In this article, the 2010 European League against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA) with synthetic and biological disease-modifying antirheumatic drugs (sDMARDs and bDMARDs, respectively) have been updated. The 2013 update has been developed by an international task force, which based its decisions mostly on evidence from three systematic literature reviews (one each on sDMARDs, including glucocorticoids, bDMARDs and safety aspects of DMARD therapy); treatment strategies were also covered by the searches. The evidence presented was discussed and summarised by the experts in the course of a consensus finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) were determined. Fourteen recommendations were developed (instead of 15 in 2010). Some of the 2010 recommendations were deleted, and others were amended or split. The recommendations cover general aspects, such as attainment of remission or low disease activity using a treat-to-target approach, and the need for shared decision-making between rheumatologists and patients. The more specific items relate to starting DMARD therapy using a conventional sDMARD (csDMARD) strategy in combination with glucocorticoids, followed by the addition of a bDMARD or another csDMARD strategy (after stratification by presence or absence of adverse risk factors) if the treatment target is not reached within 6 months (or improvement not seen at

/pdf/eular-recommendations-for-the-management-of-rheumatoid-4fujp4paik.pdf

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update

Treatment of rheumatoid arthritis (RA) may differ among rheumatologists and currently, clear and consensual international recommendations on RA treatment are not available. In this paper recommendations for the treatment of RA with synthetic and biological disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs) that also account for strategic algorithms and deal with economic aspects, are described. The recommendations are based on evidence from five systematic literature reviews (SLRs) performed for synthetic DMARDs, biological DMARDs, GCs, treatment strategies and economic issues. The SLR-derived evidence was discussed and summarised as an expert opinion in the course of a Delphi-like process. Levels of evidence, strength of recommendations and levels of agreement were derived. Fifteen recommendations were developed covering an area from general aspects such as remission/low disease activity as treatment aim via the preference for methotrexate monotherapy with or without GCs vis-à-vis combination of synthetic DMARDs to the use of biological agents mainly in patients for whom synthetic DMARDs and tumour necrosis factor inhibitors had failed. Cost effectiveness of the treatments was additionally examined. These recommendations are intended to inform rheumatologists, patients and other stakeholders about a European consensus on the management of RA with DMARDs and GCs as well as strategies to reach optimal outcomes of RA, based on evidence and expert opinion.

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs

Side Effects of Immune Checkpoint Blockade The wide range of immune-related adverse effects associated with immune checkpoint blockade can complicate this effective therapy and limit its use in patients with cancer. This review surveys the adverse effects and their management.

https://www.nejm.org/doi/pdf/10.1056/NEJMra1703481

Immune-Related Adverse Events Associated with Immune Checkpoint Blockade

http://academic.oup.com/milmed/article-pdf/146/7/506/24126715/milmed-146-7-506.pdf

Goodman and Gilman's The Pharmacological Basis of Therapeutics

Objective
To develop a new evidence-based, pharmacologic treatment guideline for rheumatoid arthritis (RA).

Methods
We conducted systematic reviews to synthesize the evidence for the benefits and harms of various treatment options. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology to rate the quality of evidence. We employed a group consensus process to grade the strength of recommendations (either strong or conditional). A strong recommendation indicates that clinicians are certain that the benefits of an intervention far outweigh the harms (or vice versa). A conditional recommendation denotes uncertainty over the balance of benefits and harms and/or more significant variability in patient values and preferences.

Results
The guideline covers the use of traditional disease-modifying antirheumatic drugs (DMARDs), biologic agents, tofacitinib, and glucocorticoids in early (<6 months) and established (≥6 months) RA. In addition, it provides recommendations on using a treat-to-target approach, tapering and discontinuing medications, and the use of biologic agents and DMARDs in patients with hepatitis, congestive heart failure, malignancy, and serious infections. The guideline addresses the use of vaccines in patients starting/receiving DMARDs or biologic agents, screening for tuberculosis in patients starting/receiving biologic agents or tofacitinib, and laboratory monitoring for traditional DMARDs. The guideline includes 74 recommendations: 23% are strong and 77% are conditional.

Conclusion
This RA guideline should serve as a tool for clinicians and patients (our two target audiences) for pharmacologic treatment decisions in commonly encountered clinical situations. These recommendations are not prescriptive, and the treatment decisions should be made by physicians and patients through a shared decision-making process taking into account patients’ values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.

https://www.onlinelibrary.wiley.com/doi/epdf/10.1002/art.39480

2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis

Glucocorticoids (GC) are effective drugs which are often used in rheumatology. However, they have a considerable potential for frequent and sometimes serious side effects that restrict their use. Their mechanisms of action are either receptor dependent (specific) or independent (unspecific) on the genomic as well as the non-genomic level. Many adverse effects are predominantly caused by transactivation while the desired effects are mostly mediated by transrepression. Treatment strategies are sub-classified into low, medium, high, very high dose and pulse therapy based on criteria such as dose, indication, duration of treatment and potential risk of adverse events. The musculoskeletal, gastrointestinal, neuro-endocrino-immunological, opthalmological and neuropsychiatric systems are examples where adverse effects may occur.

