Stimulation of the vagus nerve as a therapeutic principle.

Modulation of the parasympathetic tone leads to extensive physiological reactions at several levels, including the decreased production of proinflammatory cytokines. Many studies have demonstrated that chronic inflammatory diseases are associated with reduced parasympathetic and increased sympathetic activities. Moreover, it was demonstrated that a low parasympathetic and a high sympathetic activity in patients with rheumatoid arthritis (RA) predicts a poor therapeutic response to anti-tumor necrosis factor (TNF) treatment compared to RA patients with a more balanced autonomic nervous system. The autonomic equilibrium could be restored by electrical stimulation of the vagus nerve. Considering the patients who do not sufficiently respond to the available drugs, patients for whom the effectiveness of the drugs wanes over time, or have drug-related adverse events, a nonpharmacological approach such as bioelectronics might be a useful supplement as an instrument in the successful extension of the therapeutic armamentarium for rheumatic diseases; however, there is a great need for further studies and the development of novel therapeutic strategies in the field of neuroimmunology.

[Stimulation of the vagus nerve as a therapeutic principle. German Version]. / Stimulation des Nervus vagus als therapeutisches Prinzip.

Modulation of the parasympathetic tone leads to extensive physiological reactions at several levels, including the decreased production of proinflammatory cytokines. Many studies have demonstrated that chronic inflammatory diseases are associated with reduced parasympathetic and increased sympathetic activities. Moreover, it was demonstrated that a low parasympathetic and a high sympathetic activity in patients with rheumatoid arthritis (RA) predicts a poor therapeutic response to anti-tumor necrosis factor (TNF) treatment compared to RA patients with a more balanced autonomic nervous system. The autonomic equilibrium could be restored by electrical stimulation of the vagus nerve. Considering the patients who do not sufficiently respond to the available drugs, patients for whom the effectiveness of the drugs wanes over time, or have drug-related adverse events, a nonpharmacological approach such as bioelectronics might be a useful supplement as an instrument in the successful extension of the therapeutic armamentarium for rheumatic diseases; however, there is a great need for further studies and the development of novel therapeutic strategies in the field of neuroimmunology.

[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.

[Refeeding syndrome : Pathophysiology, treatment and which rheumatic patients are particularly at risk]. / Refeeding-Syndrom : Pathophysiologie, Therapie und welche rheumatologischen Patienten besonders gefährdet sind.

Rheumatic diseases can lead to a state of malnutrition via a variety of mechanisms. Malnutrition is defined as an insufficient availability of energy, proteins, electrolytes and other nutrients compared to the requirements of a healthy body. After such a catabolic phase, a sudden resupply of the body's full caloric needs can cause life-threatening complications due to an acute paucity of electrolytes and micronutrients. Such metabolic disturbances occurring after the reconstitution of nutrition are termed refeeding syndrome. With sufficient background knowledge about the refeeding syndrome, physicians can prevent serious complications for patients through an adequate reconstitution of caloric intake, the monitoring of relevant laboratory parameters and the supplementation of deficient electrolytes and micronutrients. This review aims to explain the pathological mechanisms driving the refeeding syndrome, to identify risk factors for developing a refeeding syndrome especially in patients with rheumatic diseases and to present strategies to prevent the occurrence of the refeeding syndrome during nutrient reconstitution.

Interaction of pain and chronic inflammation.

Rheumatic diseases are characterized by chronic inflammation of synovial joints and are often associated with persistent pain and increased pain sensitivity. The inflammatory process is a complex cascade of events involving several mediators, which can lead to a chronic condition of pain. Inflammation can stimulate angiogenesis, and angiogenesis can facilitate inflammation. Inflammatory pain arises from tissue damage via the sensitization of pain receptors (nociceptors). The main peripheral mechanism underlying nociceptive pain is a change in the activity of the nociceptors located in the affected anatomical structures (joints, tendons, and ligaments), which renders them more sensitive to normally painful stimuli (hyperalgesia) or normally non-painful stimuli (allodynia). Neuroimmune interaction has been considered to play an essential role in rheumatic disease. Neurogenic inflammation, which influences normal central nervous system signaling, leads to insufficient signaling/bioavailability of various cytokines. These central mechanisms play an important role in the increased pain sensitivity following inflammation and are responsible for the development of secondary hyperalgesia in regions beyond the injured tissue. Reduction of pain in rheumatic disease requires familiarity with various pain mechanisms.

[Neurological symptoms in a patient on anti-TNF therapy, methotrexate and prednisolone for rheumatoid arthritis]. / Neurologische Symptome bei einer Patientin unter TNF-α-Inhibitor, Methotrexat und Prednisolon bei rheumatoider Arthritis.

