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Aim. We analyzed the added value of sTfR measurement in routine clinical practice to standard parameters (SP) of iron deficiency in the detection of iron deficiency anemia (IDA) in patients with rheumatoid arthritis (RA). Methods. Blood samples from 116 patients with RA were analyzed in a prospective study. Based on biochemical parameters, patients were classified as having IDA, anemia of chronic disease (ACD), IDA with concomitant ACD (ACD/IDA), or “other anemia.” Sensitivity, specificity, positive (PPV), and negative predictive values (NPV) of sTfR and SP of iron status alone and in combination were calculated for the diagnosis of IDA in general, i.e., IDA or ACD/IDA. Results. In the whole sample, with regard to the diagnosis of iron deficiency (IDA or ACD/IDA), sTfR had a higher sensitivity compared both to the combined use of SP and to the combination of SP with sTfR (80.9% versus 66.7/54.8%). Specificity, PPV and NPV did not differ substantially. When patients were stratified in groups with high (CRP levels above the median, i.e., 24.1 mg/l) and low (CRP levels less or equal to the median) inflammation, the diagnostic superiority of sTfR was restricted to patients with high inflammation. In this group, the diagnostic performance of sTfR was superior both to the combined use of SP and the combination of SP with sTfR with higher sensitivity (100% versus 52.4%) and NPV (100% versus 77.7/76.7%) and comparable specificity and PPV. Conclusion. For the detection of iron depletion (IDA or ACD/IDA) in anemic RA patients, sTfR is superior to SP of iron deficiency only in highly inflammatory states.

Summary Objective Osteoarthritis (OA) pathogenesis involves the interaction of articular cartilage with surrounding tissues, which are innervated by tyrosine hydroxylase-positive (TH+) sympathetic nerve fibers suggesting a role of the sympathetic nervous system (SNS) during OA progression. We analyzed the effects of sympathectomy (Syx) in a murine OA model. Methods Peripheral Syx was generated by 6-hydroxydopamine (6-OHDA) injections in male C57BL/6 mice. OA was induced in wild-type (WT) and Syx mice by destabilization of the medial meniscus (DMM). TH+ fibers and splenic NE were analyzed to evaluate Syx efficiency. OA progression was examined by OARSI and synovitis scores and micro-CT. Expression of TH, α2A- and β2-adrenergic receptors (AR), and activity of osteoblasts (ALP) and osteoclasts (TRAP) was investigated by stainings. Results Syx resulted in synovial TH+ fiber elimination and splenic NE decrease. Cartilage degradation and synovitis after DMM were comparably progressive in both WT and Syx mice. Calcified cartilage (CC) and subchondral bone plate (SCBP) thickness and bone volume fraction (BV/TV) increased in Syx mice due to increased ALP and decreased TRAP activities compared to WT 8 weeks after DMMWT and Syx mice developed osteophytes and meniscal ossicles without any differences between the groups. AR numbers decreased in cartilage but increased in synovium and osteophyte regions after DMM in both WT and Syx mice. Conclusion Peripheral dampening of SNS activity aggravated OA-specific cartilage calcification and subchondral bone thickening but did not influence cartilage degradation and synovitis. Therefore, SNS might be an attractive target for the development of novel therapeutic strategies for pathologies of the subchondral bone.

Interleukin-33 (IL-33) has been investigated as a mediator in the pathogenesis of fibrosis in lung, liver, and heart. There is accumulating evidence for the involvement of the IL-33/IL-33 receptor ST2L signalling pathway in systemic sclerosis (SSc). Little is known about the role of serum sST2 in SSc, which is the subject of the present investigation.Serum levels of sST2 were measured in 49 patients with SSc, recruited prospectively between November 2017 and March 2019. Patients were divided into those with progressive and those with stable disease. Receiver operating characteristics (ROC) curve analysis was applied to study sST2 as a marker for identifying patients with progressive disease. We used multivariate logistic regression analysis to evaluate the predictive value of sST2 for progressive disease after adjustment for potential confounding factors.Serum sST2 levels in patients with progressive disease were significantly elevated compared with patients with stable disease (mean ± sem: 50.4 ± 4.7 ng/mL vs 29.2 ± 2.97 ng/mL, p 0.001). ROC curve analysis identified an sST2 cut-off value of 37.8 ng/mL as optimal for discriminating patients with progressive disease from those with stable disease (sensitivity 80.0%, specificity 79.3%, area under the curve 0.80). After controlling for potential confounding factors (age, gender, C-reactive protein, pro-brain natriuretic peptide, and sum of internal medicine comorbidities), sST2 remained predictive of progressive disease (odds ratio 1.070, 95% confidence interval 1.017-1.126, p 0.009).In the present study, sST2 serum levels were predictive of disease progression in patients with SSc.

