasoned physicians, this is not usually an easy situation. This article addresses important aspects of the preparation for a trial and its procedures. If appropriately prepared, and if necessary represented by a good attorney, these sometimes emotionally stressful situations can be mastered quite well.

[Biomarkers and imaging for diagnosis and stratification of rheumatoid arthritis and spondylarthritis in the BMBF consortium ArthroMark]. / Biomarker und Bildgebung zur Diagnose und Stratifizierung der rheumatoiden Arthritis und Spondylarthritis im BMBF-Verbund ArthroMark.

Rheumatic diseases are among the most common chronic inflammatory disorders. Besides severe pain and progressive destruction of the joints, rheumatoid arthritis (RA), spondyloarthritides (SpA) and psoriatic arthritis (PsA) impair working ability, reduce quality of life and if treated insufficiently may enhance mortality. With the introduction of biologics to treat these diseases, the demand for biomarkers of early diagnosis and therapeutic stratification has been growing continuously. The main goal of the consortium ArthroMark is to identify new biomarkers and to apply modern imaging technologies for diagnosis, follow-up assessment and stratification of patients with RA, SpA and PsA. With the development of new biomarkers for these diseases, the ArthroMark project contributes to research in chronic diseases of the musculoskeletal system. The cooperation between different national centers will utilize site-specific resources, such as biobanks and clinical studies for sharing and gainful networking of individual core areas in biomarker analysis. Joint data management and harmonization of data assessment as well as best practice characterization of patients with new imaging technologies will optimize quality of marker validation.

[Adult onset Still's disease with small vessel vasculitis]. / Adulter Morbus Still mit Kleingefäßvaskulitis.

This article presents a particularly severe case of adult onset Still's disease aggravated by small vessel vasculitis. A satisfactory therapy was concluded 1.5 years after onset of the disease. The small vessel vasculitis was difficult to treat: methotrexate (MTX), cyclophosphamide and rituximab were not sufficiently effective. Tocilizumab in combination with intravenous immunoglobulin (IVIG) induced remission and maintenance therapy was carried out with tocilizumab.

Which spinal lesions are associated with new bone formation in patients with ankylosing spondylitis treated with anti-TNF agents? A long-term observational study using MRI and conventional radiography.

OBJECTIVE: To study the relationship of spinal inflammation and fatty degeneration (FD) as detected by MRI and new bone formation seen on conventional radiographs (CRs) in ankylosing spondylitis (AS). METHODS: CRs at baseline, 2 years and 5 years and spinal MRIs at baseline and 2 years of 73 AS patients treated with infliximab in European AS Infliximab Cohort were available. Relative risks (RR) were calculated with a general linear model after adjustment for within-patient variation. RESULTS: In a total of 1466 vertebral edges (VEs) without baseline syndesmophytes, 61 syndesmophytes developed at 5 years, the majority of which (57.4%) had no corresponding detectable MRI lesions at baseline. VEs with both inflammation and FD at baseline had the highest risk (RR 3.3, p=0.009) for syndesmophyte formation at 5 years, followed by VEs that developed new FD or did not resolve FD at 2 years (RR=2.3, p=0.034), while inflammation at baseline with no FD at 2 years had the lowest risk for syndesmophyte formation at 5 years (RR=0.8). Of the VEs with inflammation at baseline, >70% resolved completely, 28.8% turned into FD after 2 years, but only 1 syndesmophyte developed within 5 years. CONCLUSIONS: Parallel occurrence of inflammation and FD at baseline and development of FD without prior inflammation after 2 years were significantly associated with syndesmophyte formation after 5 years of anti-tumour necrosis factor (TNF) therapy. However, the sequence 'inflammation-FD-new bone formation' was rarely observed, an argument against the TNF-brake hypothesis. Whether an early suppression of inflammation leads to a decrease of the risk for new bone formation remains to be demonstrated.

[Phase IV non-interventional studies in the treatment of rheumatoid arthritis with biologicals in Germany : real-life clinical practice data]. / Nichtinterventionelle Phase-IV-Studien zur Behandlung der rheumatoiden Arthritis mit Biologicals in Deutschland : Praxisbezogene klinische Daten.

