[Influence of underlying disease and immunosuppression on the immunocompetence in inflammatory rheumatic diseases]. / Einfluss von Grunderkrankung und Immunsuppression auf die Immunkompetenz bei entzündlich rheumatischen Erkrankungen.

Patients with inflammatory rheumatic diseases have a higher risk of infections in comparison to the general population. For this patient group, in addition to cardiovascular diseases, infections play an important role with respect to morbidity and mortality. Even if it is difficult to make concrete statements with respect to individual diseases, it can be assumed that there is a lower risk of infections in inflammatory joint diseases in comparison to connective tissue diseases and vasculitides. The increased risk of infections is determined by multiple factors, whereby the underlying factors are classified into three main categories: patient-related factors (age, comorbidities, lifestyle), disease-related factors (immunological dysfunction as part of the disease pathophysiology) and drug-related factors (type and dosage of the immunosuppression and/or immunomodulation). An improved understanding of the complexity of these associations enables the optimization of treatment and disease control taking the individual risk factors into account, with the aim of a significant reduction in the risk of infections.

Joint Statement (DZK, DGRh, DDG) on the Tuberculosis Risk with Treatment Using Novel Non-TNF-Alpha Biologicals.

BACKGROUND: While the risk of tuberculosis (TB) reactivation is adequately documented in relation to TNF-alpha inhibitors (TNFi), the question of what the tuberculosis risk is for newer, non-TNF biologics (non-TNFi) has not been thoroughly addressed. METHODS: We conducted a systematic review of randomized phase 2 and phase 3 studies, and long-term extensions of same, published through March 2019. Of interest was information pertaining to screening and treating of latent tuberculosis (LTBI) in association with the use of 12 particular non-TNFi. Only rituximab was excluded. We searched MEDLINE and the ClinicalTrial.gov database for any and all candidate studies meeting these criteria. RESULTS: 677 citations were retrieved; 127 studies comprising a total of 34,293 patients who received non-TNFi were eligible for evaluation. Only 80 out of the 127 studies, or 63 %, captured active TB (or at least opportunistic diseases) as potential outcomes and 25 TB cases were reported. More than two thirds of publications (86/127, 68 %) mentioned LTBI screening prior to inclusion of study participants in the respective trial, whereas in only 4 studies LTBI screening was explicitly considered redundant. In 21 studies, patients with LTBI were generally excluded from the trials and in 42 out of the 127 trials, or 33 %, latently infected patients were reported to receive preventive therapy (PT) at least 3 weeks prior to non-TNFi treatment. CONCLUSIONS: The lack of information in many non-TNFi studies on the number of patients with LTBI who were either excluded prior to participating or had been offered PT hampers assessment of the actual TB risk when applying the novel biologics. Therefore, in case of insufficient information about drugs or drug classes, the existing recommendations of the German Central Committee against Tuberculosis should be applied in the same way as is done prior to administering TNFi. Well designed, long-term "real world" register studies on TB progression risk in relation to individual substances for IGRA-positive cases without prior or concomitant PT may help to reduce selection bias and to achieve valid conclusions in the future.

[Most important vaccinations in patients with rheumatological diseases and why]. / Wichtigste Impfungen bei Patienten mit rheumatologischen Erkrankungen und warum.

For a long time, most of the infectious diseases seemed to have become under control. In particular, vaccinations have contributed to this development. In recent years newly occurring bacterial infections caused by multidrug-resistant pathogens and viral infections, such as the chikungunya virus, influenza epidemics and currently the COVID-19 pandemic, are endangering the world population. This specifically affects patients with rheumatological diseases, who often require immunosuppressive therapy and are thus at risk for infections. Vaccinations can protect those affected, both individually and by generating herd immunity, and are thus an important instrument to reduce morbidity and mortality from infections. Knowledge of the indications and application of the individual vaccinations is particularly important for consistent implementation of the current recommendations.

[Comorbidities-Their role in the treat to target concept for rheumatoid arthritis]. / Komorbiditäten ­ ihre Rolle im Treat-to-Target-Konzept für die rheumatoide Arthritis.

