Treatment of refractory subacute cuataneous lupus erythematosus with baricitinib.

We report on a patient who presented with refractory subacute cutaneous lupus erythematosus. The scaly annular and polycyclic patches/plaques, and hyperkeratotic lesions on multiple fingers improved rapidly after treatment with baricitinib.

[Pulmonary involvement in rheumatoid arthritis]. / Lungenbeteiligung bei rheumatoider Arthritis.

Pulmonary involvement in patients with rheumatoid arthritis, in particular interstitial lung diseases (RA-ILD) is of great clinical importance. Patients should be asked about symptoms of pulmonary involvement and the lungs should be clinically examined even during the diagnostic procedure and regularly during the course of the disease. Before initiation of a basic pharmacological treatment an X­ray examination of thoracic organs is obligatory. In cases of conspicuous clinical or radiological findings, extended diagnostic procedures with lung function testing (body plethysmography with diffusion measurement) and high resolution computed tomography (CT) should be performed, depending on the findings. The differential diagnosis of interstitial lung alterations in patients with RA is broad and should consider side effects of the basis medication in addition to infectious causes. The optimal pharmacological treatment of RA-ILD is not sufficiently clarified. The value of methotrexate (MTX) has changed because, in contrast to previous assumptions, a better course could be observed under MTX treatment, at least in mild to moderate courses of RA-ILD. In the case of a clinically relevant RA-ILD, tumor necrosis factor (TNF) blockers should be avoided because a dramatic deterioration of pulmonary function has sometimes been observed. Among biological disease-modifying antirheumatic drugs (DMARD), rituximab and abatacept are currently preferred. The role of Janus kinase (JAK) inhibitors in RA-ILD is currently being discussed but limited data are available. Patients with RA-ILD benefit from a close collaboration between pulmonologists and rheumatologists.

[S2e guideline: treatment of rheumatoid arthritis with disease-modifying drugs]. / S2e-Leitlinie: Therapie der rheumatoiden Arthritis mit krankheitsmodifizierenden Medikamenten.

BACKGROUND: Medication-based strategies to treat rheumatoid arthritis are crucial in terms of outcome. They aim at preventing joint destruction, loss of function and disability by early and consistent inhibition of inflammatory processes. OBJECTIVE: Achieving consensus about evidence-based recommendations for the treatment of rheumatoid arthritis with disease-modifying anti-rheumatic drugs in Germany. METHODS: Following a systematic literature research, a structured process among expert rheumatologists was used to reach consensus. RESULTS: The results of the consensus process can be summed up in 6 overarching principles and 10 recommendations. There are several new issues compared to the version of 2012, such as differentiated adjustments to the therapeutic regime according to time point and extent of treatment response, the therapeutic goal of achieving remission as assessed by means of the simplified disease activity index (SDAI) as well as the potential use of targeted synthetic DMARDs (JAK inhibitors) and suggestions for a deescalating in case of achieving a sustained remission. Methotrexate still plays the central role at the beginning of the treatment and as a combination partner in the further treatment course. When treatment response to methotrexate is inadequate, either switching to or combining with another conventional synthetic DMARD is an option in the absence of unfavourable prognostic factors. Otherwise biologic or targeted synthetic DMARDs are recommended according to the algorithm. Rules for deescalating treatment with glucocorticoids and-where applicable-DMARDs give support for the management of patients who have reached a sustained remission. DISCUSSION: The new guidelines set up recommendations for RA treatment in accordance with the treat-to-target principle. Modern disease-modifying drugs, now including also JAK inhibitors, are available in an algorithm.

[Lymphoma in rheumatic diseases]. / Lymphome bei rheumatischen Erkrankungen.

Various systemic inflammatory diseases, such as rheumatoid arthritis (RA), Sjögren's syndrome and systemic lupus erythematosus (SLE) are associated with an increased risk for the development of lymphomas. Studies on patients with RA and Sjögren's syndrome have shown that there is a clear association of the incidence of lymphoma with the severity and activity of the disease and lymphomas in particular are diseases which preferentially occur in immunosuppressed patients; therefore, knowledge of the different lymphoma subtypes, their prognosis and treatment options are important for rheumatologists. Currently, there is no evidence for an increased risk of lymphoma with the available conventional basis therapies or biologic disease-modifying antirheumatic drugs (DMARDs). The decision on how to treat a patient with previous lymphoma who requires antirheumatic treatment is more difficult as patients with previous malignancies are not included in clinical studies and in registries a bias with respect to patient selection must be taken into consideration. Decisions on the treatment approach, therefore need to be individualized and interdisciplinary management together with the treating hematologist is warranted.