BACKGROUND: In contrast to the restrictive nature of randomised controlled trials (RCT), non-interventional studies (NIS) investigate the features of a therapy in daily clinical practice. The observational plan of NIS does not dictate a treatment strategy, but is based on the product label. Unlike RCT, NIS therefore have no actual inclusion and exclusion criteria, allowing the study of broad heterogeneous patient populations. METHODS: NIS carried out in Germany with support from the pharmaceutical industry and investigating the use of biologics for the treatment of rheumatoid arthritis were identified and their findings were compared with those from the RCT of the respective biologic. RESULTS: Analysis of the identified NIS revealed the following: (1) populations in NIS were on average more than twice as large as in RCT, (2) patient characteristics in NIS and RCT were different, (3) the effectiveness of biologics in NIS was comparable to the efficacy observed in RCT, and (4) NIS collected supplementary data, e.g. on usage and dosing in clinical practice. CONCLUSION: NIS represent an important tool for the assessment of daily clinical practice. Despite methodological drawbacks, NIS provide valuable data that contribute to a more complete picture of the value of treatment with biologics. The English version of this article is available at SpringerLink (under "Supplemental").

[Rheumatoid factor or antinuclear antibodies as incidental finding]. / Positiver Rheumafaktor oder positive ANA als Zufallsbefund.

Rheumatoid factor and antinuclear antibodies are detectable in many different conditions and are ordered by various specialities. The interpretation of results, however, is quite complex.The objective of this article is to help apply these tests correctly and enable an accurate interpretation of the test results. Furthermore, we describe the steps in the differential diagnostics for selecting those patients who need to be referred to a rheumatologist.

[Biomarkers and personalized medicine]. / Biomarker und personalisierte Medizin.

Biomarkers form the basis for patient stratification and the development of individualized treatment strategies. As the understanding of the pathophysiological processes underlying rheumatic diseases increases, novel biomarkers will become available and established markers can be used more efficiently. Autoantibodies in rheumatoid arthritis (RA), for example, define a subgroup of patients with a specific risk profile and response to therapy. For this reason they have been added to the classification criteria for RA and are part of current treatment guidelines. In addition, novel markers are being evaluated and validated. For the concept of personalized medicine this indicates that the use of future therapeutic substances will be more frequently coupled to the detection of specific biomarkers. While this will decrease the number of patients who become eligible for certain treatments, it will increase efficacy and safety for patients and potentially the cost-effectiveness.

[New aspects on the pathogenesis of myositis]. / Neues zur Pathogenese der Myositiden.

Idiopathic inflammatory myopathies (IIM) are chronic inflammatory diseases of muscle characterized by proximal muscle weakness. There are three main groups of diseases, dermatomyositis, polymyositis and inclusion body myositis. The muscle tissue is invaded by the humoral autoantibody producing immune system (B-cells) and by the cellular immune system with autoaggressive and inflammation modulating cells (e.g. dendritic cells, monocytes/macrophages, CD4 + and CD8 + T-cells and natural killer cells). The presence of specific or associated autoantibodies and inflammatory cellular infiltrates with cytotoxic and immune autoreactive properties are characteristic for IIM diseases. The pathogenesis is still unknown; nevertheless, there are several hints that exogenic factors might be involved in initiation and disease progression and bacterial, fungal and viral infections are thought to be possible initiators. Up to now information on prognostic markers to help with decision-making for individual treatment are limited. In addition, there has been only limited therapeutic success including conventional or novel drugs and biologicals and comparative validation studies are needed using similar outcome measurements. Moreover, to facilitate the use and development of novel therapies, elaboration of intracellular and cell-specific regulation could be useful to understand the etiopathogenesis and allow a better diagnosis, prognosis and possibly also a prediction for individualized subgroup treatment.

[Anticytokine therapy]. / Antizytokintherapie.

Anticytokine therapies have revolutionized the treatment of chronic inflammatory diseases, particularly autoimmune diseases such as rheumatoid arthritis. As the first introduced principle of cytokine blockade in the 1990s, tumor necrosis factor (TNF)-α antagonists still represent the leading anticytokine therapy. There are currently five TNF antagonists available with indications in the fields of rheumatology, dermatology, and gastroenterology. Other therapeutic approaches have been introduced in the last 10 years, e.g., the blockade of interleukin (IL)-1, IL-6, and IL-12/23. The advantages of cytokine blockers are their rapid onset of action with high response rates and a tolerable safety profile. Nevertheless, anticytokine therapy can cause increased rates of tuberculosis and hepatitis B infections or reactivation. An appropriate screening before therapy is mandatory, and thorough monitoring of the disease course before and during therapy is also important. The development of further anticytokine drugs for the induction and maintenance of remission is, therefore, required.

Quantification of periarticular demineralization and synovialitis of the hand in rheumatoid arthritis patients.

