Classification of systemic lupus erythematosus in children and adults.

Systemic Lupus Erythematosus (SLE) is an autoimmune multisystem disease with a variable clinical phenotype and no single clinical, laboratory or pathological feature that can be used as a gold standard for disease classification or diagnosis. Classification criteria have been developed in an attempt to define homogenous groups of SLE patients for clinical research. They have been mainly validated in adult cohorts, given the much lower prevalence of SLE before puberty. The three commonly used sets of current classification criteria and their validation studies to date are described in this review. Challenges relating to classification of SLE patients, including important differences across age-groups and ethnicities, are explored along with future directions in the classification of SLE.

[Development of quality standards for patients with rheumatoid arthritis for use in Germany]. / Entwicklung von Qualitätsstandards für die Versorgung von Patient*innen mit rheumatoider Arthritis zur Anwendung in Deutschland.

Despite a qualitatively and structurally good care of patients with rheumatoid arthritis (RA) in Germany, there are still potentially amendable deficits in the quality of care. For this reason, the German Society for Rheumatology (DGRh) has therefore decided to ask a group of experts including various stakeholders to develop quality standards (QS) for the care of patients with RA in order to improve the quality of care. The QS are used to determine and quantitatively measure the quality of care, subject to relevance and feasibility. The recently published NICE and ASAS standards and a systematic literature search were used as the basis for development. A total of 8 QS, now published for the first time, were approved with the intention to measure and further optimize the quality of care for patients with RA in Germany.

Mission statement from rheumatologists in the German Society of Rheumatology (DGRh e. V.) : We live rheumatology.

Systemic disease demands systemic thinkers. In this mission statement we define rheumatology, describe the role of the German Society of Rheumatology and the rheumatologist's spirit to their discipline. Rheumatologists are dedicated to improving the quality of life of their acute, chronic, and rehabilitative patients on the basis of up to date evidence and strong physician-patient relations. We think, act and interact systemically, scientifically, consistently, transparently, reliably, inclusively, innovatively and enthusiastically.

[Rheumatology in German MD curricula]. / Rheumatologie im Medizinstudium.

Transmitting a substantial amount of basic knowledge in Rheumatology to all medical students is essential for the future medical care of patients with rheumatic diseases for two reasons: on the one hand, future general practitioners will need to master the patterns of rheumatic diseases to recognize them fast enough in new-onset patients and to refer them in time and directly to rheumatologists. On the other hand, the shortage of rheumatologists can only then be relieved in the future when we are able to inspire enthusiasm for our specialty. Adequate rheumatological structures are established only in some of the German faculties of medicine. Structural improvements happen in small steps only but were achieved at several sites. The better the local structures, the higher the chances of committed university teachers in rheumatology to reach all medical students. Probably from 2026 onwards, the learning objectives relevant for examinations will be defined by the national competence-based catalogue of learning objectives in medicine (NKLM), which is currently in the final stages of completion together with the German Federal Institute for Medical and Pharmaceutical Examinations (IMPP). It now appears that systemic autoimmune diseases and inflammatory rheumatic diseases are adequately depicted in this catalogue. If this is achieved, students will know more about these diseases in the future and will diagnose them faster in patients. Work on the NKLM is therefore of highest importance. In addition to the work on the learning objectives, up to date learning materials are required, which have to be available throughout Germany. A Rheumatology script just finished by the committee for medical student education of the German Society of Rheumatology (DGRh) and now available on the DGRh homepage should close this gap.

[Mission statement from rheumatologists in the German Society of Rheumatology (DGRh e. V.) : We live rheumatology. German version]. / Leitbild der Rheumatologinnen und Rheumatologen in der Deutschen Gesellschaft für Rheumatologie e. V. (DGRh e. V.) : Wir sind die Rheumatologie.

Systemic disease demands systemic thinkers. In this mission statement we define rheumatology, describe the role of the German Society of Rheumatology and the rheumatologist's spirit to their discipline. Rheumatologists are dedicated to improving the quality of life of their acute, chronic, and rehabilitative patients on the basis of up to date evidence and strong physician-patient relations. We think, act and interact systemically, scientifically, consistently, transparently, reliably, inclusively, innovatively and enthusiastically.

[Biologicals and small molecules for systemic lupus erythematosus]. / Biologika und "small molecules" beim systemischen Lupus erythematodes.

