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Aims: To investigate the circadian variation in IL-6 and effects of morning and night time glucocorticoids in polymyalgia rheumatica. Methods: Cytokines were measured in newly diagnosed polymyalgia rheumatica over two 24-h periods, 2 weeks apart during which they received 7 mg/day of modified-release prednisone at night or morning prednisolone. All patients then received 15 mg/day morning prednisolone. Morning IL-6 concentrations were measured after 2 weeks. Morning stiffness, changes in peak IL-6 levels and area under the curve were compared. Results: IL-6 followed a circadian rhythm with a peak at 04h00. Modified-release prednisone caused greater reduction of IL-6 and area under the curve. Conclusion: IL-6 showed marked circadian variation. The possibility that modified-release prednisone offers a treatment advantage over standard therapy should be tested in a larger study.

Objective Observations in both animal models of arthritis and patients with rheumatoid arthritis (RA) suggest a role for dopamine and its receptors in RA. Because synovial fibroblasts (SFs) contribute to inflammation and joint destruction in RA, the aim of this study was to investigate dopaminergic pathways in SFs obtained from patients with RA and, for comparison, in SFs from patients with osteoarthritis (OA) undergoing knee joint replacement surgery. Methods The expression of all dopamine receptors (D1–D5) and dopamine transporter was assessed by immunofluorescence and immunohistochemical staining. The levels of dopamine receptor and tyrosine hydroxylase messenger RNA were measured by real-time polymerase chain reaction. The intracellular content of dopamine, its precursor, and its main metabolites was assayed by high-performance liquid chromatography. The influence of dopamine on proinflammatory interleukin-6 (IL-6) and IL-8, matrix metalloproteinase 3, and tissue inhibitor of metalloproteinases 1 (TIMP-1) and TIMP-2 was studied in SFs. Results SFs possess an intrinsic dopaminergic system, including dopamine receptors, dopamine transporter, and tyrosine hydroxylase, and contain dopamine, its precursor, and its main metabolites. SFs from patients with RA, in comparison with those from patients with OA, showed increased expression of dopamine receptors D1 and D5, and exogenous dopamine strongly inhibited the production of IL-8 in patients with RA. Conclusion SFs from patients with RA and patients with OA show a dopaminergic phenotype. The expression of D1-like dopamine receptors was higher in RASFs, and this increased expression may lead to antiinflammatory effects, as demonstrated by the expression of IL-8. Studies in animal models and patients with RA are needed to assess the therapeutic potential of endogenous, local production of dopamine in synoviocytes.

Objective Sensory and sympathetic nerve fibers (SNF) innervate bone and epiphyseal growth plate. The role of neuronal signals for proper endochondral ossification during skeletal growth is mostly unknown. Here, we investigated the impact of the absence of sensory neurotransmitter substance P (SP) and the removal of SNF on callus differentiation, a model for endochondral ossification in adult animals, and on bone formation. Methods In order to generate callus, tibia fractures were set in the left hind leg of wild type (WT), tachykinin 1-deficient (Tac1 −/−) mice (no SP) and animals without SNF. Locomotion was tested in healthy animals and touch sensibility was determined early after fracture. Callus tissue was prepared for immunofluorescence staining for SP, neurokinin1-receptor (NK1R), tyrosine-hydroxylase (TH) and adrenergic receptors α1, α2 and β2. At the fracture site, osteoclasts were stained for TRAP, osteoblasts were stained for RUNX2, and histomorphometric analysis of callus tissue composition was performed. Primary murine bone marrow derived macrophages (BMM), osteoclasts, and osteoblasts were tested for differentiation, activity, proliferation and apoptosis in vitro. Femoral fractures were set in the left hind leg of all the three groups for mechanical testing and μCT-analysis. Results Callus cells stained positive for SP, NK1R, α1d- and α2b adrenoceptors and remained β2-adrenoceptor and TH-negative. Absence of SP and SNF did not change the general locomotion but reduces touch sensitivity after fracture. In mice without SNF, we detected more mesenchymal callus tissue and less cartilaginous tissue 5 days after fracture. At day 13 past fracture, we observed a decrease of the area covered by hypertrophic chondrocytes in Tac1 −/− mice and mice without SNF, a lower number of osteoblasts in Tac1 −/− mice and an increase of osteoclasts in mineralized callus tissue in mice without SNF. Apoptosis rate and activity of osteoclasts and osteoblasts isolated from Tac1 −/− and sympathectomized mice were partly altered in vitro. Mechanical testing of fractured- and contralateral legs 21 days after fracture, revealed an overall reduced mechanical bone quality in Tac1 −/− mice and mice without SNF. μCT-analysis revealed clear structural alteration in contralateral and fractured legs proximal of the fracture site with respect to trabecular parameters, bone mass and connectivity density. Notably, structural parameters are altered in fractured legs when related to unfractured legs in WT but not in mice without SP and SNF. Conclusion The absence of SP and SNF reduces pain sensitivity and mechanical stability of the bone in general. The micro-architecture of the bone is profoundly impaired in the absence of intact SNF with a less drastic effect in SP-deficient mice. Both sympathetic and sensory neurotransmitters are indispensable for proper callus differentiation. Importantly, the absence of SP reduces bone formation rate whereas the absence of SNF induces bone resorption rate. Notably, fracture chondrocytes produce SP and its receptor NK1 and are positive for α-adrenoceptors indicating an endogenous callus signaling loop. We propose that sensory and sympathetic neurotransmitters have crucial trophic effects which are essential for proper bone formation in addition to their classical neurological actions.

Objective Mesenchymal progenitor cell chondrogenesis is the biologic platform for the generation or regeneration of cartilage, but the external influence of the sympathetic nervous system on this process is not yet known. Sympathetic nerve fibers are present in articular tissue, and the sympathetic nervous system influences the musculoskeletal system by, for example, increasing osteoclastogenesis. This study was initiated to explore the role of the sympathetic neurotransmitter norepinephrine (NE) in mesenchymal stem cell (MSC)–dependent and cartilage progenitor cell (CPC)–dependent chondrogenesis. Methods Using human MSCs or CPCs, chondrogenic differentiation was induced in the presence of NE, the specific β-adrenergic receptor (β-AR) agonist isoproterenol, and the specific β-AR antagonist nadolol. We studied sympathetic nerve fibers, tyrosine hydroxylase (TH) expression, catecholamine biosynthesis, and synovial fluid levels in human joints, as well as cartilage-specific matrix deposition during differentiation. Results TH+ sympathetic nerve fibers were present in the synovial tissue, meniscus, and subchondral bone marrow. In addition, synovial fluid from patients with knee trauma demonstrated high concentrations of NE. During MSC or CPC chondrogenesis, β-AR were expressed. Chondrogenic aggregates treated with NE or isoproterenol synthesized lower amounts of type II collagen and glycosaminoglycans. NE and isoproterenol treatment dose-dependently increased the levels of cartilage hypertrophy markers (type X collagen and matrix metalloproteinase 13). Nadolol reversed the inhibition of chondrogenesis and the up-regulation of cartilage hypertrophy. Conclusion Our findings demonstrate NE-dependent inhibition of chondrogenesis and acceleration of hypertrophic differentiation. By inhibiting cartilage repair, these sympathetic influences can be important after joint trauma. These findings may be a basis for novel neurochondrogenic therapeutic options.