[Lung cancer and rheumatoid arthritis. An interdisciplinary challenge]. / Lungenkarzinom und rheumatoide Arthritis. Eine interdisziplinäre Herausforderung.

Lung cancer is a frequently occurring disease, particularly in the elderly; however, within the last 10 years the pharmaceutical treatment of lung cancer has been significantly improved. Due to a better understanding of the pathophysiological events and the identification of molecular subgroups of lung tumors, new therapeutic drugs have been developed that significantly prolong survival of patients with the respective molecular pattern. In particular immunotherapeutic agents, such as programmed death-ligand 1 (PD-L1) and programmed death 1 (PD1) antibodies have shown promising clinical results in a subgroup of lung cancer patients. Due to the high incidence of both lung cancer and rheumatic diseases they often occur together, which necessitates an interdisciplinary management. The success of improved therapy of lung cancer has led to a greater focus on the treatment of comorbidities; however, interventions into the immune system by immune checkpoint inhibitors can lead to new challenges when an autoimmune disease is simultaneously present. The possibility of an effective screening for lung cancer in the future also presents the prospect of an improvement in mortality, which raises the question of the optimal monitoring of patients with rheumatoid arthritis (RA) under immunosuppressive therapy. The aim of this review is to discuss the interaction between lung cancer and RA with respect to the currently available data.

[Do we still need clinical studies in rheumatology?]. / Brauchen wir noch klinische Studien in der Rheumatologie?

Despite a large number of approved therapies demonstrating efficacy in the treatment of rheumatic diseases, only 60-85 % of patients with the indications for rheumatoid arthritis are adequately treated in Germany. Additionally, approved therapies for other immune-mediated diseases are often entirely lacking, indicating the great medical need for the development of new innovative therapies in this specialized field. The development of new drugs is expensive due to the high costs of conducting clinical trials in all phases of development up to obtaining approval; therefore, pharmaceutical companies are looking for ways to save costs in the particular developmental stages. Although the classical regions for drug development (i.e. western Europe, the USA and Japan) offer both a high level of data quality and a good infrastructure to conduct clinical trials due to high standards of education and quality, clinical trials are expensive in these regions. Beside high costs, the comparatively low recruitment rates in these regions are one of the main reasons for the shifting of drug developmental stages from classical regions to eastern European, Latin American and Asian countries, which provide services for drug development and high recruitment rates for comparatively less money. However, there are many strong arguments for the participation of regions in western Europe, especially German sites in clinical trials. In this article these arguments are discussed and possible solutions and strategies for conducting and compensation of study centers in Germany for clinical trials in the field of rheumatology are provided.

Rituximab versus an alternative TNF inhibitor in patients with rheumatoid arthritis who failed to respond to a single previous TNF inhibitor: SWITCH-RA, a global, observational, comparative effectiveness study.

OBJECTIVES: To compare the effectiveness of rituximab versus an alternative tumour necrosis factor (TNF) inhibitor (TNFi) in patients with rheumatoid arthritis (RA) with an inadequate response to one previous TNFi. METHODS: SWITCH-RA was a prospective, global, observational, real-life study. Patients non-responsive or intolerant to a single TNFi were enrolled ≤4 weeks after starting rituximab or a second TNFi. Primary end point: change in Disease Activity Score in 28 joints excluding patient's global health component (DAS28-3)-erythrocyte sedimentation rate (ESR) over 6 months. RESULTS: 604 patients received rituximab, and 507 an alternative TNFi as second biological therapy. Reasons for discontinuing the first TNFi were inefficacy (n=827), intolerance (n=263) and other (n=21). A total of 728 patients were available for primary end point analysis (rituximab n=405; TNFi n=323). Baseline mean (SD) DAS28-3-ESR was higher in the rituximab than the TNFi group: 5.2 (1.2) vs 4.8 (1.3); p<0.0001. Least squares mean (SE) change in DAS28-3-ESR at 6 months was significantly greater in rituximab than TNFi patients: -1.5 (0.2) vs -1.1 (0.2); p=0.007. The difference remained significant among patients discontinuing the initial TNFi because of inefficacy (-1.7 vs -1.3; p=0.017) but not intolerance (-0.7 vs -0.7; p=0.894). Seropositive patients showed significantly greater improvements in DAS28-3-ESR with rituximab than with TNFi (-1.6 (0.3) vs -1.2 (0.3); p=0.011), particularly those switching because of inefficacy (-1.9 (0.3) vs -1.5 (0.4); p=0.021). The overall incidence of adverse events was similar between the rituximab and TNFi groups. CONCLUSIONS: These real-life data indicate that, after discontinuation of an initial TNFi, switching to rituximab is associated with significantly improved clinical effectiveness compared with switching to a second TNFi. This difference was particularly evident in seropositive patients and in those switched because of inefficacy.