Targeted treatment is a rheumatologist's dream, which, with the advent of biologicals and more recently small molecules, has become true for rheumatoid arthritis and is about to translate into reality for systemic lupus erythematosus (SLE). Belimumab, the first biological approved for SLE, is now also available in a subcutaneous formulation. It is notable that this drug achieved the primary endpoint in four independent trials and demonstrated substantial reduction of organ damage accrual. The B cell depletion with antibodies against CD20 remains clinically relevant and of interest for future developments and the combination of both approaches (belimumab and anti-CD20) is an exciting idea. Blockade of the type I interferon receptor with anifrolumab was effective in a phase 3 trial and blocking interleukin-12 and interleukin-23 with ustekinumab is currently being tested in a phase 3 clinical trial. The old ideas of blocking tumor necrosis factor (TNF) and interleukin­6 have also not yet been forgotten. More novel approaches comprise Janus kinase (Jak) inhibition with positive phase 2 data for baricitinib and soon inhibition of Bruton's tyrosine kinase (BTK) as well as proteasome inhibitors. The treatment of SLE could therefore soon become much more varied.

[Future of rheumatologists: what are the perspectives? : Survey of resident physicians in rheumatology in middle Germany]. / Rheumatologin/Rheumatologe in spe: Wie geht es weiter? : Befragung der rheumatologischen Assistenzärzte und -ärztinnen in Mitteldeutschland.

BACKGROUND AND OBJECTIVE: The work environment for rheumatologists has significantly changed over the last years. The healthcare of patients with rheumatic diseases is at risk due to the age structure of specialized rheumatologists in middle Germany and the limited availability of training positions for rheumatologists. In this context, it is important to have detailed information on the resident physicians in rheumatology concerning their own visions regarding their future professional career. MATERIAL AND METHODS: A questionnaire was sent to resident physicians in 25 rheumatology training hospitals in the middle of Germany (Saxony, Saxony-Anhalt and Thuringia). The questionnaire was completed and returned by 27 participants (17 women and 10 men). RESULTS: Most of the participants (60%) aimed to qualify as a specialist in internal medicine followed by a specialization in rheumatology (altogether training for a minimum of 8 years). After finishing training 44% would prefer to work in an outpatient setting while 30% planned to work in a combined outpatient and clinical setting. Of the participants 48% would prefer to work as part-time rheumatologists and 74% (women 94% and men 40%) were interested in employment in an outpatient medical healthcare center. The compatibility of family and work as well as the work-life balance was considered to be highly relevant for the future professional life. CONCLUSION: Less than half of the participants intended to work exclusively in an outpatient setting after completing the training in rheumatology. In addition, the participants preferred a part-time employment with compatibility of professional and private life. Consequently, alternative models of employment should be created in rheumatology to be attractive for future physicians. On the other hand, the study revealed that the independent rheumatological practice has a lower priority for the young rheumatologists taking part in this survey.

[Immunology of systemic inflammatory diseases]. / Immunologie der entzündlichen Systemerkrankungen.

BACKGROUND: Inflammatory rheumatic diseases are generally systemic diseases resulting from immune system dysfunction. METHODS: Relevant pathophysiological processes in the immune system are discussed using laboratory results and autoantibody tests, as well as in terms of new drugs in particular. Furthermore, an immunologically focused overview of clinically relevant approaches is presented. RESULTS: The pathophysiological role of both T and B lymphocytes as well as that of autoantibodies demonstrates that diseases such as rheumatoid arthritis (RA), connective tissue diseases, and vasculitides are autoimmune diseases. While tumor necrosis factor is apparently involved in many entities, other cytokines differentiate between RA (interleukin-6, IL-6) and spondylarthritides (IL-17, IL-23). In contrast, in crystal arthritides, IL-1 appears essential.

[The S2k guideline: Indications for knee endoprosthesis : Evidence and consent-based indications for total knee arthroplasty]. / S2k-Leitlinie: Indikation Knieendoprothese : Evidenz- und konsensbasierte Indikationsstellung in der Knie-Endoprothetik (EKIT-Knie).

Total knee arthroplasty (TKA) is one of the most frequent surgical procedures in orthopaedic surgery. Until now there have not been any standardized indication criteria, which might contribute to the large geographical differences in the frequency of TKA. This guideline aims to consent minimal requirements (main criteria), additional important aspects (minor criteria), as well as relative and absolute contraindications for TKA. The following main criteria have been consented: knee pain, radiological confirmation of osteoarthritis or osteonecrosis, inadequate response to conservative treatment, adverse impact of knee disease on the patient's quality of life and the burden of suffering due to the knee disease. Relative contraindications have been consented as severe general disease with reduced life expectancy and a BMI ≥40; absolute contraindications are an active infection and if the patient is not able to undergo major surgery.

Early symptoms of systemic lupus erythematosus (SLE) recalled by 339 SLE patients.