Objectives In rheumatoid arthritis, inadequate cortisol secretion was observed relative to inflammation, but reasons are unknown. Human adrenal glands cannot be investigated due to ethical reasons. Thus, a model of arthritis was studied to test inadequate glucocorticoid secretion and adrenocortical alterations. Methods Arthritis in DA rats was induced by collagen type II. Plasma hormone (cytokine) levels were determined by ELISA or radioimmunoassay (Luminex). Adrenocortical cells were investigated making use of in vitro culture, immunohistochemistry and imaging techniques, cholesterol uptake studies and electron microscopical morphological analyses of adrenocortical lipid droplets and mitochondria. Results During the course of arthritis, corticosterone and adrenocorticotropic hormone (ACTH) levels were only elevated on day 1 after immunisation but were in the normal range from day 5 to 55. Serum levels of corticosterone relative to IL-1β were markedly lower in arthritis than in controls. IL-1β inhibited ACTH-stimulated corticosterone secretion from adrenocortical cells in vitro. Cholesterol uptake receptor SR-BI protein was unchanged. Number of altered swollen and cavitated mitochondria increased during the course of arthritis (maximum on day 55), and this was correlated to reduced breakdown of lipid droplets and increased Sudan III-positive lipid accumulation from day 28 to 55. Reduced lipid breakdown measured as a high number of homogenous lipid droplets negatively correlated with plasma corticosterone (p=0.022). Adrenocortical tissue density of normal mitochondria positively correlated with serum corticosterone levels. Conclusions This study on inadequate adrenal glucocorticoid secretion in arthritis demonstrated altered mitochondria and altered lipid breakdown paralleled by low corticosterone levels in relation to inflammation. IL-1β is a key cytokine.

Joints are densely innervated by postganglionic sympathetic nerve fibers. These fibers control the blood flow in the joint and vascular permeability, either directly or indirectly, in cooperation with leukocytes. Chemical sympathectomy or suppression of adrenergic signaling significantly reduces inflammatory processes in the initial acute state of inflammation whereas the same procedures may increase inflammation at later stages. These findings indicate that the sympathetic nervous system supports the development of inflammation but may reduce inflammation at more chronic stages. During chronic inflammation the density of sympathetic nerve fibers in synovial tissue is reduced but other tyrosine hydroxylase-positive cells secreting noradrenaline appear in the inflamed joint. In addition to local vascular effects in the joint, the sympathetic nervous system influences numerous immune processes in the joint and in lymphoid organs. Hence the net effect of the sympathetic nervous system on inflamed tissue results from local sympathetic effects in the joint as well as from sympathetic influences on major systemic immune processes.

In chronic inflammatory diseases (CIDs), the neuroendocrine-immune crosstalk is important to allocate energy-rich substrates to the activated immune system. Since the immune system can request energy-rich substrates independent of the rest of the body, I refer to it as the "selfish immune system," an expression that was taken from the theory of the "selfish brain," giving the brain a similar position. In CIDs, the theory predicts the appearance of long-term disease sequelae, such as metabolic syndrome. Since long-standing energy requirements of the immune system determine disease sequelae, the question arose as to whether chronic psychological stress due to chronic activation of the brain causes similar sequelae. Indeed, there are many similarities; however, there are also differences. A major difference is the behavior of body weight (constant in CIDs versus loss or gain in stress). To explain this discrepancy, a new pathophysiological theory is presented that places inflammation and stress axes in the middle.

Sex hormones play an active role in inflammatory responses, with androgens being anti-inflammatory, whereas estrogens have both pro- and anti-inflammatory effects. In rheumatoid arthritis (RA) patients, low levels of androgens and high levels of estrone are found in the synovial fluid. Aromatase is the key enzyme for the conversion of androgens into estrogens. Proinflammatory cytokines stimulate aromatase activity so that the inflammatory milieu can induce conversion of androgens to estrogens. Moreover, testosterone inhibits aromatase activity. As local androgen levels are low in RA, this can contribute to high aromatase activity in the synovium. Importantly, aromatase-converted estrogens are converted into proproliferative and proinflammatory 16-hydroxylated estrogens. A hormone involved in aromatase activity is vitamin D, which downregulates aromatase in human RA macrophages. Collectively, evidence suggests a key role of aromatase in sex hormone balance during chronic inflammation and points to the importance of vitamin D as a possible new tool for aromatase modulation.

Background Neuroendocrine immunology in musculoskeletal diseases is an emerging scientific field. It deals with the aspects of efferent neuronal and neurohormonal bearing on the peripheral immune and musculoskeletal systems. This review aims to add new information that appeared since 2001. Search strategy The following PubMed search sentence was used to find a total of 15,462 references between 2001 and March 2013: "(rheum ⁎ OR SLE OR vasculitis) AND (nerve OR hormone OR neurotransmitter OR neuropeptide OR steroid)." In a continuous process, year by year, this search strategy yielded relevant papers that were screened and collected in a database, which build the platform of this review. Results The main findings are the anti-inflammatory role of androgens, the loss of androgens (androgen drain), the bimodal role of estrogens (support B cells and inhibit macrophages and T cells), increased conversion of androgens to estrogens in inflammation (androgen drain), disturbances of the gonadal axis, inadequate amount of HPA axis hormones relative to inflammation (disproportion principle), biologics partly improve neuroendocrine axes, anti-corticotropin-releasing hormone therapies improve inflammation (antalarmin), bimodal role of the sympathetic nervous system (proinflammatory early, anti-inflammatory late—most probably due to catecholamine-producing local cells), anti-inflammatory role of alpha melanocyte-stimulating hormone, vasoactive intestinal peptide, and the Vagus nerve via α7 nicotinergic receptors. Circadian rhythms of hypothalamic origin are responsible for circadian rhythms of symptoms (neuroimmune link revealed). Important new pain-sensitizing immunological pathways were found in the last decade. Conclusions The last decade brought much new information that gave birth to the first therapies of chronic inflammatory diseases on the basis of neuroendocrine immune targets. In addition, a new theory linked evolutionary medicine, neuroendocrine regulation of distribution of energy-rich fuels, and volume regulation that can explain many disease sequelae in patients with chronic inflammatory diseases.