[Switching within the active ingredient group or changing the mechanism of action. Data situation by failure of the first line biologic]. / Wechsel innerhalb der Wirkstoffgruppe oder Wechsel des Wirkprinzips. Datenlage bei Versagen des Erstbiologikums.

Despite the use of biologics many patients do not achieve remission or reduced disease activity, which raises the question of the optimal therapy when these therapy targets are not achieved. Most data from clinical studies and registry data refer to the approach following the unsuccessful use of one or more tumor necrosis factor (TNF) inhibitors. Randomized controlled studies investigating the effectiveness of a further biologic or TNF inhibitor in patients who received abatacept, tocilizumab or rituximab in the first line therapy are currently lacking, with the exception of the German MIRAI study. The majority of registry data and observational studies suggest that when the use of a TNF inhibitor is unsuccessful it is advantageous to change to a non-TNF biologic. This does not exclude that a change within the group of TNF inhibitors can represent an appropriate option, e.g. by injection or infusion reactions or secondary therapy failure. Whether determination of serum levels and neutralizing antibodies aids decision-making for individual patients, must currently remain open. The option to change within an active ingredient group of biologics only currently applies to the group of TNF inhibitors; however, with the development of further antibodies inhibiting interleukin 6, this question will also apply to this group of substances. The question of the optimal strategy after failure of the first and second line biologics will be asked more frequently when the therapy targets of remission and low disease activity are more stringently strived for. Predictive markers for an optimal approach to the sequential administration of biologics are lacking. In order to answer this question clinical studies which investigate the therapeutic approach in a randomized and controlled manner will be necessary in the future.

[Recommendations on the use of rituximab for ANCA-associated vasculitis]. / Empfehlungen zum Einsatz von Rituximab bei ANCA-assoziierten Vaskulitiden.

Rituximab (Rtx) has been approved in Germany since April 2013 for treatment of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). This therapy can be used in severe manifestations of these diseases and in relapses. It is administered as infusions of 375 mg rituximab per m(2) every 4 weeks after high dose intravenous prednisolone for 3 days and continued parallel to concomitant oral prednisolone therapy. Recommendations for the indications and use for antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) are described in addition to previous publications on recommendations for rheumatoid arthritis.

[Recommendations for use of rituximab in patients with rheumatoid arthritis]. / Empfehlungen zum Einsatz von Rituximab bei Patienten mit rheumatoider Arthritis.

Treatment with rituximab (RTX) has been approved since 2006 for patients with rheumatoid arthritis who previously failed to respond to tumor necrosis factor (TNF) inhibitor therapy or who experienced side effects. In these updated treatment recommendations new data relating to evaluation of the therapeutic response, retreatment, the role of predictive factors as well as safety data are incorporated and discussed.

[Evidence-based recommendations for the management of undifferentiated peripheral inflammatory arthritis (UPIA). The German perspective on the international 3e initiative]. / Evidenzbasierte Empfehlungen zum Management einer undifferenzierten peripheren entzündlichen Arthritis (UPIA). Die deutsche Perspektive zur internationalen 3e-Initiative.