OBJECTIVE To perform a cross-sectional survey to estimate prevalence of and potential risk factors for Leptospira spp infection and exposure in peri-urban wildlife throughout California. ANIMALS 723 animals representing 12 wildlife species. PROCEDURES Blood and urine samples were obtained from wildlife in California from 2007 to 2017. Live animals were captured in humane traps, anesthetized, and released. Carcasses were donated by wildlife services and necropsied for urine, blood, and kidney tissue samples. Samples were tested for antibodies against 6 serovars of Leptospira spp with a microscopic agglutination test and for pathogenic Leptospira spp DNA with a real-time PCR assay targeting the LipL32 gene. Potential risk factors for Leptospira spp exposure were assessed by logistic regression. Genetic relatedness of Leptospira spp were assessed with DNA sequencing of the rrs2 gene and multiple locus sequence analysis. RESULTS Statewide Leptospira spp seroprevalence was 39.1%, and prevalence of positive PCR assay results for Leptospira spp DNA was 23.0%. Risk factors for Leptospira spp exposure included being an adult, being from northern California, and being a western gray squirrel, coyote, striped skunk, raccoon, gray fox, or mountain lion. Antibodies against serovar Pomona predominated in most species, followed by serovar Copenhageni. Complete rrs2 sequences were identified as Leptospira interrogans and multiple locus sequence type analysis revealed sequence type 140. CONCLUSIONS AND CLINICAL RELEVANCE Pathogenic Leptospira spp appeared to be common and widespread among peri-urban wildlife in California. Our data highlight the potential for exposure to infectious disease for both humans and domestic animals at the urban-wildland interface.

In autoimmune rheumatic diseases, oestrogens can stimulate certain immune responses (including effects on B cells and innate immunity), but can also have dose-related anti-inflammatory effects on T cells, macrophages and other immune cells. By contrast, androgens and progesterone have predominantly immunosuppressive and anti-inflammatory effects. Hormone replacement therapies and oral contraception (and also pregnancy) enhance or decrease the severity of autoimmune rheumatic diseases at a genetic or epigenetic level. Serum androgen concentrations are often low in men and in women with autoimmune rheumatic diseases, suggesting that androgen-like compounds might be a promising therapeutic approach. However, androgen-to-oestrogen conversion (known as intracrinology) is enhanced in inflamed tissues, such as those present in patients with autoimmune rheumatic diseases. In addition, it is becoming evident that the gut microbiota differs between the sexes (known as the microgenderome) and leads to sex-dependent genetic and epigenetic changes in gastrointestinal inflammation, systemic immunity and, potentially, susceptibility to autoimmune or inflammatory rheumatic diseases. Future clinical research needs to focus on the therapeutic use of androgens and progestins or their downstream signalling cascades and on new oestrogenic compounds such as tissue-selective oestrogen complex to modulate altered immune responses.

