Peripheral Inflammatory Disease Research Articles

Second-Generation Prostaglandin Receptor EP2 Antagonist, TG8-260, with High Potency, Selectivity, Oral Bioavailability, and Anti-Inflammatory Properties.

EP2, a G-protein-coupled prostaglandin-E2 receptor, has emerged as a seminal biological target for drug discovery. EP2 receptor activation is typically proinflammatory; therefore, the development of EP2 antagonists to mitigate the severity and disease pathology in a variety of inflammation-driven central nervous system and peripheral disorders would be a novel strategy. We have recently developed a second-generation EP2 antagonist TG8-260 and shown that it reduces hippocampal neuroinflammation and gliosis after pilocarpine-induced status epilepticus in rats. Here, we present details of synthesis, lead optimization on earlier leads that resulted in TG8-260, potency and selectivity evaluations using cAMP-driven time-resolved fluorescence resonance energy-transfer (TR-FRET) assays and [H3]-PGE2-binding assays, absorption, distribution, metabolism, and excretion (ADME), and pharmacokinetics. TG8-260 (2f) showed Schild K B = 13.2 nM (3.6-fold more potent than the previous lead TG8-69 (1c)) and 500-fold selectivity to EP2 against other prostanoid receptors. Pharmacokinetic data indicated that TG8-260 has a plasma half-life of 2.14 h (PO) and excellent oral bioavailability (77.3%). Extensive ADME tests indicated that TG8-260 is a potent inhibitor of CYP450 enzymes. Further, we show that TG8-260 displays antagonistic activity on the induction of EP2 receptor-mediated inflammatory gene expression in microglia BV2-hEP2 cells; therefore, it can serve as a tool for investigating anti-inflammatory pathways in peripheral inflammatory disease animal models.

Response to a letter by M. Slouma et al

A letter by Slouma et al highlights several important matters regarding the recently reported association of serum levels of interleukin (IL)-22 with the clinical diagnosis of axial spondyloarthritis (AxSpA).1 While the full spectrum of action and pathological significance of IL-22 has not been fully elaborated, the involvement of this cytokine in the pathogenesis of various systemic disorders has been demonstrated or suggested. Thus, the potential diagnostic utility of this test should be limited to the differentiation of AxSpA from non-inflammatory conditions, such as osteitis condensans ilii, fibromyalgia and myofascial pain, enthesopathy, facet joint disease, and diffuse idiopathic systemic hyperostosis, which were diagnosed in this study in the group of patients with an alternative to AxSpA diagnosis. We completely agree with Slouma et al that the presence of some chronic systemic disorders can cause a bias in the interpretation of the test. Thus, it is important to mention that none of the enrolled patients was diagnosed with any malignant or chronic disease with possible inflammatory pathogenesis, excluding 3 smokers with mild chronic obstructive pulmonary disease; serum levels of IL-22 were at the low end in these patients. The IL-22 levels did not depend on the presence of peripheral arthritis, uveitis, psoriasis, or inflammatory bowel disease in our study; however, the numbers of patients with the extra-spinal manifestations were too low to make statistical calculations. The total sample size of the study was also judged to be insufficient for making final recommendations on the practical utilization of IL-22 test for AxSpA diagnosis, and as it was advocated by Slouma et al, and also acknowledged in the manuscript, further prospective studies examining the diagnostic utility of IL-22 testing in patients with suspected AxSpA are warranted. The authors declare no conflict of interest.