INTRODUCTION: Peripheral arthritis is the most common presenting complaint in clinical rheumatology. Unequivocal identification of the underlying entity can be difficult, particularly at an early stage. Such cases are commonly referred to as undifferentiated peripheral inflammatory arthritis (UPIA). Since evidence-based recommendations for the clinical management of UPIA are lacking, this international 3e initiative convened 697 rheumatologists from 17 countries to develop appropriate recommendations. METHODS: Based on a systematic literature research in Medline, EMBASE, Cochrane Library, and the ACR/EULAR abstracts of 2007/2008, 10 multinational recommendations were developed by 3 rounds of a Delphi process. In Germany, a national group of experts worked on 3 additional recommendations using the same method. The recommendations were discussed among the members of the 3e initiative and the degree of consensus was analyzed as well as the potential impact of the recommendations on clinical practice. RESULTS: A total of 39,756 references were identified, of which 250 were systematically reviewed for the development of 10 multinational recommendations concerning differential diagnosis, diagnostic and prognostic value of clinical assessments, laboratory tests and imaging techniques, and monitoring of UPIA. In addition, 3 national recommendations on the diagnostic and prognostic value of a response to anti-inflammatory therapy on the analysis of synovial fluid and on enthesitis were developed by the German experts based on 35 out of 5542 references. CONCLUSIONS: The article translates the 2011 published original paper of the international 3e initiative (Machado et al., Ann Rheum Dis 70:15-24, 2011) and reports the methods and results of the national vote and the additional 3 national recommendations.

[Orphan diseases in rheumatology. Exemplified by polyarteritis nodosa]. / "Orphan diseases" in der Rheumatologie. Beispiel Polyarteriitis nodosa.

The term orphan disease is used for those diseases which are diagnosed in less than 5 out of 10,000 persons. An example of an orphan disease in rheumatology is panarteritis nodosa (PAN), the clinical manifestation of which ranges from mild forms to life-threatening situations. The scientific publications on the diagnosis and therapy of PAN are usually limited to casuistics and small case studies. Treatment of this disease is usually carried out analogue to other forms of vasculitis but the therapeutics used are not formally approved for PAN. With this in mind it is much more realistic to treat such patients in specialized centers or at least to allow an evidence-based medical treatment in, for example network associations, using the targeted documentation of patients.

[New kinase inhibitors]. / Neue Kinasehemmer.

Treatment of rheumatoid arthritis (RA) has dramatically changed during the last 15 years. A limited number of conventional disease-modifying antirheumatic drugs (DMARD) in combination with non-steroid anti-inflammatory drugs (NSAID) and corticosteroids are facing a variety of biologics that are increasingly being used. Because of the high costs of biologics as well as the necessity for subcutaneous or intravenous administration, there is currently a growing interest in new and potent oral compounds such as the small molecules. Inflammatory pathways and mechanisms in signal transduction have been characterized in detail. Instead of neutralizing the action of a proinflammatory cytokine by antagonizing its biologic effect by an antibody, these small molecules interfere with the intracellular pathways of the inflammatory cascade. Intracellular kinases are among these enzymes which are crucially involved in intracellular signal transduction. Kinase inhibitors have been successfully used within the last few years in the treatment of various hematological malignancies, such as imatinib in patients with chronic myeloid leukemia. More recently, the Janus kinase (JAK) inhibitor tofacitinib has been evaluated as a potential new treatment option in RA and is awaiting approval. While an overview about JAK inhibition will be given elsewhere, other inhibitors such as spleen tyrosine kinase (Syk) inhibitor, mitogen-activated protein kinase (MAPK) inhibitor and Bruton's tyrosine kinase (Btk) inhibitor are currently in preclinical and clinical development.

[Nervous system side effects of disease modifying treatments of rheumatoid arthritis]. / Nebenwirkungen der medikamentösen Therapie rheumatischer Erkrankungen am Nervensystem.

Antirheumatic medication is of crucial importance within the treatment concept of chronic inflammatory disorders. Side effects may affect various organ systems, among which are neurologic manifestations. If patients have comorbidities involving the nervous system this should be taken into consideration before choosing an individual immunosuppressant or immunomodulatory compound, as any worsening of the underlying neurologic disease should be avoided. In this article, relevant neurologic disorders will be described with respect to the clinical manifestations, differential diagnosis and treatment. In the second part, pharmaceuticals and biologicals which are frequently used as part of an antirheumatic regimen are discussed with respect to the potential to induce side effects specifically related to the nervous system.