Objective The European League Against Rheumatism and the American College of Rheumatology jointly embarked on a new classification criteria for systemic lupus erythematosus (SLE) project. Its first phase involved generation of a broad set of items potentially useful for classification of SLE. This study was undertaken to add the patient perspective to an expert Delphi approach and an early patient cohort study. Methods A national cross-sectional study was conducted. A self-report questionnaire was published in the "Schmetterling" (Butterfly), the quarterly journal of the German SLE patient association. Individuals with SLE were asked to anonymously complete the questionnaire, which asked for demographic details, organ manifestations, autoantibodies and symptoms. Results A total of 339 completed questionnaires out of 2498 were returned, a response rate of 13.6%; 83.2% reported they were ANA positive and 81.7% reported joint, 66.1% skin and 33.0% renal involvement. For the time before and in the first year after their SLE diagnosis, the majority reported fatigue (89.4%), joint pain (86.7%), photosensitivity (79.4%) and myalgia (76.1%). Of interest, more than half of the patients reported fever as an early symptom (53.7%). Conclusion For a Caucasian European SLE patient population, the overall characteristics suggest meaningful representation. While many symptoms were reported as expected, the high percentage of patients reporting fever and the significant number of patients with unexpected gastrointestinal complaints are of particular interest. These data add to the information on early SLE symptoms informing the development process of new SLE classification criteria.

[Safety and efficacy of off-label use of biologic therapies in patients with inflammatory rheumatic diseases refractory to standard of care therapy : Data from a nationwide German registry (GRAID2)]. / Sicherheit und Wirksamkeitshinweise zum Off-label-Einsatz von Biologikatherapien nach Versagen konventioneller Therapien bei Patienten mit entzündlich rheumatischen Erkrankungen : Ergebnisse eines nationalen Registers (GRAID2).

BACKGROUND: The German Registry of Autoimmune Diseases 2 (GRAID2) is a retrospective, non-interventional, multicenter registry study collecting data from patients with inflammatory, mainly rheumatic diseases refractory to standard of care therapy and treated with an off-label biologic therapy. The retrospective documentation comprised case history, diagnosis, course of disease (including safety and global efficacy). The objective was to evaluate the global clinical outcome and safety of off-label biologic therapy in clinical practice. RESULTS: Data from 311 patients with an overall observation period of 338.5 patient-years were collected. The mean patients age was 47.8 years with 56.9% females. The most frequently documented diagnoses comprised rejection prophylaxis/therapy after renal transplantation (NTX, 18.3%), ANCA-vasculitides (17.4%), systemic lupus erythematosus (SLE, 10.3%), autoinflammatory fever syndromes (8.4%), autoimmune myositis (7.4%) and pemphigus (5.8%). Documented biologic therapies included rituximab (RTX, 70.1%), tocilizumab (TCZ, 9.3%), infliximab (IFX, 7.1%), anakinra (ANK, 5.5%), adalimumab (ADA, 3.5%), etanercept (ETA, 2.3%) and certolizumab (CTZ, 0.6%). After initiation of off-label biologic treatment, tolerability was assessed by the physicians as "very good"/"good" in 95.5%. Altogether, 275 adverse events were documented and of these, 104 were classified as serious adverse events and occurred in 62 patients. In 19 of these patients severe infections (30.6%) were documented, resulting in a rate of 5.6 severe infections per 100 patient years. A total of six deaths were documented, while five of these cases were rated as not related to the biologics treatment. Notably, the use of RTX in patients with small vessel vasculitides and of TCZ in patients with large vessel vasculitides prior to their approval support their relevance in clinical management of patients with severe diseases. CONCLUSION: The results of this registry together with data of GRAID1 provide evidence that use of off-label biologic therapies in patients with inflammatory rheumatic diseases refractory to conventional treatment did not result in any new safety signal already known for these compounds or subsequently shown by clinical trials in certain entities.

[Still's disease in children and adults]. / Morbus Still im Kindes- und Erwachsenenalter.

Systemic juvenile idiopathic arthritis (sJIA) is characterized by fever, arthritis, and other signs of systemic inflammation. Historically, sJIA was named Still's disease after George Frederic Still, who first reported patients. Individuals who manifest after the 16th birthday are diagnosed with adult onset Still's disease (AOSD). The pathophysiology of sJIA and AOSD are incompletely understood. Increased activation of inflammasomes and the expression of proinflammatory cytokines play a central role. S100 proteins, which can activate Toll-like receptors, thus, maintaining positive feedback loops, have also been detected at increased levels in sera from sJIA patients. Reduced expression of the immune-modulatory cytokine IL-10 may further contribute to immune cell activation and the production of proinflammatory molecules. Here, we discuss the clinical picture, differential diagnoses, the current pathophysiological understanding, and treatment options in sJIA and AOSD.

[Still's disease in children and adults]. / Morbus Still im Kindes- und Erwachsenenalter.