Water retention is a typical feature of acute inflammatory episodes, chiefly implemented by the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis. This is an important compensatory mechanism counteracting expected water loss, e.g., due to sweating. Both the SNS and HPA axis are activated in polymyalgia rheumatica (PMR). As retention mechanisms may similarly apply in this disease, we hypothesized increased water retention in PMR.Using bioimpedance analysis body composition was investigated in 64 healthy controls and 32 treatment-naive PMR patients. All PMR patients satisfied the 2012 EULAR/ACR classification criteria for PMR. 32 PMR patients were tested before and after 7 days of glucocorticoid-based therapy. Serum levels of pro-atrial natriuretic peptide (proANP) were investigated in all PMR patients and 15 healthy controls.Extracellular water (ECW) was markedly higher in PMR patients than in controls (mean ± SD: 49.1 ± 6.0% versus 36.3 ± 2.5% of total body water, p 0.001). Patients with PMR demonstrated significantly higher serum levels of proANP compared to controls. Even before glucocorticoid treatment was initiated, systolic and diastolic blood pressure were higher in PMR patients compared to controls. Extracellular water levels did not change in PMR patients upon 7 days of intensified treatment.This study demonstrated increased extracellular water and elevated serum levels of proANP as signs of fluid overload in patients with PMR. Volume changes are imprinted as long-lasting mechanisms as water distribution is not affected by short-term anti-inflammatory therapy.HINTERGRUND: Akute entzündliche Erkrankungen stimulieren Wassereinlagerungen, die hauptsächlich durch das sympathische Nervensystem (SNS) sowie durch die Hypothalamus-Hypophysen-Nebennierenrinde-Achse (HHN) initiiert werden. Dies ist ein wichtiger Ausgleichsmechanismus bei dem zu erwartenden Wasserverlust, zum Beispiel durch vermehrtes Schwitzen und Fieber. Da das SNS und die HHN-Achse bei der Polymyalgia rheumatica (PMR) aktiviert werden, ist auch bei dieser Erkrankung eine Volumenbelastung zu erwarten, was in dieser Studie untersucht wurde.Mit der Bioimpedanzanalyse wurde die Körperzusammensetzung bei 64 gesunden Kontrollpersonen und 32 unbehandelten Patienten mit PMR untersucht. Alle Patienten erfüllten die EULAR/ACR-Klassifikationskriterien (European League Against Rheumatism/American College of Rheumatology) der PMR von 2012. Die 32 Patienten mit PMR wurden vor und 7 Tage nach Einleitung einer Glukokortikoidtherapie getestet. Der Spiegel des proatrialen natriuretischen Peptids (proANP) wurde bei allen Patienten mit PMR und 15 gesunden Kontrollpersonen gemessen.Der Anteil des extrazellulären Wassers war bei Patienten mit PMR im Vergleich zu gesunden Kontrollen deutlich höher (Mittelwert ± SD, Standardabweichung: 49,1 ± 6,0 vs. 36,3 ± 2,5 % des Gesamtkörperwassers, p 0,001). Der Plasmaspiegel des ANP war bei Patienten mit PMR signifikant höher als bei den Kontrollpersonen. Noch vor Beginn der Glukokortikoidtherapie war der systolische und diastolische Blutdruck bei Patienten mit PMR im Vergleich zu den Kontrollpersonen erhöht. Nach 7 Tagen systemischer Steroidtherapie veränderte sich der Anteil des Extrazellulärwassers bei Patienten mit PMR nicht signifikant.Diese Studie zeigt, dass bei Patienten mit PMR eine Zunahme des Extrazellulärwassers sowie erhöhte Serumkonzentrationen des proANP als Zeichen der Volumenbelastung vorliegen. Grundlage hierfür sind langanhaltende Veränderungen der Volumenregulation, welche kurzfristig nicht durch eine antiinflammatorische Therapie beeinflussbar sind.

Leptospirosis is a globally important, fatal disease of humans, and over 160 species of animals are associated with more than 250 bacterial serovars in 64 species, but its ecology varies regionally...

The sensu lato (s.l.) complexes of Borrelia burgdorferi and Anaplasma phagocytophilum include pathogenic genospecies each with distinct ecologies in northern California, yet, most work conflates the genospecies of each pathogen into one sensu lato species. Detailed understanding of the differences in geographic distributions and ecology among genospecies is lacking. We aimed to evaluate whether two B. burgdorferi and two A. phagocytophilum genospecies in high-risk locations in coastal northern California were spatially clustered and if presence of a particular genospecies was associated with geographical site, host species, or other demographic or ecological variables. DNA sequencing was performed to differentiate genospecies of Borreliae and Anaplasma from PCR-positive dusky-footed woodrats (Neotoma fuscipes) and sciurids (chipmunks, Tamias spp., and Douglas squirrels, Tamiasciurus douglasii) at four sites in northwestern California. Logistic regression was performed to assess associations of genospecies with the predictor variables host species, host sex, site, season, and year. Spatial clustering was assessed using a Poisson spatial scan statistic in SaTScan. Host species was a significant predictor for Borrelia bissettiae, B. burgdorferi sensu stricto (s.s.), A. phagocytophilum s.s., and the DU1 Anaplasma genospecies. Woodrats were significantly more likely to be PCR-positive for B. bissettiae and A. phagocytophilum DU1 genospecies, while A. phagocytophilum s.s. and B. burgdorferi s.s. were significantly associated with sciurids. We report a single Borrelia lanei in an Allen's chipmunk (Tamias senex) from the Hoopa Valley Tribal Reservation. A significant spatial cluster of A. phagocytophilum s.s. was detected at Hendy Woods State Park in Mendocino County. These results highlight the need to better understand genospecies partitioning according to host species to further assess human risks, aid in future surveillance, and inform targeted research.