P24 Ankylosing spondylitis & uveitis - challenges in management

Case report - IntroductionAnkylosing spondylitis is a chronic inflammatory condition involving spine, chest and sacroiliac joints. It can be associated with extra spinal manifestations which include uveitis and enthesitis, as well as other features of an inflammatory spondyloarthropathy including psoriasis and inflammatory bowel disease. It is characterised by the presence of inflammatory back pain, limited range of spinal movement, sacroiliitis on imaging, excess spinal bone formation and a high prevalence of HLA-B27. The main aims of treatment are to improve symptoms and retain function as well as to prevent disease complications.Case report - Case descriptionA 49-year-old male diagnosed with ankylosing spondylitis at the age of 23 (HLA-B27 positive, classical radiographic features on plain radiographs and MRI), with background of meningitis and subsequent epilepsy (not on treatment since the age of 13), severe hip osteoarthritis and osteoporosis. He has peripheral elbow and knee synovitis. At the age of 27 he developed sight-threatening bilateral recurrent anterior uveitis complicated by cystoid macular oedema (causing central vision loss). Initial management included anti-inflammatories and steroids. He progressed to biologics but developed a rash on adalimumab. He was switched to infliximab in 2010. In 2015 it was switched due to reduced response to golimumab which was non-beneficial. Subsequently he was switched to etanercept but after 3 months it was discontinued due to eye flare. The patient’s therapy was switched to certolizumab, which was non-beneficial for spine and discontinued. In 2016, infliximab was retried as the patient thought it worked best. Unfortunately, in 2018 patient developed Infliximab antibodies and treatment was changed to secukinumab. After 9 months this was stopped owing to ongoing active eye and spine disease. Adalimumab was re-tried; however, it was discontinued as it was showing no benefit. In 2020 Eeanercept (Benepali) was re-tried; however, only for 4 months because of severe flare of joint and eye disease. Tofacitinib was commenced but was non-beneficial and hence it was discontinued. Currently he continues on ixekizumab, oral prednisolone and also receives steroid eye and joint injections. On commencing biologics he was on methotrexate; however, the patient stopped. He was switched to mycophenolate mofetil which he remained on for 10 years. It was switched to methotrexate to try and control peripheral inflammatory joint disease better (re-tried for the second time) which the patient has recently discontinued as he felt it was non-beneficial.Case report - DiscussionThe case is very challenging. The patient’s disease continues to flare despite changing therapies. He continues to get flares in his back disease, eye disease and peripheral synovitis. His latest BASDI was 5.1 and VAS was 9/10. Measurements: intermalleolar distance 15cm, modified Schober’s 4cm, right lateral flexion 3.8cm and left lateral flexion 11cm. His latest MRI of whole spine and SI joints (in 2020) showed signs of previously active seronegative spondyloarthropathy with established cervical and thoracic ankyloses as well as bilateral sacroiliac joint ankylosis. There is a need for repeated steroid injections to the knees as well as the eyes. He continues on oral prednisolone which was first started in 2006. This is associated with multiple side effects, i.e., osteoporosis. The patient has already completed 8 years of bisphosphonate therapy. He is under regular review with the osteoporosis clinic. His bone density scan showed worsening bone mineral density and bisphosphonates had to be restarted. The patient adjusted medications depending on his symptoms. Recently he also discontinued methotrexate as he felt it was of no benefit to him at all. We are very limited at present to find combined medications to manage both the patient’s inflammatory back disease and inflammatory eye disease.Case report - Key learning pointsThis patient was diagnosed with ankylosing spondylitis 26 years ago. To date he has tried 5 different anti-TNF agents (two of which have also been re-tried at a different time point). This failed to control his disease as he continued to experience flares in either inflammatory back or eye disease. The biologic classes were also changed – he has tried one IL-17A agent as well as a JAK-I. Unfortunately, they both failed to control his disease. He currently continues on a second IL-17A; however, he still requires steroid eye and joint injections as well as systemic steroids. Throughout the years he has tried different DMARDs – most recently methotrexate. Unfortunately, the patient decided to discontinue it as he felt it was of no benefit to him. All of the above indicates that there is still a need to find a collaborative treatment option that will control the patient’s inflammatory back disease, inflammatory eye disease and peripheral synovitis. The aim would be, if possible, to decrease the steroid dose as well (currently on prednisolone 15mg daily) in order to prevent the steroid-associated side effects.

Brain profiling in murine colitis and human epilepsy reveals neutrophils and TNF\u03b1 as mediators of neuronal hyperexcitability