A shift from anti- to proinflammatory steroid hormones has been observed in chronic inflammation. We tested the hypothesis that this shift occurs also in kidney transplant rejection together with a rise of urinary catecholamine degradation product concentrations as a consequence of locally produced cytokines, thus further promoting rejection.We examined 8 patients with an early rejection episode in the protocol biopsy ∼2 weeks, 9 with biopsy-proven rejection at 2-3 months, and 18 without rejection, both at 2 weeks and 3 months after transplantation. Metanephrine, normetanephrine, and 2- and 16-hydroxyestrogens concentrations were measured by EIA.The median urinary concentrations of normetanephrine, but not metanephrine, were significantly higher in acute kidney transplant rejection in the first 2 weeks after transplantation (P.05). During acute kidney transplant rejection at 2-3 months, but not in the first 2 weeks, after transplantation, 2-, but not 16-hydroxyestrogens, concentrations were significantly decreased (P.05).We demonstrated that the downstream product of noradrenaline conversion normetanephrine was elevated in kidney transplant rejection in the first weeks after transplantation. This change may promote rejection together with an important proinflammatory and mitogenic steroid hormone shift, which becomes increasingly relevant over time.

The effects of social stress on several blood immune measures and collagen-induced arthritis (CIA) were investigated in Wistar rats using the resident–intruder confrontation paradigm to induce stress of different intensity. Male intruders were exposed for one week to a dominant opponent either repeatedly for 4 h daily (moderate stress) or continuously (severe stress). Arthritis was induced by intradermal injection of collagen type II (CII) into the tail skin at the end of day 3 of confrontation. Only severe stress was associated with decreased CD4 and CD8 T cells, and the increase in granulocyte numbers and body mass loss was more pronounced under these conditions. Only severe stress reduced the susceptibility to arthritis by about 50%. Severity scores did not differ in the first five days after disease onset between all groups. Subsequent experiments focused on severely stressed rats indicated that disease progressed until day 10 only in control animals, but not in severely stressed males. Stressor exposure resulted in increased blood monocyte numbers, but these males failed to accumulate macrophages into the skin at the site of CII injection. High numbers of attacks experienced by intruders correlated with delayed disease onset in severely stressed rats. We hypothesize that severe stress persisting after disease induction exhibits beneficial effects on the susceptibility of CIA and propose that the specific endocrine and immunological profile associated with severe stress is an important factor for disease outcome – a factor which probably explains many of the conflicting data of previous stress studies on CIA.

The peripheral nervous system is critically involved in metabolism of joint tissue and intervertebral disks (IVD). Nerve fibers of sympathetic and sensory origin innervate synovial tissue and subchondral bone of diarthrodial joints. In pathophysiological situations as in osteoarthritis (OA), rheumatoid arthritis (RA), and IVD degeneration, innervation patterns of sympathetic and sensory nerve fibers are partly altered in joint tissue and IVD.

Background & Aims Splanchnic vasodilation is an essential disturbance in portal hypertension. Increased systemic sympathetic nerve activity is well known, but potential corresponding vascular desensitization is incompletely characterized. Release of splanchnic sympathetic neurotransmitters noradrenaline (NA) and co-transmitter neuropeptide Y (NPY) remains to be elucidated. Finally, the effects of exogenous NPY on these mechanisms are unexplored. Methods Portal vein ligated cirrhotic, and control rats were used for in vitro perfusion of mesenteric arteries. Depletion of vascular pressure response was induced by repetitive electric sympathetic perivascular nerve stimulation (PNS) and performed in the absence and presence of exogenous NPY. Additionally, PNS-induced release of NA and NPY was measured. Results Mesenteric PNS-induced pressure response was lower in portal hypertension. Depletion of the pressure response to PNS, representing the degree of desensitization, was enhanced in portal hypertension. NA release was elevated, whereas NPY release was attenuated in cirrhosis. Administration of exogenous NPY led to marked recovery from desensitization and vasoconstrictive improvement in cirrhotic rats, being associated with more pronounced decrease of NA release. Conclusions Pronounced depletion of splanchnic arterial pressure-response to repetitive sympathetic nerve stimulation in cirrhosis is partly attributable to altered NA release as well as to deficient NPY release. External NPY restores vascular contractility and attenuates pathologically elevated NA release in the portal hypertensive mesenteric vasculature, revealing post-, and prejunctional effects at the vascular smooth muscle motor endplate; therefore outlining encouraging therapeutic strategies.

Aims In rheumatoid arthritis and collagen type II arthritis (CIA), sympathetic nerve fibers get lost in inflamed tissue. The process is probably induced by nerve repellent factors like semaphorin 3F (SEMA3F). Repulsion of sympathetic nerve fibers in inflamed tissue has proinflammatory effects due to the loss of anti-inflammatory neurotransmitters. We hypothesized that design molecules like antibodies and specific peptides that inhibit nerve fiber repulsion can ameliorate CIA. Materials and methods Two blocking antibodies were used and four blocking peptides were generated using the phage display technique with the targets of SEMA3F and plexin-A2. All blocking molecules were tested in vitro using a sympathetic neurite outgrowth assay. CIA was induced by collagen type II in mice. Key findings In the neurite outgrowth assay, the two antibodies against plexin-A2 and neuropilin-2 as well as the four blocking peptides – two SEMA3F analogous peptides (WLFQRDPGDR, QATVKWLFQRDPGDRR) and two plexin A2 analogous peptides (DSSDQFSFDYELEQN, DSSIQFFSFEKDKERI) - were able to block sympathetic nerve fiber repulsion in vitro (at 150–600 nmol/l). Administration of the two antibodies prophylactically on day 4 after immunization did not change clinical CIA. Similarly, using the top candidate antibody to plexin-A2 after CIA onset (mild score of 4 points, maximum = 52 points), did not ameliorate CIA. The tested blocking peptides were not recovered in peripheral blood after i.v. and i.p. administration. Significance While designer molecules blocked nerve fiber repulsion in vitro, therapeutic administration in vivo did not change CIA. Possible strategies to overcome negative effects demonstrated in vivo are discussed.

