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The research consortium Neuroimmunology and Pain (Neuroimpa) explores the importance of the relationships between the immune system and the nervous system in musculoskeletal diseases for the generation of pain and for the course of fracture healing and arthritis.The spectrum of methods includes analyses at the single cell level, in vivo models of arthritis and fracture healing, imaging studies on brain function in animals and humans and analysis of data from patients.Proinflammatory cytokines significantly contribute to the generation of joint pain through neuronal cytokine receptors. Immune cells release opioid peptides which activate opioid receptors at peripheral nociceptors and thereby evoke hypoalgesia. The formation of new bone after fractures is significantly supported by the nervous system. The sympathetic nervous system promotes the development of immune-mediated arthritis. The studies show a significant analgesic potential of the neutralization of proinflammatory cytokines and of opioids which selectively inhibit peripheral neurons. Furthermore, they show that the modulation of neuronal mechanisms can beneficially influence the course of musculoskeletal diseases.Interventions in the interactions between the immune system and the nervous system hold a great therapeutic potential for the treatment of musculoskeletal diseases and pain.

After two decades of enormous improvements in anti-inflammatory therapy with biologics long-standing disease sequelae in chronic inflammatory diseases (CID) can be recognized, such as fatigue, anorexia/malnutrition, cachectic obesity, insulin resistance, dyslipidemia, changes of steroid hormone axes (e. g. loss of androgens), increased sympathetic nervous tone/decreased parasympathetic nervous tone, inflammation-related anemia and osteopenia. This article demonstrates for the first time in the German language a new theory to explain the pathophysiology of these disease sequelae. It includes concepts from evolutionary medicine and neuroendocrine regulation of energy allocation. The core statement is: the networks of energy regulation and energy allocation have been evolutionarily positively selected for transient inflammatory episodes (not for CIDs due to the negative selection pressure) but long-standing use of these adaptive programs for CID support systemic disease sequelae. These considerations might help to deviate focus from pure anti-inflammatory treatment to adequate diagnosis and therapy of systemic disease sequelae.

Circadian rhythms play an important role in the function of the body. Among others, the activity of the immune system is subject to daily variability which explains the different intensity of rheumatic symptoms during the day (e.g. morning stiffness). Circadian rhythms are subject to continuous adaptation via external time signals (zeitgebers), such as light-dark periods, time of food intake, as well as daily activity and resting periods. Following an acute phase shift of these external zeitgebers, e.g. via transmeridian travel (east-west or west-east), the body has to adjust all circadian systems to these new circumstances during an adjustment response, which lasts for several days. The classical symptoms of jet lag, such as tiredness during the day, mood swings and cognitive malfunction occur during this adjustment period. The impact of acute phase shifts as a result of transmeridian travel in subjects with rheumatic disorders, as well as strategies to prevent jet lag will be discussed in the following article.

Clinical observations in chronic inflammatory diseases have demonstrated the significant influence of neuroendocrine mechanisms on the immune system: (1) Amelioration of rheumatoid arthritis during pregnancy; (2) preponderance of women versus men with respect to autoimmune diseases; (3) negative effects of ovulation-inducing therapy, oral contraceptives, and hormone replacement therapy; (4) protective effect of hemiplegia; (5) influence of psychological stress on inflammation; and (6) influence of circadian rhythms on inflammatory symptoms.The effects of different hormones and neurotransmitters on the immune system are influenced by: (1) the immune stimulus (foreign antigens or autoantigens) and subsequent antigen-specific immune responses, (2) the cell types involved during different phases of the disease, (3) the target organ with its specific microenvironment, (4) the timing of hormone or neurotransmitter increase in relation to the disease course, (5) the concentration of hormones and neurotransmitters, (6) the variability in expression of receptors depending on the microenvironment and the cell type, and (7) the intra- and extracellular peripheral metabolism of hormones and neurotransmitters leading to important biologically active metabolites with quite different anti- and proinflammatory functions.The circadian rhythm of disease-related symptoms with a peak in the early morning hours confirms that the neuroendocrine system has a strong influence on these chronic immune/inflammatory diseases. The influence is transmitted by the circadian fluctuation in the activity of hormonal and neuronal pathways linking the brain to immune cell activation.These considerations could lead to novel therapeutic strategies for rheumatic diseases in the future.

Recent insights into the mechanisms of genomic and non-genomic glucocorticoid actions have stimulated the search for novel glucocorticoid receptor ligands. These efforts are driven by the need to improve the benefit-risk ratio of these important drugs. Glucocorticoids are very frequently and successfully used drugs which mediate important immunosuppressive and anti-inflammatory effects, but unfortunately they have pleiotropic effects causing a number of adverse reactions which limit their clinical use, especially at higher dosages and for longer periods. For this reason, novel glucocorticoid receptor ligands are being developed, among them selective glucocorticoid receptor agonists (SEGRAs). SEGRAs are drugs that predominantly induce transrepression effects (inhibition of protein synthesis), whereas the transactivation activity (induction of protein synthesis) is significantly reduced as compared with conventional glucocorticoid drugs. This makes sense since it became evident over the last few years that many adverse effects are predominantly caused by the transactivation mechanism, whereas anti-inflammatory effects are mostly mediated by transrepression mechanisms. Other interesting examples for exciting new developments are NO-glucocorticoids and long-circulating liposomal glucocorticoids. It is, however, true of all these developments that further in vivo and in vitro investigations and clinical trials will have to define in more detail their safety-efficacy profile in order to answer the questions whether these drugs as "improved glucocorticoids" will enter clinical medicine in the near future.

Vasculitides are rare diseases characterized by inflammation of blood vessels. According to diameter of the blood vessels involved in the inflammatory process, the clinical presentation and the histological appearance, different vasculitic syndromes may be distinguished. Primary vasculitides are of unknown origin while secondary vasculitides may be caused by drugs, malignancy or infection. Panarteriitis nodosa caused by chronic Hepatitis B and mixed cryoglobulinemia secondary to chronic Hepatitis C are classical examples of vasculitides triggered by infections. However, these are rare complications of chronic viral hepatitis. Patients infected by HIV frequently suffer from vasculitis, which may be caused by opportunistic infections and by defects in immune regulation. In numerous case reports, various other infectious particles have been reported to cause different forms of vasculitis, either by direct infection of endothelial cells or by induction of an immunologic process leading to blood vessel destruction. Immunologically mediated vasculitis secondary to infection may be due to a predisposing reactivity of the patient's immune system. After successful treatment of the infection, the vasculitis usually subsides. Therefore, all patients with vasculitis should be evaluated for underlying infection.