Background: Different parts of an organism like the gut, endocrine, nervous and immune systems constantly exchange information. Understanding the pathogenesis of various systemic chronic diseases increasingly relies on understanding how these subsystems orchestrate their activities. Methods: We started from the working hypothesis that energy is a fundamental quantity that governs activity levels of all subsystems and that interactions between subsystems control the distribution of energy according to acute needs. Based on physiological knowledge, we constructed a mathematical model for the energy flow between subsystems and analysed the resulting organismal responses to in silico infections. Results: The model reproduces common behaviour in acute infections and suggests several host parameters that modulate infection duration and therapeutic responsiveness. Moreover, the model allows the formulation of conditions for the induction of chronic infections and predicts that alterations in energy released from fat can lead to the transition from clearance of acute infections to a chronic inflammatory state. Impact: These results suggest a fundamental role for brain and fat in controlling immune response through systemic energy control. In particular, it suggests that lipolysis resistance, which is known to be involved in obesity and ageing, might be a survival programme for coping with chronic infections.

Stress-associated somatic and psychiatric disorders are often linked to non-resolving low-grade inflammation, which is promoted at least in part by glucocorticoid (GC) resistance of distinct immune cell subpopulations. While the monocyte/macrophage compartment was in the focus of many clinical and preclinical studies, the role of myeloid-derived suppressor cells (MDSCs) in stress-associated pathologies and GC resistance is less understood. As GC resistance is a clear risk factor for posttraumatic complications in patients on intensive care, the exact interplay of physical and psychosocial traumatization in the development of GC resistance needs to be further clarified. In the current study we employ the chronic subordinate colony housing (CSC) paradigm, a well-characterized mouse model of chronic psychosocial stress, to study the role of myeloid cells, in particular of MDSCs, in innate immune activation and GC resistance following combined psychosocial and physical (e.g., bite wounds) trauma. Our findings support the hypothesis that stress-induced neutrophils, polymorphonuclear (PMN)-MDSCs and monocytes/monocyte-like (MO)-MDSCs get primed and activated locally in the bone marrow as determined by toll-like receptor (TLR)2 upregulation and increased basal and lipopolysaccharide (LPS)-induced in vitro cell viability. These primed and activated myeloid cells emigrate into the peripheral circulation and subsequently, if CSC is accompanied by significant bite wounding, accumulate in the spleen. Here, PMN-MDSCs and monocytes/MO-MDSCs upregulate TLR4 expression, which exclusively in PMN-MDSCs promotes NF-κB hyperactivation upon LPS-stimulation, thereby exceeding the anti-inflammatory capacities of GCs and resulting in GC resistance.

PurposeRecent studies demonstrated a contribution of adrenoceptors (ARs) to osteoarthritis (OA) pathogenesis. Several AR subtypes are expressed in joint tissues and the β2-AR subtype seems to play a major role during OA progression. However, the importance of β2-AR has not yet been investigated in knee OA. Therefore, we examined the development of knee OA in β2-AR-deficient (Adrb2-/-) mice after surgical OA induction.MethodsOA was induced by destabilization of the medial meniscus (DMM) in male wildtype (WT) and Adrb2-/- mice. Cartilage degeneration and synovial inflammation were evaluated by histological scoring. Subchondral bone remodeling was analyzed using micro-CT. Osteoblast (alkaline phosphatase - ALP) and osteoclast (cathepsin K - CatK) activity were analyzed by immunostainings. To evaluate β2-AR deficiency-associated effects, body weight, sympathetic tone (splenic norepinephrine (NE) via HPLC) and serum leptin levels (ELISA) were determined. Expression of the second major AR, the α2-AR, was analyzed in joint tissues by immunostaining.ResultsWT and Adrb2-/- DMM mice developed comparable changes in cartilage degeneration and synovial inflammation. Adrb2-/- DMM mice displayed elevated calcified cartilage and subchondral bone plate thickness as well as increased epiphyseal BV/TV compared to WTs, while there were no significant differences in Sham animals. In the subchondral bone of Adrb2-/- mice, osteoblasts activity increased and osteoclast activity deceased. Adrb2-/- mice had significantly higher body weight and fat mass compared to WT mice. Serum leptin levels increased in Adrb2-/- DMM compared to WT DMM without any difference between the respective Shams. There was no difference in the development of meniscal ossicles and osteophytes or in the subarticular trabecular microstructure between Adrb2-/- and WT DMM as well as Adrb2-/- and WT Sham mice. Number of α2-AR-positive cells was lower in Adrb2-/- than in WT mice in all analyzed tissues and decreased in both Adrb2-/- and WT over time.ConclusionWe propose that the increased bone mass in Adrb2-/- DMM mice was not only due to β2-AR deficiency but to a synergistic effect of OA and elevated leptin concentrations. Taken together, β2-AR plays a major role in OA-related subchondral bone remodeling and is thus an attractive target for the exploration of novel therapeutic avenues.