Systemic juvenile idiopathic arthritis (sJIA) is characterized by fever, arthritis, and other signs of systemic inflammation. Historically, sJIA was named Still's disease after George Frederic Still, who first reported patients. Individuals who manifest after the 16th birthday are diagnosed with adult onset Still's disease (AOSD). The pathophysiology of sJIA and AOSD are incompletely understood. Increased activation of inflammasomes and the expression of proinflammatory cytokines play a central role. S100 proteins, which can activate Toll-like receptors, thus, maintaining positive feedback loops, have also been detected at increased levels in sera from sJIA patients. Reduced expression of the immune-modulatory cytokine IL-10 may further contribute to immune cell activation and the production of proinflammatory molecules. Here, we discuss the clinical picture, differential diagnoses, the current pathophysiological understanding, and treatment options in sJIA and AOSD.

[Tapering and termination of immunosuppressive therapy : Systemic lupus erythematosus]. / Ausschleichen und Beenden von immunsuppressiven Therapien : Systemischer Lupus erythematodes.

Similar to patients with other rheumatic diseases, patients with systemic lupus erythematosus (SLE) nowadays can also have the desire to terminate immunosuppressive and immunomodulatory medications. In order to provide appropriate advice to patients, the two main issues are the risk of severe adverse events under long-term therapy with any drug and the perceived risk of a flare, in particular of severe flares. The risks of long-term therapy vary greatly between drugs, ranging from severe unacceptable risks with cyclophosphamide and higher dose glucocorticoids to low risks usually outweighed by long-term benefits with hydroxychloroquine. The individual risk of flares is often difficult to estimate but clinical remission and at least 3 years of immunosuppression are recommended for lupus nephritis. The duration of remission can also be shorter in cases of milder forms of disease. This review article tries to put the available evidence into a clinical perspective and to derive concrete recommendations.

Risk for lower intestinal perforations in patients with rheumatoid arthritis treated with tocilizumab in comparison to treatment with other biologic or conventional synthetic DMARDs.

OBJECTIVE: To investigate the risk of developing lower intestinal perforations (LIPs) in patients with rheumatoid arthritis (RA) treated with tocilizumab (TCZ). METHODS: In 13 310 patients with RA observed in the German biologics register Rheumatoid Arthritis: Observation of Biologic Therapy, 141 serious gastrointestinal events possibly associated with perforations were reported until 31 October 2015. All events were validated independently by two physicians, blinded for treatment exposure. RESULTS: 37 LIPs (32 in the colon/sigma) were observed in 53 972 patient years (PYs). Only two patients had a history of diverticulitis (one in TCZ). Age, current/cumulative glucocorticoids and non-steroidal anti-inflammatory drugs were significantly associated with the risk of LIP. The crude incidence rate of LIP was significantly increased in TCZ (2.7/1000 PYs) as compared with all other treatments (0.2-0.6/1000 PYs). The adjusted HR (ref: conventional synthetic (cs) disease-modifying anti-rheumatic drugs (DMARDs)) in TCZ was 4.48 (95% CI 2.0 to 10.0), in tumour necrosis factor-α inhibitor (TNFi) 1.04 (0.5 to 2.3) and in other biologic DMARDs 0.33 (0.1 to 1.4). 4/11 patients treated with TCZ presented without typical symptoms of LIP (acute abdomen, severe pain). Only one patient had highly elevated C reactive protein (CRP). One quarter of patients died within 30 days after LIP (9/37), 5/11 under TCZ, 2/13 under TNFi and 2/11 under csDMARD treatment. CONCLUSIONS: The incidence rates of LIP under TCZ found in this real world study are in line with those seen in randomised controlled trials of TCZ and higher than in all other DMARD treatments. To ensure safe use of TCZ in daily practice, physicians and patients should be aware that, under TCZ, LIP may occur with mild symptoms only and without CRP elevation.

[Myelodysplastic syndrome, acute leukemia and stem cell transplantation]. / Myelodysplastisches Syndrom, akute Leukämie und Stammzelltransplantation.

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic stem cell disorders. They are characterized by inefficient hematopoiesis leading to peripheral cytopenia of one or more lineages and a variable risk of transformation into acute myeloid leukemia. They may either arise de novo as well as following exposition to environmental toxins, previous radiotherapy or chemotherapy or in the context of autoinflammatory diseases and related therapy. Characteristic cytogenetic abnormalities, along with the numbers of hematopoietic lineages affected and bone marrow blasts, enable an assessment of the risk of leukemic transformation. Acute leukemias are characterized by an accumulation of immature myeloid or lymphatic progenitor cells with limited differentiation capacity in the bone marrow. Proliferation of blast cells leads to suppression of normal hematopoiesis resulting in peripheral pancytopenia or leukocytosis associated with anemia and thrombocytopenia. Acute leukemias following MDS are defined as high-risk diseases. Intensive induction therapy followed by allogeneic stem cell transplantation is currently regarded as the only potentially curative treatment strategy. In this article the basic aspects of current diagnostics and treatment strategies for MDS and acute leukemia are outlined. Because of similarities with rheumatic inflammatory diseases, manifestations and treatment of graft versus host disease (GvHD) are also included.