Glukokortikoide in der Rheumatologie

Infektionen gehoren zu den haufigsten klinischen Problemen bei Patienten mit rheumatischen Erkrankungen, die auf einer Intensivstation mit Glukokortikoiden behandelt werden mussen. Bisher existieren keine Empfehlungen zur standardisierten Steuerung der Glukokortikoidtherapie in derartigen Situationen. Diese Arbeit liefert auf Basis einer Literaturrecherche einen Uberblick uber evidenz- und eminenzbasierte Empfehlungen zur Steuerung einer Glukokortikoidtherapie unter intensivmedizinischen Bedingungen am Beispiel des systemischen Lupus erythematodes. Es erfolgte eine systematische Literaturrecherche mittels Meshterm-Suche in der Datenbank PubMed. Infektionen gehoren zu den haufigsten Ursachen fur die Behandlung von Rheumapatienten auf einer Intensivstation. Im Falle des systemischen Lupus erythematodes ist es eine besondere Herausforderung, die Infektion von einer erhohten Krankheitsaktivitat zu unterscheiden bzw. das parallele Auftreten zu behandeln. Patienten auf einer Intensivstation sind aufgrund ihrer Erkrankungsschwere einem erhohten korperlichen Stresslevel ausgesetzt, weshalb auf Symptome einer Nebennierenrindeninsuffizienz besonderes Augenmerk gelegt werden sollte. Evidenzbasierte Empfehlungen zur Prophylaxe einer adrenalen Krise existieren ausschlieslich in Bezug auf das perioperative Vorgehen, nicht jedoch fur die Situation des Vorliegens schwerer Infektionen. Die Anwendung von Glukokortikoiden beim systemischen Lupus erythematodes ist haufig chronisch, und es besteht ein erhohtes Infektionsrisiko. Im Falle von Infektionen (oder gleichzeitig bestehendem Krankheitsschub) sollte eine adaquate antiinfektive Therapie erfolgen, die Therapie mit Glukokortikoiden entsprechend adjustiert und gleichzeitig sollten Symptome der Nebennierenrindeninsuffizienz beachtet werden.

Zur Steuerung einer Glukokortikoidtherapie beim kritisch kranken Rheumapatienten am Beispiel des systemischen Lupus erythematodes

Neuro-endocrine immune mechanisms play an important immunomodulatory role for rheumatic diseases as evidenced by long-recognized effects of glucocorticoids, gender, pregnancy, hemiparalysis, and stress on various clinical and epidemiological aspects. Recently, some regulatory pathways have been identified between the neuroendocrine and immune systems which seem to be altered in these diseases. Cooperation between the autonomic nervous system and the hypothalamic pituitary adrenal axis (HPA axis) is important to dampen the reaction of the immune system. In chronic inflammatory diseases such as rheumatic diseases these systems have become deficient. Moreover, hyperexcitability of sensory nerves due to peripheral and central neuronal sensitization can support the local inflammatory process.

Neuro-endokrine-immunologische Mechanismen bei rheumatischen Erkrankungen – Ein Kongressbericht

Die Dermatomyositis und Polymyositis im Erwachsenenund im Kindesalter sprechen in der Regel gut auf Glucocorticoide und/oder immunsuppressive Substanzen an. Bei therapieresistenten, schweren Verläufen, bei Unverträglichkeit oder bei Kontraindikationen der Standardtherapie können Infusionen von Immunglobulin-Präparaten eingesetzt werden. Angesichts der mäßigen Datenlage bei hohen Kosten soll die Indikation streng gestellt werden. Indikationsstellung und Durchführung der Therapie setzen entsprechende Erfahrungen voraus. Bei der Einschlusskörperchen-Myositis ist eine Therapie mit Immunglobulininfusionen nicht indiziert.

i.v.-Immunglobuline bei chronischen idiopathischen Myositiden

At sites of inflammation, monocytes carry out specific immune functions while facing challenging metabolic restrictions. Here, we investigated the potential of human monocytes to adapt to conditions of gradually inhibited oxidative phosphorylation (OXPHOS) under glucose free conditions. We used myxothiazol, an inhibitor of mitochondrial respiration, to adjust two different levels of decreased mitochondrial ATP production. At these levels, and compared to uninhibited OXPHOS, we assessed phagocytosis, production of reactive oxygen species (ROS) through NADPH oxidase (NOX), expression of surface activation markers CD16, CD80, CD11b, HLA-DR, and production of the inflammatory cytokines IL-1β, IL-6 and TNF-α in human monocytes. We found phagocytosis and the production of IL-6 to be least sensitive to metabolic restrictions while surface expression of CD11b, HLA-DR, production of TNF-α, IL-1β and production of ROS through NOX were most compromised by inhibition of OXPHOS in the absence of glucose. Our data demonstrate a short-term hierarchy of immune functions in human monocytes, which represents novel knowledge potentially leading to the development of new therapeutics in monocyte-mediated inflammatory diseases.

Frank Buttgereit

Papers

Glukokortikoide in der Rheumatologie

Zur Steuerung einer Glukokortikoidtherapie beim kritisch kranken Rheumapatienten am Beispiel des systemischen Lupus erythematodes

Neuro-endokrine-immunologische Mechanismen bei rheumatischen Erkrankungen – Ein Kongressbericht

i.v.-Immunglobuline bei chronischen idiopathischen Myositiden

Production of IL-6 and Phagocytosis Are the Most Resilient Immune Functions in Metabolically Compromised Human Monocytes.