Prokineticin 2 (PK2) is a secreted protein involved in several pathological and physiological processes, including the regulation of inflammation, sickness behaviors, and circadian rhythms. Recently, it was reported that PK2 is associated with the pathogenesis of collagen-induced arthritis in mice. However, the role of PK2 in the pathogenesis of rheumatoid arthritis (RA) or osteoarthritis (OA) remains unknown. In this study, we collected synovial tissue, plasma, synovial fluid, and synovial fibroblasts (SF) from RA and OA patients to analyze the function of PK2 using immunohistochemistry, enzyme-linked immunosorbent assays, and tissue superfusion studies. PK2 and its receptors prokineticin receptor (PKR) 1 and 2 were expressed in RA and OA synovial tissues. PKR1 expression was downregulated in RA synovial tissue compared with OA synovial tissue. The PK2 concentration was higher in RA synovial fluid than in OA synovial fluid but similar between RA and OA plasma. PK2 suppressed the production of IL-6 from TNFα-prestimulated OA-SF, and this effect was attenuated in TNFα-prestimulated RA-SF. This phenomenon was accompanied by the upregulation of PKR1 in OA-SF. This study provides a new model to explain some aspects underlying the chronicity of inflammation in RA.

In experimental arthritis, glucocorticoid secretion is inadequate relative to inflammation. We hypothesized that IL-1 is a key factor for inadequate glucocorticoid secretion in arthritic rats. Collagen type II—induced arthritis (CIA) in DA rats was the model to study effects of IL-1 on adrenal function. In the CIA model, an increase of intraadrenal MHCII-positive cells was observed. MHCII-positive cells or bone marrow-derived dendritic cells inhibited glucocorticoid secretion of adrenal gland cells. IL-1, but also IL-18 and the inflammasome were critical in glucocorticoid inhibition. Arthritic compared to control adrenal gland cells produced higher amounts of CXC chemokines from MHCII+ adrenal cells, particularly CINC-2, which is strongly dependent on presence of IL-1. In CIA, macrophages and/or dendritic cells inhibit glucocorticoid secretion via IL-1 in adrenal glands. These findings show that activated macrophages and/or dendritic cells inhibit glucocorticoid secretion in experimental arthritis and that IL-1β is a decisive factor.

Bone marrow-derived mesenchymal stem cells (BMSCs) represent an alternative to chondrocytes to support cartilage regeneration in osteoarthritis (OA). The sympathetic neurotransmitter norepinephrine (NE) has been shown to inhibit their chondrogenic potential, however, their proliferation capacity under NE influence has not been studied yet. Therefore, we used BMSCs obtained from trauma and OA donors and compared the expression of adrenergic receptors (AR). Then, BMSCs from both donor groups were treated with NE, as well as with combinations of NE and &alpha, 1-, &alpha, 2- or &beta, 1/2-AR antagonists (doxazosin, yohimbine or propranolol). Activation of AR-coupled signaling was investigated by analyzing ERK1/2 and protein kinase A (PKA) phosphorylation. A similar but not identical subset of ARs was expressed in trauma (&alpha, 2B-, &alpha, 2C- and &beta, 2-AR) and OA BMSCs (&alpha, 2A-, &alpha, 2B-, and &beta, 2-AR). NE in high concentrations inhibited the proliferation of both trauma and OA BMCSs significantly. NE in low concentrations did not influence proliferation. ERK1/2 as well as PKA were activated after NE treatment in both BMSC types. These effects were abolished only by propranolol. Our results demonstrate that NE inhibits the proliferation and accordingly lowers the regenerative capacity of human BMSCs likely via &beta, 2-AR-mediated ERK1/2 and PKA phosphorylation. Therefore, targeting &beta, 2-AR-signaling might provide novel OA therapeutic options.