Treat to target (T2T) strategies and comorbidities are closely related. Strong evidence exists for reducing the risk and extent of comorbidities, such as cardiovascular (CV) diseases, depression and infections by implementing T2T concepts and inducing good disease control of rheumatoid arthritis (RA) in this way. On the other hand existing comorbidities may hinder implementation of T2T concepts by aggravating RA or influencing rheumatologists to overcautiously use DMARD treatment. Among a long list of potentially relevant comorbidities with RA, in this review two particularly relevant accompanying diseases with respect to T2T, CV diseases and infections, are selected for discussion in detail. The CV comorbidities are the main cause of death for RA patients and are triggered by RA-associated inflammatory mechanisms. Their negative influence on implementation of T2T strategies can be stopped or at least reduced by optimal control of RA activity with the help of selecting drugs with cardioprotective properties (such as biologicals, methotrexate and hydroxychloroquine) as well as assessing and treating traditional CV risk factors. Infections are among most important adverse events of DMARD treatment and can disturb the optimal use of these drugs and so hinder the success of the T2T strategy. Optimal infection prophylaxis and identification of high risk patients are particularly important and minimization of glucocorticoid use is critical to reduce the risk of infections. In summary, comorbidities are important potential risk factors for the success of T2T strategies.

[Infections]. / Infektionen.

The individual risk assessment concerning infections in patients with rheumatic diseases is based on the detailed personalized documentation of relevant risk factors, such as the underlying disease itself, the intensity of immunosuppressive therapy and the severity of any comorbidities. From the perspective of infectiology, the history of repeated and severe infections as well as previous illnesses, such as (latent) tuberculosis and chronic hepatitis B or C need to be considered. In some instances prophylactic antibiotic therapy might be required, which should otherwise be avoided in order to prevent selection of resistant pathogens. Furthermore, vaccinations are particularly suitable to specifically minimize the risk for frequent infectious diseases.

Simple screening tools predict death and cardiovascular events in patients with rheumatic disease.

OBJECTIVES: Patients with rheumatic disease (RD) have an increased mortality risk compared with the general population, mainly due to cardiovascular disease (CVD). We aimed to identify patients at high risk of CVD and mortality by comparing three screening tools suitable for clinical practice. METHOD: In this prospective, single-centre study, consecutive patients with rheumatoid arthritis (RA), systemic autoimmune disease (SAI), or spondyloarthritides (SpA) including psoriatic arthritis underwent a comprehensive cardiovascular risk assessment. Patients were predefined as being at high risk for cardiovascular events or death if any of the following were present: European Systematic COronary Risk Evaluation (SCORE) ≥ 3%, N-terminal pro-brain natriuretic peptide (NT-proBNP) ≥ 200 pg/mL, or any pathological electrocardiogram pattern. RESULTS: The patient population (n = 764) comprised 352 patients with RA, 260 with SAI, and 152 with SpA. After a median follow-up of 5.2 years, 6.0% of RD patients had died (7.0%, 7.2%, and 1.4% of patients in the RA, SAI, and SpA subgroups), and 5.0% had experienced a cardiovascular event (5.0%, 6.4%, and 2.8%, respectively). For all RD patients and the RA and SAI subgroups, NT-proBNP ≥ 200 pg/mL and SCORE ≥ 3% identified patients with a 3.5-5-fold increased risk of all-cause death and cardiovascular events. Electrocardiogram pathology was associated with increased mortality risk, but not with cardiovascular events. CONCLUSION: NT-proBNP ≥ 200 pg/mL or SCORE ≥ 3% identifies RA and SAI patients with increased risk of cardiovascular events and death. Both tools are suitable as easy screening tools in daily practice to identify patients at risk for further diagnostics and closer long-term follow-up.

[In-label treatment of inflammatory joint diseases]. / In-label-Therapie entzündlicher Gelenkerkrankungen.

The correct use of therapeutic agents in accordance with their approved label is a requirement for a safe therapy and is often linked to the possibility of reimbursement; however, the use of drugs outside the label approval (off-label treatment) is a commonly used practice in rheumatology. This occurs because sufficient clinical trials are often lacking, particularly for rare diseases. This overview gives an insight into the correct use of disease-modifying antirheumatic drugs (DMARDs). It should be noted that there are divergent treatment guidelines that are based on guidelines or recommendations from public authorities, such as the Federal Joint Committee (GBA). A further example is that modifying the dose when the treatment goal is reached is only intended for some of the drugs in the course of the disease. Clinical trials which address such questions could help to modify or add to the label, as for example has now been successfully achieved for the treatment with certolizumab in pregnancy.

[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.

Zytopenien : Anämie, Leukopenie und Thrombopenie.

Hematological alterations can often be observed during rheumatic diseases. The effects can be clinically severe, ranging from anemia of different grades of severity, through increased risk of hemorrhage due to thrombocytopenia up to severe infections as a result of high-grade leukocytopenia. The clinical sequelae for patients are predominantly determined by the extent of cytopenia. The underlying disease itself can initially be considered as the cause. Examples are anemia as a result of chronic inflammation, antibody-mediated thrombocytopenia as in systemic lupus erythematosus (SLE) or granulocytopenia within the framework of Felty's syndrome. Immunosuppressive treatment also often leads to alterations in the blood constituents. Although some substances, such as cyclophosphamide can suppress all three cell types, there are also selective effects, such as isolated thrombocytopenia under treatment with tocilizumab and JAK inhibitors. The differential diagnostic clarification of cytopenia can be difficult and necessitates a systematic work-up of the course of the disease and the subsequent treatment. The reviews of anemia, leukocytopenia and thrombocytopenia presented here summarize the most important components of the differentiation of hematological alterations in patients with rheumatic diseases.