UNLABELLED: The bone mineral density (BMD) measurement of the hand in rheumatoid arthritis (RA) patients is no standard measurement method as yet. The aim was to contribute to the standardization of the hand BMD measurement, especially of periarticular regions. As results, we found best precision values for the wrist and a significant correlation between hand and spine/femur BMD depending on disease activity and disease duration. INTRODUCTION: This study was conducted to investigate (i) the precision of periarticular hand BMD measuring, (ii) the periarticular demineralization of the hand, (iii) the correlation between periarticular hand BMD and spine/femur BMD, and (iv) the correlation of hand BMD to hand synovitis. METHODS: A number of 52 RA patients were examined by BMD measurement of the femoral neck, spine, whole hand, metacarpophalangeal (MCP) joints II-V, personal identity profile (PIP) joints II-V, and wrist using dual-energy X-ray absorptiometry (DXA). Synovitis of the hand was examined by ultrasonography and magnetic resonance imaging (MRI). Three subgroups were further analyzed: early RA, established RA with moderate and with high disease activity. Early RA and established RA patients with high disease activity were Followed up after 12 months. RESULTS: We found (1) best precision of BMD measurement for the wrist, (2) BMD in RA significantly reduced if compared to normal controls, (3) a highly significant positive correlation between hand and spine/femur BMD and the power of correlation to depend on disease activity and disease duration (high correlation in RA with moderate disease activity and early RA, very high correlation in RA with high disease activity), (4) a negative correlation between hand BMD and hand synovitis in RA with high disease activity, and (5) a significant reduction of synovitis but no change in hand BMD after 12 months, respectively. CONCLUSIONS: This study shows a highly significant correlation between hand BMD and spine/femur BMD in RA patients depending on disease activity and disease duration. We conclude to measure BMD at different sites including hands in order to quantify bone loss in RA patients most properly.

Toward a data-driven evaluation of the 2010 American College of Rheumatology/European League Against Rheumatism criteria for rheumatoid arthritis: is it sensible to look at levels of rheumatoid factor?

OBJECTIVE: Recently, new classification criteria for rheumatoid arthritis (RA) have been devised by methodology that used first a quantitative approach (data from databases), then a qualitative approach (consensus; based on paper patients), and finally a common sense-based approach (evaluation of the former phases). Now the individual items that make up these criteria are being evaluated. This study was undertaken to analyze the item "autoantibodies," in particular rheumatoid factor (RF) level. METHODS: Three separate cohorts comprising a total of 972 patients with undifferentiated arthritis were studied for RA development (according to the 1987 American College of Rheumatology criteria) and arthritis persistence. The positive predictive value (PPV), negative predictive value (NPV), and likelihood ratios (LRs) were compared between different levels of RF and the presence of anti-citrullinated protein antibody (ACPA). A similar comparison was made in 686 RA patients for the rate of joint destruction and achievement of sustained disease-modifying antirheumatic drug-free remission during 7 years of followup. The variation in RF levels obtained by different measurement methods in the same RF-positive sera was explored. RESULTS: Compared to high RF levels, presence of ACPA had a better balance between positive LR and negative LR and between PPV and NPV for RA development. The additive value of ACPA assessment after testing for RF level was higher than vice versa. The association between high RF level and RA severity was not as strong as that between ACPA antibodies and RA severity. The RF level obtained by different methods in the same patients' sera varied considerably. CONCLUSION: Our findings indicate that determination of RF level is subject to large variation; high RF level has limited additive prognostic value compared to ACPA positivity. Thus, omitting RF level and using RF presence, ACPA presence, and ACPA level may improve the 2010 criteria for RA.

[Biomarkers in rheumatology. Biomarkers and imaging for the diagnosis and stratification of rheumatoid arthritis and spondylarthritis in the ArthroMark network funded by the Federal Ministry of Education and Research]. / Biomarker in der Rheumatologie. Biomarker und Bildgebung zur Diagnose und Stratifizierung der rheumatoiden Arthritis und Spondylarthritis im BMBF-Verbund ArthroMark.

The introduction of biologics has continuously increased the demand for biomarkers for early diagnosis and therapeutic stratification. ArthroMark, a research network funded by the Federal Ministry of Education and Research, aims to establish such biomarkers for rheumatoid arthritis and spondyloarthritides. Biobanks and previous work on genotyping, gene expression and autoreactivity profiling build the basis. Bioinformatic networks will help to harmonize the investigations and a clinical study with modern imaging techniques to characterize the functional relevance of the new biomarkers as effectively as possible. To validate the markers for diagnostic application the network aims to expand gradually.

Effects of etanercept versus sulfasalazine in early axial spondyloarthritis on active inflammatory lesions as detected by whole-body MRI (ESTHER): a 48-week randomised controlled trial.