Objective. In rheumatoid arthritis (RA) synovial fluid, levels of the endocannabinoids anandamide (AEA) and 2-arachidonylglycerol are elevated. Since synovial fibroblasts (SFs) possess all of the enzymes necessary for endocannabinoid synthesis, it is likely that these cells contribute significantly to elevated endocannabinoid levels. While glucocorticoids initiate endocannabinoid synthesis in neurons, this study was undertaken to test whether cortisol also regulates endocannabinoid levels in mesenchymal cells such as SFs, and whether this interferes with integrin-mediated adhesion. Methods. Adhesion was determined in 1-minute intervals over 60 minutes using an xCELLigence system. Slopes from individual treatment groups were averaged and compared to the control. Fatty acid amide hydrolase (FAAH) and cyclooxygenase 2 (COX-2) were detected by immunocytochemistry, and AEA was detected by mass spectrometry. Results. Cortisol increased the adhesion of RASFs and osteoarthritis SFs with a maximum of 200% at both 10 7 M and 10 8 M. When cortisol was administered together with either cannabinoid receptor 1 (CB1) antagonist (rimonabant; 100 nM), CB2 antagonist (JTE907; 100 nM), transient receptor potential vanilloid channel 1 (TRPV-1) antagonist (capsazepine; 1 M), FAAH inhibitor, or COX-2 inhibitor, adhesion was reduced below the level in controls. Concomitant inhibition of FAAH and COX-2 reversed these effects. Mass spectrometry revealed the presence of AEA in SFs. Conclusion. Our findings indicate that glucocorticoid-induced adhesion is dependent on CB1/ CB2/TRPV-1 activation. Since AEA is produced in SFs, this endocannabinoid is the most likely candidate to mediate these effects. Since AEA levels are regulated by COX-2 and FAAH, inhibition of both enzymes along with low-dose glucocorticoids may provide a therapeutic option to maximally boost the endocannabinoid system in RA, with possible beneficial effects.

Loss of sympathetic nerve fibers (SNFs) occurs in inflamed tissue; and select semaphorins, upregulated during inflammation, stimulate repulsion/loss of SNFs. However, it is unknown whether other factors released locally in inflamed tissue, such as norepinephrine, dopamine, and 17β-estradiol, are also repellent. In order to study the effects of hormones on SNF repulsion, an SNF outgrowth assay was used. The repellent activity of semaphorins 3C was weaker than of semaphorin 3F. Tumor necrosis factor α (TNF-α) repelled nerve fibers with moderate to strong effects (from 0-100% repulsion). High concentrations of dopamine and norepinephrine (10(-6) M) induced weak but significant nerve fiber repulsion (up to 20%). Norepinephrine at 10(-8) M was comparable with 10(-6) M at inducing nerve fiber outgrowth. Stimulation with low concentrations of 17β-estradiol (10(-10) M, but not 10(-8) M) repelled SNFs. These results demonstrate that not only specific axon guidance molecules, such as semaphorins 3F and 3C, but also hormonal factors and TNF-α influence SNF repulsion and outgrowth.

Objective Proliferating pannus is in many aspects similar to placental tissue. Both fibroblast-rich tissues have high vascularity, and tissue from patients with rheumatoid arthritis (RA) and patients with osteoarthritis (OA) demonstrates conversion of androgenic prehormones to downstream estrogens. We undertook this study to investigate similarities between proliferating pannus and placental tissue by focusing on angiogenic placenta growth factor 1 (PlGF-1) in patients with OA and patients with RA. Methods We used immunohistochemistry to study the presence of PlGF-1, its synovial distribution, and the PlGF-1–expressing synovial cell type. The relationship between PlGF-1 and conversion of the biologically inactive placental prehormone dehydroepiandrosterone sulfate (DHEAS) to the biologically active dehydroepiandrosterone (DHEA) was investigated in mixed synovial cells. The effects of DHEA on PlGF-1 expression were studied by intracellular fluorescence-activated cell sorting analysis. Results PlGF-1–positive cells were detected in the lining and sublining areas in patients with RA and patients with OA, and cellular density was similar. Double staining revealed that PlGF-1–positive cells were macrophages. In RA and OA, the density of PlGF-1–positive cells correlated positively with the density of macrophages and the density of type IV collagen–positive vessels. The supernatant concentration of 3H-DHEA after conversion from 3H-DHEAS and the density of aromatase-positive cells were positively correlated with the density of PlGF-1–positive cells only in OA. Low DHEA concentrations (≤10−9M) had stimulatory effects on PlGF-1 when compared to serum concentrations (10−8M to 10−7M) in the monocytic cell line THP-1 and in primary mixed synovial cells. Conclusion PlGF-1 functions similarly in inflamed synovium and in the placenta. It is related to vessel formation and, in OA patients, to androgen/estrogen conversion. Evolutionarily conserved functions of PlGF-1 for placental phenomena are obviously also present in synovial inflammation.

We tested the hypothesis that increased urinary cytokine concentrations may indicate an acute kidney transplant rejection. Eight patients with an early rejection in their protocol biopsy about 14days after transplantation (group A), 9 patients with a biopsy proven rejection 2-3months after transplantation (group B) and 18 patients without acute rejection in their protocol biopsies both at 14days and 3months (group C, represents the control group) were chosen for this study. At the time of biopsy, the mean urinary concentration of interleukin 6 (IL6), soluble IL6 receptor (sIL6R), tumor necrosis factor receptor 1 (TNFR1), and soluble vascular cell adhesion molecule -1 (sVCAM-1) were significantly higher in patients with an early acute transplant rejection, i.e. in group A compared to patients in the control group (p0.01). Additionally we found already 14days after transplantation significantly higher concentrations of urinary sIL6R and sVCAM-1 in group B patients who suffered of late acute rejection compared to patients with no acute rejection (group C, p0.05). No significant correlation could be shown for interleukin 1 receptor antagonist (IL1ra), TNF, and TNFR2. In conclusion, elevated urinary concentrations of IL6, sIL6R, TNFR1 and sVCAM-1 clearly indicate an early acute transplant rejection. Especially sVCAM-1 may also serve as an early marker of an upcoming late rejection. However, further studies are warranted to verify the value of individual cytokine profiles to predict acute rejection episodes.