BackgroundPatients with chronic inflammatory disorders such as inflammatory bowel disease frequently experience neurological complications including epilepsy, depression, attention deficit disorders, migraines, and dementia. However, the mechanistic basis for these associations is unknown. Given that many patients are unresponsive to existing medications or experience debilitating side effects, novel therapeutics that target the underlying pathophysiology of these conditions are urgently needed.MethodsBecause intestinal disorders such as inflammatory bowel disease are robustly associated with neurological symptoms, we used three different mouse models of colitis to investigate the impact of peripheral inflammatory disease on the brain. We assessed neuronal hyperexcitability, which is associated with many neurological symptoms, by measuring seizure threshold in healthy and colitic mice. We profiled the neuroinflammatory phenotype of colitic mice and used depletion and neutralization assays to identify the specific mediators responsible for colitis-induced neuronal hyperexcitability. To determine whether our findings in murine models overlapped with a human phenotype, we performed gene expression profiling, pathway analysis, and deconvolution on microarray data from hyperexcitable human brain tissue from patients with epilepsy.ResultsWe observed that murine colitis induces neuroinflammation characterized by increased pro-inflammatory cytokine production, decreased tight junction protein expression, and infiltration of monocytes and neutrophils into the brain. We also observed sustained neuronal hyperexcitability in colitic mice. Colitis-induced neuronal hyperexcitability was ameliorated by neutrophil depletion or TNFα blockade. Gene expression profiling of hyperexcitable brain tissue resected from patients with epilepsy also revealed a remarkably similar pathology to that seen in the brains of colitic mice, including neutrophil infiltration and high TNFα expression.ConclusionsOur results reveal neutrophils and TNFα as central regulators of neuronal hyperexcitability of diverse etiology. Thus, there is a strong rationale for evaluating anti-inflammatory agents, including clinically approved TNFα inhibitors, for the treatment of neurological and psychiatric symptoms present in, and potentially independent of, a diagnosed inflammatory disorder.

Mapping of Translocator Protein (18 kDa) in Peripheral Sterile Inflammatory Disease and Cancer through PET Imaging.

Positron emission tomography (PET) imaging of the translocator 18 kDa protein (TSPO) with radioligands has become an effective means of research in peripheral inflammatory conditions that occur in many diseases and cancers. The peripheral sterile inflammatory diseases (PSIDs) are associated with a diverse group of disorders that comprises numerous enduring insults including the cardiovascular, respiratory, gastrointestinal, or musculoskeletal system. TSPO has recently been introduced as a potential biomarker for peripheral sterile inflammatory diseases (PSIDs). The major critical issue related to PSIDs is its timely characterization and localization of inflammatory foci for proper therapy of patients. As an alternative to metabolic imaging, protein imaging expressed on immune cells after activation is of great importance. The five transmembrane domain translocator protein-18 kDa (TSPO) is upregulated on the mitochondrial cell surface of macrophages during inflammation, serving as a potential ligand for PET tracers. Additionally, the overexpressed TSPO protein has been positively correlated with various tumor malignancies. In view of the association of escalated TSPO expression in both disease conditions, it is an immensely important biomarker for PET imaging in oncology and PSIDs. In this review, we summarize the most outstanding advances on TSPO-targeted PSIDs and cancer in the development of TSPO ligands as a potential diagnostic tool, specifically discussing the last five years.

Quantile-dependent expressivity of serum C-reactive protein concentrations in family sets.

Background“Quantile-dependent expressivity” occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g., C-reactive protein, CRP) is high or low relative to its distribution. We have previously shown that the heritabilities (h2) of coffee and alcohol consumption, postprandial lipemia, lipoproteins, leptin, adiponectin, adiposity, and pulmonary function are quantile-specific. Whether CRP heritability is quantile-specific is currently unknown.MethodsSerum CRP concentrations from 2,036 sibships and 6,144 offspring-parent pairs were analyzed from the Framingham Heart Study. Quantile-specific heritability from full-sib (βFS, h2 ={(1 + 8rspouseβFS)0.5 − 1}/(2rspouse)) and offspring-parent regression slopes (βOP, h2 = 2βOP/(1 + rspouse)) were estimated robustly by quantile regression with nonparametric significance determined from 1,000 bootstrap samples.ResultsQuantile-specific h2 (±SE) increased with increasing percentiles of the offspring’s age- and sex-adjusted CRP distribution when estimated from βOP (Ptrend = 0.0004): 0.02 ± 0.01 at the 10th, 0.04 ± 0.01 at the 25th, 0.10 ± 0.02 at the 50th, 0.20 ± 0.05 at the 75th, and 0.33 ± 0.10 at the 90th percentile, and when estimated from βFS (Ptrend = 0.0008): 0.03±0.01 at the 10th, 0.06 ± 0.02 at the 25th, 0.14 ± 0.03 at the 50th, 0.24 ± 0.05 at the 75th, and 0.53 ± 0.21 at the 90th percentile.ConclusionHeritability of serum CRP concentration is quantile-specific, which may explain or contribute to the inflated CRP differences between CRP (rs1130864, rs1205, rs1800947, rs2794521, rs3091244), FGB (rs1800787), IL-6 (rs1800795, rs1800796), IL6R (rs8192284), TNF-α (rs1800629) and APOE genotypes following CABG surgery, stroke, TIA, curative esophagectomy, intensive periodontal therapy, or acute exercise; during acute coronary syndrome or Staphylococcus aureus bacteremia; or in patients with chronic rheumatoid arthritis, diabetes, peripheral arterial disease, ankylosing spondylitis, obesity or inflammatory bowel disease or who smoke.