[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.

[Rheumatology - Integration into student training (RISA) : Current structure of clinical rheumatology in German universities (RISA III)]. / Rheumatologie - Integration in die studentische Ausbildung (RISA) : Zur aktuellen Struktur der internistischen Rheumatologie an deutschen Hochschulen (RISA III).

The German Society of Rheumatology and the Committee for Student Training investigated what effects the structures in university medicine have on student teaching. In February 2014 a questionnaire was sent to the teaching staff and Deans of each of the 37 medical faculties. Of the locations seven were classified as being independent rheumatological university hospitals and nine universities had a W2/W3/C3 grade professor as head of a department of clinical rheumatology but answerable to superiors. In the 37 faculties in Germany the proportion of lecture hours, the proportion of obligatory lecture hours, the number of hours for practical exercises and the number of hours for bedside teaching were distributed very differently and as a rule higher in universities with academic freedom. Not all medical faculties have obligatory teaching in the field of clinical rheumatology. On average medical students see five patients with rheumatological symptoms during their studies. In summary, over the past years it has not been possible to successfully utilize the great importance of rheumatology for society and the innovation potential of this discipline in order to improve the integration of clinical rheumatology into universities.

[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.

[Prophylaxis and treatment of infections in elderly patients with rheumatism]. / Prophylaxe und Behandlung von Infektionen beim älteren Rheumapatienten.

In general, the risk of serious infections increases with age, mainly explained by immunosenescence and accumulation of comorbidities. Those patients with rheumatoid arthritis who are of advanced age and require treatment with immunosuppressive agents are at particular risk to develop an infectious disease. Actual requirement and kind of treatment on the one hand, and risk of infection on the other hand, have to be considered carefully for each patient. For example, in high-risk patients, it is important to use glucocorticoids in a minimal way, i.e. in low doses and as short as possible. Vaccination, especially against influenza and pneumococci, plays an essential role in preventing infectious diseases, particularly in the elderly. Nevertheless, in cases of suspected bacterial infection, empiric antibiotic therapy should be started promptly. Due to the burden of drugs taken by patients of advanced age, the benefits and possible side effects as well as potential drug interactions have to be carefully considered. In summary, drug treatment of the elderly requires bearing in mind the complete health status of the individual patient.

[Safety of antirheumatic drug treatment in the elderly]. / Sicherheit der Rheumatherapie im Alter.

Mainly due to the general demographic changes and decreasing mortality in rheumatic diseases based on therapeutic progress, the proportion of older patients treated by rheumatologists is growing. Drug treatment in the elderly, however, harbors certain risks including age-specific pharmacokinetic features and high rates of multimorbidity and polypharmacy resulting in a risk of drug interactions and adherence problems. Nevertheless, older patients suffering from rheumatic diseases ought to be treated with the same intensity and same targets as the younger counterparts. Bearing all these facts in mind it is a balancing act for rheumatologists to find an optimal treatment for the individual elderly patient. Fear of risks should not lead to hesitant use of drugs leaving these patients alone with treatment deficits, as some studies have suggested.

Screening for latent tuberculosis infection: performance of tuberculin skin test and interferon-γ release assays under real-life conditions.

OBJECTIVES: To characterise optimal screening strategies for latent tuberculosis infection (LTBI) prior to the initiation of anti-tumour necrosis factor therapy. METHODS: Patients in 62 German rheumatology centres were evaluated for LTBI. Each patient was screened with a tuberculin skin test (TST) and one form of an interferon-γ release assay (IGRA), either TSPOT.TB (TSPOT) or Quantiferon TB Gold (QFT). RESULTS: A total of 1529 patients with rheumatological disease were tested with a TST, 844 with TSPOT and 685 with QFT. TST was positive in 11.3% (n=173). The prevalence of LTBI was 8.0% when defined as a positive TST and no previous Bacille Calmette-Guérin (BCG) vaccination and 7.9% when based on a positive IGRA. Combining both estimates increased the prevalence of LTBI to 11.1%. Clinical risk factors for LTBI were found in 122 patients (34 with a history of prior TB, 81 close contacts and 27 with suggestive chest x-ray lesions). A compound risk factor (CRF) was defined as the presence of at least one of these three risk factors. Statistical analyses were conducted to examine the association between CRF and LTBI test outcomes. In multivariate analysis, TST was influenced by CRF (OR 6.2; CI 4.08 to 9.44, p<0.001) and BCG vaccination status (OR 2.9; CI 2.00 to 4.35, p<0.001). QFT and TSPOT were only influenced by CRF (QFT: OR 2.6; CI 1.15 to 5.98, p=0.021; TSPOT: OR 8.7; CI 4.83 to 15.82, p<0.001). ORs and the agreement of TST and IGRA test results varied by rheumatological disease. CONCLUSION: LTBI test results in an individual patient need to be considered in the context of prior BCG vaccination and clinical risk factors. In patient populations with low rates of TB incidence and BCG vaccination, the use of both TST and IGRA may maximise sensitivity in detecting LTBI but may also reduce specificity.