During the last 10 years, a series of exciting observations has led to a new theory of pathophysiology using insights from evolutionary biology and neuroendocrine immunology to understand the sequelae of chronic inflammatory disease. According to this theory, disease sequelae can be explained based on redirection of energy-rich fuels from storage organs to the activated immune system. These disease sequelae are highly diverse and include the following: sickness behavior, anorexia, malnutrition, muscle wasting–cachexia, cachectic obesity, insulin resistance with hyperinsulinemia, dyslipidemia, increase of adipose tissue near inflamed tissue, alterations of steroid hormone axes, elevated sympathetic tone and local sympathetic nerve fiber loss, decreased parasympathetic tone, hypertension, inflammation-related anemia, and osteopenia. Since these disease sequelae can be found in many animal models of chronic inflammatory diseases with mammals (e.g., monkeys, mice, rats, rabbits, etc.), the evolutionary time line goes back at least 70 million years. While the initial version of this theory could explain prominent sequelae of chronic inflammatory disease, it did not however address two features important in the pathogenesis of immune-mediated diseases: the time point when an acute inflammatory disease becomes chronic, and the appearance of hypertension in chronic inflammation. To address these aspects more specifically, a new version of the theory has been developed. This version defines more precisely the moment of transition from acute inflammatory disease to chronic inflammatory disease as a time in which energy stores become empty (complete energy consumption). Depending on the amount of stored energy, this time point can be calculated to be 19–43 days. Second, the revised theory addresses the mechanisms of essential hypertension since, on the basis of water loss, acute inflammatory diseases can stimulate water retention using a positively selected water retention system (identical to the energy provision system). In chronic smoldering inflammation, however, there is no increased water loss. In contrast, there is increased water generation in inflamed tissue and inflammatory cells, and the activation of the water retention system persists. This combination leads to a net increase of the systemic fluid volume, which is hypothesized to be the basis of essential hypertension (prevalence in adults 22–32%).

Objectives Theoretical considerations support the hypothesis that functionally relevant genes were not positively selected for symptomatic chronic inflammatory diseases (CIDs) because of 3 major reasons: 1) high negative selection pressure with loss of reproducibility; 2) no selection pressure at all (many CIDs of today manifest in higher ages, and due to low life expectancy of our ancestors, they did not suffer from CIDs that we know today); 3) there was no time for natural selection (various CIDs did not exist long enough). Nevertheless, genes can be transferred before outbreak of a CID and can confer an increased risk. However, these genes were positively selected for fitness in reproduction and survival at younger ages independent of a symptomatic CID (antagonistic pleiotropy). Thus, relevant genes were conserved for non-life-threatening inflammatory episodes (NOLTIES) such as infection or wound healing, which did not impede positive selection. Importantly, blastocyst implantation and embryogenesis are NOLTIES. We hypothesized that factors relevant in blastocyst implantation and embryogenesis are also found in active tissue inflammation of a CID. Methods Rheumatoid arthritis (RA) was used as a paradigmatic CID. An extensive database search in PubMed and OMIM of the U.S. National Library of Medicine was conducted. Results Many important similarities between RA and blastocyst implantation/embryogenesis were found including stem cell pathways, hormonal pathways, angiogenesis, neuronal pathways, the wingless (Wnt) pathway, the Notch pathway, the TGF-beta superfamily, matrix metalloproteinases, and others. Conclusions It turned out that many factors of RA inflammation were borrowed from the non-life-threatening episode of blastocyst implantation and embryogenesis.

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.

Aim: The effect of prednisone on the morning joint stiffness of rheumatoid arthritis (RA) is enhanced by night-time (2 am) administration. It has been hypothesized that this may be due to suppression of the pathological early-morning rise in plasma IL-6, but this has not yet been measured. A theoretical disadvantage of night-time prednisone is increased suppression of the hypothalamic–pituitary–adrenal axis and reduced peak plasma cortisol levels, usually attained at approximately 7 am. This study measured 24-h variations in IL-6, other cytokines and cortisol in patients before and after a 2-week course of night-time prednisone to address both these questions. Materials & methods: Nine patients with active RA were clinically assessed and had 24-h blood sampling before and after a 2-week course of timed-release tablet (TRT) prednisone (5 mg per day). Patients took the TRT orally at 10 pm and the prednisone was released at 2 am. Changes in circadian variation in cortisol and IL-6 and clinical measures were ...

In rheumatoid and collagen-induced arthritis (CIA) relative insufficiency of adrenal glands (AG) in later stages of the disease is known. Additionally, migration of macrophages and dendritic cells (DCs) into AG has been described. We hypothesized that these cells contribute to inadequate glucocorticoid secretion. CIA was induced in DA rats. Cytokines in supernatants from whole AG cells, AG cells after magnetic bead separation for macrophage/DC markers MHCII and CD11b, and from bone marrow-derived DCs (BMDC) were quantified with ELISA. The corticosterone secretion from whole AG cells in co-culture with BMDCs was quantified with ELISA. BMDCs generated from arthritic rats expressed significantly more IL-1b, CINC-1,-2,-3, and LIX (all p

There has been a consistent gap in understanding how TNF-α neutralization affects the disease state of arthritis patients so rapidly, considering that joint inflammation in rheumatoid arthritis is a chronic condition with structural changes. We thus hypothesized that neutralization of TNF-α acts through the CNS before directly affecting joint inflammation. Through use of functional MRI (fMRI), we demonstrate that within 24 h after neutralization of TNF-α, nociceptive CNS activity in the thalamus and somatosensoric cortex, but also the activation of the limbic system, is blocked. Brain areas showing blood-oxygen level-dependent signals, a validated method to assess neuronal activity elicited by pain, were significantly reduced as early as 24 h after an infusion of a monoclonal antibody to TNF-α. In contrast, clinical and laboratory markers of inflammation, such as joint swelling and acute phase reactants, were not affected by anti-TNF-α at these early time points. Moreover, arthritic mice overexpressing human TNF-α showed an altered pain behavior and a more intensive, widespread, and prolonged brain activity upon nociceptive stimuli compared with wild-type mice. Similar to humans, these changes, as well as the rewiring of CNS activity resulting in tight clustering in the thalamus, were rapidly reversed after neutralization of TNF-α. These results suggest that neutralization of TNF-α affects nociceptive brain activity in the context of arthritis, long before it achieves anti-inflammatory effects in the joints.

The immunomodulatory effect of the autonomic nervous system has raised considerable interest over the last decades. Studying the influence on the immune system and the role in inflammation of the sympathetic as well as the parasympathetic nervous system not only will increase our understanding of the mechanism of disease, but also could lead to the identification of potential new therapeutic targets for chronic immune-mediated inflammatory diseases, such as rheumatoid arthritis (RA). An imbalanced autonomic nervous system, with a reduced parasympathetic and increased sympathetic tone, has been a consistent finding in RA patients. Studies in animal models of arthritis have shown that influencing the sympathetic (via alpha- and beta-adrenergic receptors) and the parasympathetic (via the nicotinic acetylcholine receptor alpha 7nAChR or by electrically stimulating the vagus nerve) nervous system can have a beneficial effect on inflammation markers and arthritis. The immunosuppressive effect of the parasympathetic nervous system appears less ambiguous than the immunomodulatory effect of the sympathetic nervous system, where activation can lead to increased or decreased inflammation depending on timing, doses and kind of adrenergic agent used. In this review we will discuss the current knowledge of the role of both the sympathetic (SNS) and parasympathetic nervous system (PNS) in inflammation with a special focus on the role in RA. In addition, potential antirheumatic strategies that could be developed by targeting these autonomic pathways are discussed. (C) 2011 The Feinstein Institute for Medical Research, www.feinsteininstitute.org Online address: http://www.molmed.org doi: 10.2119/molmed.2011.00065