[German 2012 guidelines for the sequential medical treatment of rheumatoid arthritis. Adapted EULAR recommendations and updated treatment algorithm]. / S1-Leitlinie der DGRh zur sequenziellen medikamentösen Therapie der rheumatoiden Arthritis 2012. Adaptierte EULAR-Empfehlungen und aktualisierter Therapiealgorithmus.

Following the EULAR recommendations published in 2010 German guidelines for the medical treatment of rheumatoid arthritis were developed based on an update of the systematic literature search and expert consensus. Methotrexate is the standard treatment option at the time of diagnosis, preferably in combination with low dose glucocorticoids. Combined disease-modifying antirheumatic drugs (DMARD) therapy should be considered in patients not responding within 12 weeks. Treatment with biologicals should be initiated in patients with persistent high activity no later than 6 months after conventional treatment and in exceptional situations (e.g. early destruction or unfavorable prognosis) even earlier. If treatment with biologicals remains ineffective, changing to another biological is recommended after 3-6 months. In cases of long-standing remission a controlled reduction of medical treatment can be considered.

Effectiveness and safety of the interleukin 6-receptor antagonist tocilizumab after 4 and 24 weeks in patients with active rheumatoid arthritis: the first phase IIIb real-life study (TAMARA).

OBJECTIVES: To confirm the effectiveness and safety of the interleukin 6-receptor antagonist tocilizumab in patients with rheumatoid arthritis (RA) in a setting close to real-life medical care in Germany. METHODS: A multicentre open-label phase IIIb study was undertaken. Patients with active RA with a 28-joint Disease Activity Score (DAS28) >3.2 despite previous disease-modifying antirheumatic drugs (DMARDs) were treated with tocilizumab 8 mg/kg every 4 weeks. The primary end point was the proportion of patients achieving LDAS ≤3.2 at week 24; secondary end points included American College of Rheumatology (ACR), European League Against Rheumatism (EULAR) or Clinical Disease Activity Index (CDAI) responses and decrease in acute phase. Analyses in subgroups such as rheumatoid factor (RF)-positive versus RF-negative patients and patients with an inadequate response to treatment with DMARDs (DMARD-IR) versus those with an inadequate response to tumour necrosis factor (TNF) antagonists (TNF antagonist-IR) were performed. Safety was assessed by adverse event documentation. RESULTS: 286 patients were treated and 83.6% completed the study. 41.6% had previously been treated with TNF antagonists. 57% of the intention-to-treat patients achieved the primary end point of LDAS, 47.6% achieved DAS remission <2.6 and a EULAR 'good response' was achieved by 54.9%; ACR50/70 response rates at week 24 were 50.7% and 33.9%, respectively. The mean±SD decrease in CDAI from baseline to week 24 was 71±29%. C reactive protein levels normalised rapidly within 1 week. Major improvements in fatigue, pain and morning stiffness were observed in the first 4 weeks and further improved until week 24. DAS28, EULAR and ACR responses at week 24 did not differ between RF-positive and RF-negative patients. TNF antagonist-naive patients responded better than patients who had previously failed on TNF antagonists. The safety profile of tocilizumab was comparable to that previously observed in the phase III trial programme. Serious infections were observed in 3.1% of patients. CONCLUSIONS: Tocilizumab is highly effective in a setting close to real-life medical care with a rapid and sustained improvement in signs and symptoms of RA. A manageable safety profile was seen over the 24-week study period.

Inhibition of joint damage and improved clinical outcomes with rituximab plus methotrexate in early active rheumatoid arthritis: the IMAGE trial.

OBJECTIVES: Rituximab is an effective treatment in patients with established rheumatoid arthritis (RA). The objective of the IMAGE study was to determine the efficacy of rituximab in the prevention of joint damage and its safety in combination with methotrexate (MTX) in patients initiating treatment with MTX. METHODS: In this double-blind randomised controlled phase III study, 755 MTX-naïve patients with active RA were randomly assigned to MTX alone, rituximab 2×500 mg + MTX or rituximab 2×1000 mg + MTX. The primary end point at week 52 was the change in joint damage measured using a Genant-modified Sharp score. RESULTS: 249, 249 and 250 patients were randomly assigned to MTX alone, rituximab 2×500 mg + MTX or rituximab 2×1000 mg + MTX, respectively. At week 52, treatment with rituximab 2×1000 mg + MTX compared with MTX alone was associated with a reduction in progression of joint damage (mean change in total modified Sharp score 0.359 vs 1.079; p=0.0004) and an improvement in clinical outcomes (ACR50 65% vs 42%; p<0.0001); rituximab 2×500 mg + MTX improved clinical outcomes (ACR50 59% vs 42%; p<0.0001) compared with MTX alone but did not significantly reduce the progression of joint damage. Safety outcomes were similar between treatment groups. CONCLUSIONS: Treatment with rituximab 2×1000 mg in combination with MTX is an effective therapy for the treatment of patients with MTX-naïve RA. ClinicalTrials.gov identifier NCT00299104.