Leptospirosis is reported infrequently in wild and domestic felids. We estimated the prevalence of Leptospira spp. infection and exposure using real-time PCR and serology, respectively, in 136 mountain lions (Puma concolor) and 39 bobcats (Lynx rufus) that died or were euthanized between 2009 and 2017 from several regions of California, US. Felids were classified as Leptospira-positive if they were test-positive using real-time PCR targeting the LipL32 gene of pathogenic Leptospira spp. or microscopic agglutination test for six serovars of Leptospira spp. The overall Leptospira spp. prevalence was 46% (63/136) for mountain lions and 28% (11/39) for bobcats. The most common serovar detected in both felid species was Leptospira interrogans serovar Pomona. Age class and geographic location were significantly associated with Leptospira spp. in mountain lions, but not in bobcats. Interstitial nephritis, predominately lymphocytic, was diagnosed in 39% (41/106) of mountain lions and 16% (4/25) of bobcats evaluated histologically and was significantly associated with being Leptospira spp.-positive in both species. Our findings suggest that Leptospira spp. infection is common and widespread in California's wild felids and may have clinical impacts on renal and overall health of individuals. Key words: Bobcat, Leptospira spp., leptospirosis, Lynx rufus, mountain lion, nephritis, pathology, Puma concolor.

Der Forschungsverbund Neuroimmunologie und Schmerz (Neuroimpa) untersucht die Bedeutung der Beziehungen zwischen dem Immunsystem und dem Nervensystem bei muskuloskeletalen Erkrankungen fur die Entstehung von Schmerzen und fur den Verlauf von Frakturheilung und Arthritiden. Das Methodenspektrum umfasst Untersuchungen an Einzelzellen, In-vivo-Modelle von Arthritis und Frakturheilung, bildgebende Verfahren zum Studium von Gehirnfunktionen an Tier und Mensch sowie die Analyse von Patientendaten. Proinflammatorische Zytokine tragen uber neuronale Zytokinrezeptoren signifikant zur Entstehung von Gelenkschmerzen bei. Immunzellen sezernieren Opioidpeptide, die uber Opioidrezeptoren peripherer Nozizeptoren hypoalgetisch wirken. Die Knochenneubildung nach Fraktur wird durch das Nervensystem signifikant unterstutzt. Das sympathische Nervensystem fordert die Entwicklung immunologisch induzierter Arthritiden. Die Studien zeigen ein bedeutsames analgetisches Potenzial der Neutralisierung von proinflammatorischen Zytokinen und von selektiv peripher wirkenden Opioiden. Ferner zeigen sie, dass die Modulation neuronaler Mechanismen muskuloskeletale Krankheitsverlaufe gunstig beeinflussen kann. Eingriffe in die Interaktionen zwischen dem Immunsystem und dem Nervensystem bergen ein groses therapeutisches Potenzial fur die Behandlung von muskuloskeletalen Erkrankungen und Schmerzen.

Epigenetic modifiers of the histone deacetylase (HDAC) family contribute to autoimmunity, cancer, HIV infection, inflammation, and neurodegeneration. Hence, histone deacetylase inhibitors (HDACi), which alter protein acetylation, gene expression patterns, and cell fate decisions, represent promising new drugs for the therapy of these diseases. Whereas pan-HDACi inhibit all 11 Zn2+-dependent histone deacetylases (HDACs) and cause a broad spectrum of side effects, specific inhibitors of histone deacetylase 6 (HDAC6i) are supposed to have less side effects. We present the synthesis and biological evaluation of Marbostats, novel HDAC6i that contain the hydroxamic acid moiety linked to tetrahydro-β-carboline derivatives. Our lead compound Marbostat-100 is a more potent and more selective HDAC6i than previously established well-characterized compounds in vitro as well as in cells. Moreover, Marbostat-100 is well tolerated by mice and effective against collagen type II induced arthritis. Thus, Marbostat-100 repr...