The etiology of chronic inflammatory diseases (CIDs) is usually based on four criteria: (1) genetic susceptibility, (2) complex environmental priming, (3) exaggerated and continuous immune response against harmless self or foreign antigen, and (4) tissue destruction with a continuous wound response without proper healing but with a fibrotic scarring response. These elements do not include the systemic components of CIDs. Due to improved health care with excellent therapies in CIDs, it becomes more and more clear that many systemic responses need to be future targets of therapies. It is suggested that "the systemic response" should be added to the four etiologic criteria that constitute the full picture of CIDs. As shown in the present review, the systemic response becomes comprehensible in the context of evolutionary medicine and energy regulation. Next to the brain and muscles, the immune system is the third major energy consumer in the body. In the context of long-term activation of the immune system during CIDs, the subsequent stimulation of systemic neuroendocrine pathways is necessary to re-allocate energy-rich fuels to the activated immune system. However, re-allocation of energy-rich fuels is the basis of systemic disease sequelae of CIDs, one of which is the metabolic syndrome. It is suggested that Selye's alarm reaction of the 1930s, which is necessary to re-allocate energy-rich fuels to the body, should be called "energy appeal reaction". In CIDs, a continuous energy appeal reaction triggers systemic detrimental consequences for the rest of the body.

Stressful life events can change the clinical expression of rheumatoid arthritis (RA). Stress increases the proinflammatory load in healthy individuals and patients with RA. A new study demonstrates that short-term experimental stress transiently increases serum IL-1β and IL-2 levels in patients with RA, but how does stress affect chronic inflammation?

The endothelium is a dynamic, heterogeneous, disseminated organ that possesses vital secretory, synthetic, metabolic and immunological functions. Endothelial dysfunction has been implicated as a key factor in the development of organ-specific vascular diseases. This minireview gives a brief overview on EC (endothelial cell) biomarkers in arterial and venous endothelium and critically discusses the different sources of ECs that are most frequently applied in in vitro assays and research. The relevance of organ- and disease-specific endothelial cell cultures for studying cellular responses as a basis for improving therapeutic interventions is highlighted with particular emphasis on endothelial dysfunction in transplant-associated coronary artery disease, in atherosclerotic lesions and in response to diabetes mellitus.

Introduction Spontaneous bacterial peritonitis (SBP) is mainly caused by bacterial translocation of enteric Gram-negative bacteria, predominantly Escherichia coli . The sympathetic nervous system (SNS) is activated in advanced cirrhosis, particularly in the splanchic circulation, and exerts potent immunosuppressive actions. However, the role of splanchnic SNS activity in bacterial translocation and bacterial spreading in cirrhosis remains unclear. Methods E coli or Stapylococcus aureus (10 6 CFU) were given intraperitoneally. After 6 h, mesenteric lymph nodes (MLN), liver, spleen, lung and peripheral blood were harvested from ascitic cirrhotic rats (LC) and healthy controls with and without splanchnic sympathectomy (SE). The bacterial tissue burden was determined by standard microbiological culture techniques. In vitro phagocytic activity of peritoneal polymorphonuclear leucocytes was assessed by FACS analysis. Results Under basal conditions SE reduced bacterial translocation to MLN in LC rats from 45% to 17%. LC rats had a marked increase in bacteraemia after E coli and S aureus challenge and an increased incidence and degree of E coli translocation to MLN, liver, spleen and lung compared with control rats. SE prevented bacteraemia in LC rats after E coli but not after S aureus challenge. Prior SE abolished the difference in incidence as well as the bacterial tissue burden in each organ after E coli application in LC rats, being no longer significantly different from control rats with or without SE. The protective effects of SE against E coli were associated with a greater influx of mononuclear cells into the peritoneal cavity and increased phagocytic activity of peritoneal polymorphonuclear leucocytes. Conclusions In cirrhosis with bacterial peritonitis, hyperactivity of the splanchnic sympathetic nervous system contributes to the translocation of E coli but not S aureus to MLN and extraintestinal sites. This indicates a key role for sympathetic drive in the impairment in host defence against Gram-negative bacteria in cirrhosis.

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.

The circadian rhythm of symptoms in patients with chronic inflammatory diseases is well known. Circadian rhythms could be used to identify targets for time-adapted antiinflammatory therapies, which are administered prior to the flare of cytokine synthesis and inflammatory activity. In recent years, the diurnal variations in rheumatoid arthritis have been described precisely for pain, stiffness, and functional disability, as well as the underlying cyclic variations in hormone levels and cytokine concentrations. This review summarizes the current knowledge on circadian rhythms in other rheumatic diseases, focusing on polymyalgia rheumatica and ankylosing spondylitis.

Both genetic and environmental factors contribute to rheumatoid arthritis (RA) as well as osteoarthritis (OA). For RA, most of the known genetic markers are linked with genes from immunological pathways. Recent genome-wide association studies (GWAS) on RA identified known and novel susceptibility genes like HLA-DRB1, PTPN22, STAT4, TRAF1/C5, OLIG3/TNFAIP3, CD40, CCL21, MMEL1-TNFRSF14, CDK6, PRKCQ, IL2RB, and KIF5A-PIP4K2C. These association signals explain more than 50% of the genetic influence on RA. In contrast, less GWAS data for OA exist. Most OA susceptibility genes arose from classical candidate gene analyses and were not replicated in all study samples. Neuroendocrine factors are hypothesized to play an important role both in RA and OA etiology. Here, we discuss these findings and present an outlook for genetic association studies after GWAS.

Immunological, epidemiological, and clinical evidence suggest that female sex hormones play an important role in the etiology and pathophysiology of chronic immune/inflammatory diseases. Several significant factors generate confusion and opposite conclusions in evaluating the role of estrogens in these diseases, including relatively superficial translational studies from animals to the human condition, the different effects of estrogens on their different receptors or on different target cells, the different estrogen concentrations employed, and opposite effects (especially on cell proliferation) exerted by different peripheral estrogen metabolites. A preponderance of 16alpha-hydroxylated estrogens, as observed in rheumatoid arthritis synovial fluids, is an unfavorable sign in synovial inflammation. Since 17beta-estradiol administered during hormone replacement therapy will rapidly increase estrone sulfate after conversion in adipose tissue by aromatases, hormone replacement therapy can have proinflammatory effects by providing estrone sulfate to the inflamed synovial tissue. In addition, it appears that the use of combined oral contraceptives is associated with an increased risk of at least systemic lupus erythematosus. In conclusion, estrogens are generally considered as enhancers of cell proliferation and humoral immune response.