[§ 116b SGB V (social insurance code, book five) for rheumatology patients. An empirical assessment on the basis of administrative data]. / § 116b SGB V in der rheumatologischen Versorgung. Eine empirische Abschätzung anhand von Routinedaten.

BACKGROUND: The choice between outpatient and inpatient care is currently undergoing major changes within the German health care system with the amendment of § 116b SGB V. This study investigates what proportion of hitherto inpatient rheumatologic care could potentially be given on an outpatient basis. METHODS: The analysis is based on administrative inpatient data from 2004 to 2008 covering approximately 23.6 million private health insurance insurants. The selection of patients with rheumatological diseases was based on diagnosis according to ICD-10 of § 116b SGB V. RESULTS: From 2004 to 2008 the number of all rheumatologic cases increased by 13.9%, while the average length of hospital stay decreased from 9.46 days to 8.08 days and the number of attending hospitals declined by 3.1%. The number of rheumatologic cases with a short inpatient stay (≤2 days) increased by 32.3%. We define the ambulatory potential as the proportion of patients with a short length of stay to the total of inpatient rheumatologic cases; this increased from 25.7% to 29.9%. DISCUSSION: Not all patients with a short inpatient stay can be transferred problem-free to ambulatory care. No channeling of patients to specialized centres has taken place thus far in Germany. Quality of care at the hospitals studied has not been considered. Further data are needed to link administrative data with quality care data.

[Is it possible to compare different studies on efficacy of biologicals in patients with rheumatoid arthritis? : mixed treatment comparison as a new tool for indirect comparison of clinical studies]. / Ist der Vergleich verschiedener Studien zur Wirksamkeit von Biologika bei Patienten mit rheumatoider Arthritis möglich? : "Mixed treatment comparison" als neuer Ansatz zum indirekten Vergleich klinischer Studien.

Head-to-head studies as randomized, double blind clinical studies are the best method for directly comparing the efficacy of different therapeutic strategies. However, at the moment no such studies are available for biological agents in the treatment of patients with rheumatoid arthritis. Therefore it is only possible to compare different treatment strategies by indirect comparisons, for example by adjusted indirect comparison or mixed treatment comparison (MTC). The MTC is accepted by European authorities as supportive clinical evidence. As with the case of meta-analyses the quality of an indirect comparison is determined by the homogeneity of the studies included in the analysis.A short review of eight published indirect comparisons of the efficacy of biological agents in the treatment of patients with rheumatoid arthritis showed that the results with respect to tumor necrosis factor (TNF) blockers are similar and that there are differences in the efficacy of non-TNF biological agents.

[Strategies for improved healthcare of people with the endemic disease rheumatism exemplified by rheumatoid arthritis]. / Strategien zur verbesserten Versorgung von Menschen mit der Volkskrankheit "Rheuma" am Beispiel der rheumatoiden Arthritis.

New therapeutic principles and considerable diagnostic advances have made it possible to define different rheumatic diseases and especially rheumatoid arthritis (RA) at an early stage and by starting an early and aggressive medication a considerable proportion of patients with RA will reach the status of low disease activity or even remission. With the additional development of composite measures to estimate the disease activity of RA, it was the goal of an international working group consisting of rheumatologists and patients to develop recommendations for treating rheumatoid arthritis in a similar way as for patients with hypertension or diabetes, with the aim to achieve remission as often as possible. This treat-to-target initiative has taken off in quite a number of different countries including Germany leading to discussions on how this initiative can be integrated into the specific national healthcare systems and what possibilities would exist for its implementation. To develop strategies for an improved healthcare of people suffering from rheumatic diseases and using RA as an example, action elements and postulates were developed which will be discussed in more detail in the present manuscript.