A 78-year-old woman with rheumatoid arthritis on TNF-α inhibitor, methotrexate and prednisolone presented with severe but unspecific symptoms such as leg weakness, shivering, bifrontal headache, nausea and staggering. The broad range of differential diagnoses lead to intricate and time-consuming diagnostic procedures. Serology, magnetic resonance imaging and microbiological investigations represent important steps to make the final diagnosis of cerebral toxoplasmosis. Both diagnostic approach and therapy require close cooperation of different disciplines. Therapies of rheumatoid arthritis as well as of toxoplasmosis are based on a long-term treatment and could be associated with numerous harmful side effects. Continuous monitoring and permanent adjustment of therapy regimes are therefore mandatory.

[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.

[Depression as comorbidity of rheumatoid arthritis]. / Depression als Komorbidität bei rheumatoider Arthritis.

Depressive disorders are among the most common comorbidities in patients not only with rheumatoid arthritis (RA) but also with other forms of inflammatory rheumatic diseases. The prevalence of a depressive disorder in RA is estimated to be between 9.5% and 41.5% depending on the study and with women being more affected. After adjusting for sex, age and other parameters the risk of depression in RA was significantly elevated with an odds ratio of 1.63 (95% CI, 1.43-1.87) compared to the general population. In RA the risk of developing a depressive disorder is highest in the first 5 years and depression is a better predictor of work disability than disease activity and response to treatment. Depression in RA is associated with more pain, fatigue and impaired quality of life, whereby the association between depression and RA is bidirectional. Therefore, the risk to develop a depression is increased with impaired function as measured by the health assessment questionnaire (HAQ) and there is evidence that increased disease activity increases the risk for depression in RA. In addition, a depressive disorder also affects the subjective severity of patient-reported outcomes (PRO), such as tender joints and the global patient assessment with respect to disease activity and thus exhibiting a direct influence on the DAS28. Finally, it could be shown that depression unfavorably influences the response to therapy, the rate of remission is lower and the mortality is increased in RA patients. Taken together, this indicates that it is necessary to detect a depression in patients with RA as early as possible in order to initiate appropriate treatment of depression in such cases.

[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.

Insufficient vaccination rates in patients with systemic lupus erythematosus in a German outpatient clinic.

BACKGROUND: Patients with systemic lupus erythematosus (SLE) are at an increased risk of acquiring infections due to the disease itself and the immunosuppressive therapy. Furthermore, infections largely contribute to overall SLE mortality. Vaccinations against preventable diseases are therefore of particular importance for these patients. AIMS: To estimate vaccination frequencies among patients with SLE, we studied patients in a survey and calculated vaccination rates based on their vaccination documents. Patients were recruited from our outpatient clinic during one of their routine visits. For the statistical analysis, they have been stratified by age (≥60 vs. <60 years) for further subgroup analysis due to age-related recommendations for some vaccines. RESULTS: Among the patients studied (n = 68) we found rather low vaccination rates in particular for the strongly recommended vaccines against pneumococcus and influenza (21% and 49%, respectively). Furthermore, protection rates for important basic vaccinations were found to be low, e. g. pertussis protection for 31% of patients. Beside these findings, we saw age-dependant differences for a variety of vaccines: while the pneumococcus vaccination was more often given to patients ≥60 years, measles, pertussis, diphtheria and hepatitis B vaccinations were found significantly more often in younger patients. CONCLUSIONS: Vaccination rates have to be improved among SLE patients, in particular for vaccines protecting from respiratory tract infections such as pneumococcus and influenza.

[Autoimmune reactions to immune checkpoint inhibitors]. / Autoimmunologische Reaktionen bei Immun-Checkpoint-Inhibitoren.

Immune checkpoint inhibitors (ICI) have dramatically changed the face of cancer treatment and are gaining in importance. The ICIs have now been approved for the treatment of advanced cancers, including melanoma, non-small-cell and small cell lung cancers, renal cell carcinoma, Hodgkin's lymphoma, head and neck cancers and urothelial carcinoma and further indications are to be expected. The organs most affected by an autoimmune reaction are the intestines, the musculoskeletal system, skin, endocrine organs, the liver and the lungs. As the indications for immune checkpoint blockade expand and ICIs are used in combination, it becomes increasingly more important for rheumatologists to recognize immune-related adverse events (irAEs), their connection to cancer immunotherapy and how to treat these events appropriately. The role of rheumatologists will take on growing importance as immunotherapies become more common as standard treatment of cancer and when used earlier in the course of the disease. Previously controlled autoimmune diseases can deteriorate when using ICIs, so this is a consideration when evaluating patients. Increased awareness of inflammatory arthritis, as well as other rheumatic manifestations as an adverse association with cancer immunotherapies, is imperative for making the diagnosis. Treatment algorithms are based on the severity of symptoms but in the case of rheumatic disease, treatment often needs to be tailored to the individual. The general strategy for evaluation and management of irAEs includes a thorough evaluation for infections. Mild irAE may be self-limiting, while more severe reactions are generally steroid responsive, albeit with potentially high dosage requirements.