The morning stiffness and pain of rheumatoid arthritis (RA) is accompanied by a rise in serum interleukin-6 (IL-6) from 2 am to 7 am. Using a formulation that releases prednisone at 2 am (after ingestion at 10 pm), we studied the circadian dynamics of serum IL-6, other cytokines, and cortisol in 9 patients before and after 2 weeks, therapy. Significant improvements occurred in morning stiffness, pain, disease activity, and the acute-phase response. Only IL-6 showed measurable cytokine circadian variation, its high pretreatment peak was abolished, and changes in IL-6 correlated with the changes in morning stiffness. Following treatment, afternoon and evening serum cortisol was reduced, but in the early morning cortisol peak concentration increased. Thus the severity of morning symptoms is related to nocturnal serum IL-6 concentration. The specific timing of the medication, linked to the interaction between IL-6 and the hypothalamic-pituitary-adrenal (HPA) axis, may correct a postulated deficiency in HPA control in RA.

The opioid tetrapeptides endomorphins (EM)-1 and EM-2 are widely expressed in central nervous system and immune tissues of rats and humans. Their analgesic properties are well characterized but they also have anti-inflammatory properties. EM-1 significantly attenuated the onset of hindpaw inflammation in adjuvant-induced arthritis in rats. Immunohistochemical staining demonstrated the presence of EMs in T cells, macrophages, and fibroblasts in synovial tissues from patients with osteo- or rheumatoid arthritis (RA). In an ex vivo superfusion system, EM-1 potently inhibited the release of proinflammatory cytokines interleukin (IL)-6 and IL-8 from synovial tissues from patients with osteo- or RA. These results demonstrate that EMs are endogenously synthesized within human immune cells and have the potential to act as potent therapeutic agents in the treatment of chronic inflammatory disease. We discuss the clinical potential for EM analogues chemically modified to resist proteolytic degradation and identify modified protease-resistant analogues with enhanced bioactivity.

In inflammatory lesions, sympathetic nerve fibers get lost soon after the start of inflammation. To be able to identify and examine the factors that are responsible for this repulsion of the sympathetic nerve fibers we established an in vitro assay. Sympathetic trunk ganglia of postnatal mice were used for the outgrowth of axons. They were plated on poly-D-lysine-coated culture slides. Axons were encouraged to grow out by the addition of nerve growth factor-7S (NGF) from murine submaxillary gland. Using live imaging it was clearly shown that SEMA3F is a nerve-repellent factor. Two different types of nerve fiber repulsion were observed. The assay turned out to be an excellent model for the investigation of axon guidance factors of sympathetic neurons (nerve fiber repulsion/nerve fiber attraction).

The pathogenesis of rheumatoid arthritis (RA) is still an unresolved puzzle. Many factors and inflammatory cells play together to initiate a chronic inflammatory process that, if untreated, leads to complete destruction of involved joints. Recent success in treating severe forms of RA with B cell-depleting or -modifying agents revived the concept that the B cell might play a pivotal role in the pathogenesis of some forms of arthritis. However, the rather unspecific treatment approach affecting all B cells, no matter if autoreactive or not, leads to potential harmful side-effects, e.g., severe infections. Therefore, finding regulatory systems that more specifically modulate B cell function is important to improve current treatment options. One such regulatory system is the sympathetic nervous system (SNS), which is known to modulate B cell function, but also profoundly influences arthritis development and severity. This review develops the hypothesis that the SNS via modulating B cell function influences arthritis development and progression. For this purpose data is presented that shows (1) how the SNS influences B cell function, (2) how the SNS influences arthritis development and severity, and (3) how B cells are involved in the disease process with an emphasis on possible contact points for SNS neuromodulation.

Energy regulation (EnR) is most important for homoeostatic regulation of physiological processes. Neuroendocrine pathways are involved in EnR. We can separate factors that provide energy-rich fuels to stores [parasympathetic nervous system (PSNS), insulin, insulin-like growth factor-1, oestrogens, androgens and osteocalcin] and those that provide energy-rich substrates to consumers [sympathetic nervous system (SNS), hypothalamic-pituitary-adrenal axis, thyroid hormones, glucagon and growth hormone]. In chronic inflammatory diseases (CIDs), balanced energy-rich fuel allocation to stores and consumers, normally aligned with circadian rhythms, is largely disturbed due to the vast fuel consumption of an activated immune system (up to 2000 kJ day(-1)). Proinflammatory cytokines such as tumour necrosis factor or interleukins 1beta and 6, circulating activated immune cells and sensory nerve fibres signal immune activation to the rest of the body. This signal is an appeal for energy-rich fuels as regulators are switched on to supply energy-rich fuels ('energy appeal reaction'). During evolution, adequate EnR evolved to cope with nonlife-threatening diseases, not with CIDs (huge negative selection pressure and reduced reproduction). Thus, EnR is inadequate in CIDs leading to many abnormalities, including sickness behaviour, anorexia, hypovitaminosis D, cachexia, cachectic obesity, insulin resistance, hyperinsulinaemia, dyslipidaemia, fat deposits near inflamed tissue, hypoandrogenaemia, mild hypercortisolaemia, activation of the SNS (hypertension), CID-related anaemia and osteopenia. Many of these conditions can contribute to the metabolic syndrome. These signs and symptoms become comprehensible in the context of an exaggerated call for energy-rich fuels by the immune system. We propose that the presented pathophysiological framework may lead to new therapeutical approaches and to a better understanding of CID sequence.