PURPOSE: To evaluate the potential of etanercept versus sulfasalazine to reduce active inflammatory lesions on whole-body MRI in active axial spondyloarthritis with a symptom duration of less than 5 years. METHODS: Patients were randomly assigned to etanercept (n=40) or sulfasalazine (n=36) treatment over 48 weeks. All patients showed active inflammatory lesions (bone marrow oedema) on MRI in either the sacroiliac joints or the spine. MRI was performed at weeks 0, 24 and 48 and was scored for active inflammatory lesions in sacroiliac joints and the spine including posterior segments and peripheral enthesitis by two radiologists, blinded for treatment arm and MRI time point. RESULTS: In the etanercept group, the reduction of the sacroiliac joint score from 7.7 at baseline to 2.0 at week 48 was significantly (p=0.02) larger compared with the sulfasalazine group from 5.4 at baseline to 3.5 at week 48. A similar difference in the reduction of inflammation was found in the spine from 2.2 to 1.0 in the etanercept group versus from 1.4 to 1.3 in the sulfasalazine group between baseline and week 48, respectively (p=0.01). The number of enthesitic sites also improved significantly from 26 to 11 in the etanercept group versus 24 to 26 in the sulfasalazine group (p=0.04 for difference). 50% of patients reached clinical remission in the etanercept group versus 19% in the sulfasalazine group at week 48. CONCLUSION: In patients with early axial spondyloarthritis active inflammatory lesions detected by whole-body MRI improved significantly more in etanercept versus sulfasalazine-treated patients. This effect correlated with a good clinical response in the etanercept group.

Subset size, activation threshold and distribution of autoreactive MZ and FO B cells do not differ in a sex-specific manner in the NZB/W F1 murine lupus model: an experimental mouse study.

OBJECTIVES: Systemic lupus erythematosus (SLE) shows a strong sex bias, preferentially affecting females, and B cells are thought to play a pivotal role in its pathogenesis. Here, we compared the splenic B-cell compartments, their autoreactivity and activation threshold of female and male NZB/W F1, a murine lupus model reflecting the sex bias observed in patients with SLE. METHODS: Autoantibody levels and the amount of autoantibody secreting cells were determined using ELISA and ELISPOT. Flow cytometry and immunofluorescence were applied to analyse the composition of the splenic B-cell pool. Purified follicular (FO) and marginal zone (MZ) B cells were stimulated and the frequency of autoreactive cells was determined. Finally, the proliferative response of FO and MZ B cells upon stimulation was assessed using CFSE dilution and [(3)H]-Thymidin incorporation. RESULTS: Higher autoantibody titres were detected in female NZB/W F1 mice, which were mainly produced in the spleen. Analysing the composition of the splenic B-cell subsets, no differences were found prior to disease development. Autoreactive dsDNA-specific B cells were mostly found in the MZ compartment, while SmD1((83-119))-reactive cells were more evenly distributed. Equal frequencies of autoreactive B cells were found in female and malemice, and no difference in the response to polyclonal stimuli of the cells of both sexes was detected. CONCLUSIONS: No differences in the composition or functionality of splenic B cells were observed that account for the different disease course in both sexes.

CTLA-4 (CD152) blockade does not cause a pro-inflammatory cytokine profile in regulatory T cells.

OBJECTIVES: The activation of T cells is closely regulated. One cell intrinsic mechanism is based on the expression of inhibitory molecules; another is mediated by regulatory T (Treg) cells. The co-regulatory molecule CTLA-4 is constitutively expressed by Treg cells and up-regulated in effector-T-cells after activation. Recently, it was described that Treg cells can display an unstable phenotype and convert into pathogenic pro-inflammatory cytokine secreting cells. Here we have analysed the role of CTLA-4 in the regulation of cytokine production by T-helper (Th) cells with a special focus on Treg cells. METHODS: Proliferation of unstimulated CTLA-4 knock-out and wild-type cells as well as their activation status and the impact of CTLA-4 blockade on proliferation of Treg and effector T cells under stimulation were analysed by flow cytometry. Furthermore, the cytokine concentrations were analysed by a multiplex suspension assay. RESULTS: CTLA-4 knock-out T cells proliferated without stimulation and displayed an activated phenotype ex vivo. Proliferation of effector but also that of Treg cells was controlled by CTLA-4. The blockade of CTLA-4 led to an increased secretion of GM-CSF, IL-1ß, IL-2, and IFN-γ by Th cells. However, the blockade of CTLA-4 in Treg cells did not cause any conversion into pathogenic pro-inflammatory T cells, since the non-cytokine secreting phenotype remained unchanged. CONCLUSIONS: These results have major implications on therapies targeting the CTLA-4-system, e.g. by CTLA4-Ig or anti-CTLA-4-antibodies, as the blockade of CTLA-4 did not unlock the stability of Treg cells.