[Therapy refractory polyarthritis and fever]. / Therapierefraktäre Polyarthritis und Fieber.

Primary manifestation of an autoinflammatory systemic disease was found in a 15-year-old patient, which initially ran a fulminant course. The course was first controlled by therapy with steroids and cyclosporin A. In the course of the disease, the patient developed a therapy refractory polyarthritis, which failed to respond to a combination of disease-modifying antirheumatic drugs (DMARDs) and tumor necrosis factor (TNF) inhibitors. A good disease control could only be achieved with an interleukin 6 (IL-6) blockade and DMARDs.

[Extra-articular manifestations of rheumatoid arthritis]. / Extraartikuläre Manifestationen der rheumatoiden Arthritis.

Rheumatoid arthritis (RA) represents an autoimmune disease affecting mostly joints, in particular small finger and toe joints. In addition RA can show extra-articular manifestations in many organs. Information on the frequency of extra-articular manifestations (EAMs) in RA varies greatly in different publications from 17.8% to 40.9% and EAMs tend to become higher with increasing duration and severity of the disease. The exact etiology and pathogenesis are still unclear but vasculitic alterations together with deposition of immune complexes can often be found histopathologically in affected organs. It must also be taken into consideration that EAMs can also be a result of the pharmaceutical therapy. The organ findings can vary greatly which is also reflected in the multitude of clinical symptoms. Possible target organs are the blood vessels, kidneys, central nervous system, cardiovascular system, the lungs, eyes, skin, nails as well as blood and the hemopoetic system. The prognosis for RA becomes progressively worse in the presence of EAMs. Regular and continuous control investigations are necessary in order to be able to diagnose EAMs early and to begin therapy. Therapy includes the administration of non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs) and especially in advanced stages cyclophosphamide or biologicals. Therapy is still very empirical due to the lack of appropriate studies.

[Tuberculosis : diagnostics and prophylaxis]. / Tuberkulose : Diagnostik und Prophylaxe.

Infection with Mycobacterium tuberculosis causes primarily formation of granulomatous tubercles in the lungs. In the absence of any clinical symptoms it is named latent tuberculosis infection which can be an origin of reactivation, especially as a consequence of an impaired response of the immune system. Complete anamnesis, radiographic methods and bacteriological analysis (microscopy, culture, PCR) are useful for diagnosis of tuberculosis. Since 2005 newer in vitro tests are available using interferon-gamma release assays (IGRAs). Compared to the tuberculin skin test it is possible to differentiate between infection with M. tuberculosis and individuals vaccinated with the Bacillus Calmette-Guérin (BCG) vaccine. These new in vitro tests are part of a screening procedure which has to be performed before starting immunosuppressive therapy with tumor necrosis factor-alpha (TNF-α) inhibitors. In cases of latent tuberculosis infection administration of isoniazid for 9 months is recommended.

[Value of fall-risk tests for patients with rheumatoid arthritis]. / Wertigkeit von Sturzrisikotests bei Patienten mit rheumatoider Arthritis.

The aim of the study was to quickly and efficiently determine the risk of falling in patients with rheumatoid arthritis over the age of 46 with established methods, to discover parameters which influence the risk of falling and fractures. The study group consisted of 67 patients (median age 69±7.4 years, duration of disease <10 years 71%).With the help of the present data on fractures the performance of the chair-rising (CR) test, the timed up-and-go (TUG) test and the tandem stand (TS) test plus determination of the average daily and cumulative glucocorticoid (GC) dosage, it was possible to detect parameters which influence the risk of falling and fractures.Higher age (>60 years), overweight, deficits in muscle strength in the lower extremities and very low GC dosage (≤5 mg) were found to be associated with an increased risk of falling, which is accompanied by an increased risk of fractures.

[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.