Objective We undertook this study to examine the effects of estradiol on chondrogenesis of human bone marrow–derived mesenchymal stem cells (MSCs), with consideration of sex-dependent differences in cartilage repair. Methods Bone marrow was obtained from the iliac crest of young men. Density-gradient centrifugation–separated human MSCs proliferated as a monolayer in serum-containing medium. After confluence was achieved, aggregates were created and cultured in a serum-free differentiation medium. We added different concentrations of 17β-estradiol (E2) with or without the specific estrogen receptor inhibitor ICI 182.780, membrane-impermeable E2–bovine serum albumin (E2-BSA), ICI 182.780 alone, G-1 (an agonist of G protein–coupled receptor 30 [GPR-30]), and G15 (a GPR-30 antagonist). After 21 days, the aggregates were analyzed histologically and immunohistochemically; we quantified synthesized type II collagen, DNA content, sulfated glycosaminoglycan (sGAG) concentrations, and type X collagen and matrix metalloproteinase 13 (MMP-13) expression. Results The existence of intracellular and membrane-associated E2 receptors was shown at various stages of chondrogenesis. Smaller aggregates and significantly lower type II collagen and sGAG content were detected after treatment with E2 and E2-BSA in a dose-dependent manner. Furthermore, E2 enhanced type X collagen and MMP-13 expression. Compared with estradiol alone, the coincubation of ICI 182.780 with estradiol enhanced suppression of chondrogenesis. Treatment with specific GPR-30 agonists alone (G-1 and ICI 182.780) resulted in a considerable inhibition of chondrogenesis. In addition, we found an enhancement of hypertrophy by G-1. Furthermore, the specific GPR-30 antagonist G15 reversed the GPR-30–mediated inhibition of chondrogenesis and up-regulation of hypertrophic gene expression. Conclusion The experiments revealed a suppression of chondrogenesis by estradiol via membrane receptors (GPR-30). The study opens new perspectives for influencing chondrogenesis on the basis of classic and nonclassic estradiol signaling.

We studied whether, in parallel to the activity of the hypothalamus-pituitary-adrenal axis and the sympathetic nervous system, hypothalamic cytokine expression and monoaminergic neurotransmitter concentrations are affected during the development and chronification of arthritis induced by immunization of rats with type II collagen. Corticosterone levels were increased only transiently, and were even below the normal range as the disease progressed. Increased adrenaline blood levels and hypothalamic IL-1β and IL-6 overexpression were observed only during the induction phase of the disease. The increase in hypothalamic noradrenaline content during the symptomatic phase was paralleled by a gradual loss of sympathetic fibers in the joints. Depletion of hypothalamic noradrenergic neurons at this time did not affect the symptomatology. Contrary to observations in healthy animals, no correlation between hypothalamic IL-1β expression and noradrenaline content was observed in rats with arthritis. The dissociation between hypothalamic cytokine gene expression and noradrenergic neuronal activity, the lack of sustained stimulation of the stress axes, and the loss of sympathetic signals in the joints indicate that the communication between afferent immune messages to the central nervous system and two main efferent anti-inflammatory pathways under control of the brain are disrupted during experimental arthritis.

To stop or not to stop immunosuppressive therapy in the perioperative setting puts the clinician to a challenge. The risk of potential wound infection with possible septic or even lethal consequences needs to be weighted against exacerbation of the rheumatic disease. However, exacerbation of autoimmune inflammatory activity needs to be treated with increasing immunosuppressive medication, thus leading to enhanced risk of local and systemic infection as well. Unfortunately, up to now there is no data from randomized, double-blind controlled clinical trials available on how to steer immunosuppressive therapy in the perioperative setting, making evidence-based recommendations difficult. Neither is there good evidence, if the risk of infectious complications under immunosuppressive therapy differs according to the type and localization of surgery performed. Finally, immunosuppressive co-medication, like glucocorticoid dosage, is not adequately addressed in the available studies, making interpretation of these studies even more problematic. Therefore, a decision has to be made on an individual basis. We discuss the available data on DMARD and biologics therapy in the perioperative setting and describe our own perioperative management with different DMARDs and biologics.

Objective IA injections of SIJs with corticosteroids are often performed in patients suffering from low back pain due to active sacroiliitis. However, SIJ injections are technically demanding, and therefore the clinical outcome of ultrasound-guided corticosteroid SIJ injections was analysed in relation to the accuracy of the injection. Methods Ultrasound-guided injections were performed with 40 mg triamcinolone and 0.78 mg gadolinium in 20 SIJ of 14 consecutive patients suffering from active sacroiliitis. Immediately following SIJ injection, MRI scanning was initiated to verify the correct placement of the drug. Clinical outcome of the intervention was determined using a numerical pain rating scale (NRS) at Days 1 and 28. Results Despite ultrasound guidance, only 8 injections (40%) were exactly positioned into the SIJ space, whereas the other 12 injections (60%) missed the SIJ. However, there were no significant differences observed in the clinical outcome between the IA-injected group and the peri-articular-injected group. There was similar pain relief observed in both groups 24 h and 28 days following the intervention [IA injection group: mean NRS-baseline: 6.8 (range 4-9), NRS-24 h: 4.3 (range 1-7) and NRS-day 28: 3.5 (range 1-5); peri-articular injection group: mean NRS-baseline: 7.0 (range 5-10), NRS-24 h: 4.1 (range 1-10) and NRS-day 28: 4.5 (range 1-8)]. Conclusion These results demonstrate that IA SIJ injections remain technically challenging despite ultrasound guidance. However, peri-articular deposition of triamcinolone appears sufficient for pain and symptom control in patients suffering from active sacroiliitis.

Objective The pro-opiomelanocortin (POMC)–derived neuropeptide α-melanocyte–stimulating hormone (α-MSH) mediates its effects via melanocortin (MC) receptors. This study was carried out to investigate the expression patterns of the MC system and the effects of α-MSH in human articular chondrocytes. Methods Articular chondrocytes established from human osteoarthritic joint cartilage were analyzed by reverse transcription–polymerase chain reaction (RT-PCR) and Western blotting for the expression of MC receptors, POMC, and prohormone convertases (PCs). MC-1 receptor (MC-1R) expression in articular cartilage was further studied by immunohistochemistry. Ca2+ and cAMP assays were used to monitor α-MSH signaling, while studies of α-MSH function were performed in cultures with chondrocyte micromass pellets stimulated with α-MSH. Expression of cytokines and extracellular matrix (ECM) components was determined by real-time RT-PCR, Western immunoblotting, and enzyme-linked immunosorbent assays. Results MC-1R expression was detected in articular chondrocytes in vitro and in articular cartilage in situ. In addition, expression of transcripts for MC-2R, MC-5R, POMC, and PCs was detected in articular chondrocytes. Stimulation with α-MSH increased the levels of intracellular cAMP, but not Ca2+, in chondrocytes. Both messenger RNA and protein expression of various proinflammatory cytokines, collagens, matrix metalloproteinases (MMPs), and SOX9 was modulated by α-MSH. Conclusion Human articular chondrocytes are target cells for α-MSH. The effects of α-MSH on expression of cytokines and MMPs suggest that this neuropeptide plays a role in inflammatory and degenerative processes in cartilage. It is conceivable that inflammatory reactions can be mitigated by the induction of endogenous MCs or administration of α-MSH to the affected joints. The induction pattern of regulatory and structural ECM components such as collagens as well as SOX9 and anabolic and catabolic cytokines points to a function of α-MSH as a trophic factor in skeletal development during endochondral ossification rather than as a factor in homeostasis of permanent cartilage.