[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.

[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.

Efficacy, tolerability and safety of cannabinoids in chronic pain associated with rheumatic diseases (fibromyalgia syndrome, back pain, osteoarthritis, rheumatoid arthritis): A systematic review of randomized controlled trials.

BACKGROUND: In the absence of an ideal treatment for chronic pain associated with rheumatic diseases, there is interest in the potential effects of cannabinoid molecules, particularly in the context of global interest in the legalization of herbal cannabis for medicinal use. METHODS: A systematic search until April 2015 was conducted in Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, www.cannabis-med.org and clinicaltrials.gov for randomized controlled trials with a study duration of at least 2 weeks and at least ten patients per treatment arm with herbal cannabis or pharmaceutical cannabinoid products in fibromyalgia syndrome (FMS), osteoarthritis (OA), chronic spinal pain, and rheumatoid arthritis (RA) pain. Outcomes were reduction of pain, sleep problems, fatigue and limitations of quality of life for efficacy, dropout rates due to adverse events for tolerability, and serious adverse events for safety. The methodology quality of the randomized controlled trials (RCTs) was evaluated by the Cochrane Risk of Bias Tool. RESULTS: Two RCTs of 2 and 4 weeks duration respectively with nabilone, including 71 FMS patients, one 4-week trial with nabilone, including 30 spinal pain patients, and one 5-week study with tetrahydrocannbinol/cannabidiol, including 58 RA patients were included. One inclusion criterion was pain refractory to conventional treatment in three studies. No RCT with OA patients was found. The risk of bias was high for three studies. The findings of a superiority of cannabinoids over controls (placebo, amitriptyline) were not consistent. Cannabinoids were generally well tolerated despite some troublesome side effects and safe during the study duration. CONCLUSIONS: Currently, there is insufficient evidence for recommendation for any cannabinoid preparations for symptom management in patients with chronic pain associated with rheumatic diseases.

[S3 guidelines on long-term opioid treatment in non-cancer pain. Recommendations for opioid use in clinical rheumatology]. / S3-Leitlinie "Langzeitanwendung von Opioiden bei nicht tumorbedingten Schmerzen". Empfehlungen zum Einsatz von Opioiden für den klinisch tätigen Rheumatologen.

The long-term use of opioids for chronic pain can be problematic in many respects. Besides potentially harmful and considerable undesired side effects and possible drug abuse, the indications for prescription, efficacy and safety in the long run have to be considered. The recently updated S3 guidelines on long-term opioid treatment in non-cancer pain (LONTS) provide recommendations with the highest currently available evidence. This article summarizes the most relevant contents for the clinical rheumatologist.

[Differential diagnosis of sternoclavicular arthritis]. / Differenzialdiagnose der Sternoclaviculararthritis.

A 47-year-old male patient presented with a 6-month history of a painful swelling in the region of the right sternoclavicular joint together with fatigue. Initial investigations including X-rays of the sternoclavicular joint did not reveal any pathological conditions. Eventually, a CT scan revealed marked joint destruction, pulmonary condensation, and enlargement of the adrenal glands. Subsequent procedures, such as joint fluid aspiration and bronchoalveolar lavage, proved to be positive for Mycobacterium tuberculosis. After initiation of a standard combination therapy (four tuberculostatic drugs) the general condition of the patient stabilized and he was discharged from hospital after 4 weeks.

[Pain management in elderly patients]. / Schmerztherapie bei älteren Patienten.

Given the current demographic changes there are an increasing number of elderly and very elderly patients in outpatient and inpatient care. Elderly and very elderly patients often suffer from pain and musculoskeletal conditions are a common cause of pain in the elderly. An effective pain management should not be withheld from elderly patients with rheumatic diseases. Untreated pain in elderly patients leads to functional impairment and immobility. In addition, the quality of life of patients is negatively affected and can lead to a loss of autonomy and/or social withdrawal. The treatment of elderly and very elderly patients is particularly challenging. There are special features that need to be considered in the choice of treatment. Altered pain presentation, comorbidities, nonadherence, polypharmacy and side effects of pain medications require a critical risk-benefit assessment and ongoing treatment monitoring of this special group of patients.