Polysaccharide-experienced effector T cells induce IL-10 in FoxP3+ regulatory T cells to prevent pulmonary inflammation.

Inhibition of peripheral inflammatory disease by carbohydrate antigens derived from normal gut microbiota has been demonstrated for the GI tract, brain, peritoneum, and most recently the airway. We have demonstrated that polysaccharide A (PSA) from the commensal organism Bacteroides fragilis activates CD4+ T cells upon presentation by the class II major histocompatibility complex, and that these PSA-experienced T cells prevent the development of lung inflammation in murine models. While the PSA-responding T cells themselves are not canonical FoxP3+ regulatory T cells (Tregs), their ability to prevent inflammation is dependent upon the suppressive cytokine IL-10. Using an adoptive T cell transfer approach, we have discovered that PSA-experienced T cells require IL-10 expression by PSA-naïve recipient animals in order to prevent inflammation. A cooperative relationship was found between PSA-activated effector/memory T cells and tissue-resident FoxP3+ Tregs both in vivo and in vitro, and it is this cooperation that enables the suppressive activity of PSA outside of the gut environment where exposure takes place. These findings suggest that carbohydrate antigens from the normal microbiota communicate with peripheral tissues to maintain homeostasis through T cell-to-T cell cooperation.

Benefit in long-term response and mortality of treatment with intravenous immunoglobulin prior to plasmapheresis in peripheral polyneuropathies

ObjectivesThe benefits of plasmapheresis (PA) for neurologic autoimmune diseases have been widely demonstrated. Little is known about the long-term neurologic prognosis and course after PA and immunosuppressive (IS) and/or intravenous immunoglobulin (IVIG) treatment. We aimed to analyse features associated with short-term response and long-term outcome and prognosis (neurologic status and mortality) of peripheral polyneuropathy (PP) and central nervous system acute inflammatory disease (CNSAID) treated with PA. Patients and methodsA descriptive, retrospective single-centre study from January 2005 to December 2012. ResultsThere were 26 episodes, which included 16 CNSAID and 10 PP cases. First line therapy included PA (n=4), IS drugs (n=15), and IVIG (n=7). Responses were achieved in 80% and 50% of PP and CNSAID cases, respectively. For PP, first line treatment with IVIG and no IS treatment prior to or during PA were variables associated with short-term response (P=0.067), good or stable neurologic status at the end of follow-up (P=0.008), and lower mortality rate (P=0.008). For CNSAID, initial EDSS score≥7 (P=0.019) was related to long-term good or stable neurologic status. During the study period, 177 sessions were conducted; 3.4% had technical complications and 8.5% clinical complications. However, these incidents were all minor and no PA session had to be discontinued. ConclusionThe response rates achieved in our patients were similar to those of other research. PA has a safe profile but double-blind, controlled studies are needed to evaluate the synergy of sequential treatment with IGIV followed by PA and the possible benefit for long-term outcome.

Tuberculous sacroiliitis: A cause of bone marrow edema in magnetic resonance imaging.

A 43-year-old female presented with progressive left buttock pain for 6 months. Her pain was worse at night and was not relieved by activity. She had morning stiffness for 5–10 min. She had no constitutional symptoms, history of peripheral arthritis, dactylitis, enthesitis, psoriasis, and inflammatory bowel disease. She denied having a past or family history of tuberculosis (Tb). She was administered with sulfasalazine and non-steroidal anti-inflammatory drugs (NSAIDs), but her condition did not improve. Laboratory examination revealed an ESR of 21 mm/h and a CRP of 1.43 mg/dL (normal range, 0.0–0.8 mg/dL). Pelvic antero-posterior radiograph showed minimal sclerosis with joint space changes of the left sacroiliac joint (SIJ). Paracoronal T1-weighted (Figure 1a) and short tau inversion recovery (STIR) (Figure 1b) magnetic resonance (MR) images revealed joint space enlargement with increased joint fluid in the left SIJ as well as heterogeneous bone marrow edema and hyperintense lesion spreading to periarticular soft tissues. Gadolinium-enhanced axial fat suppressed T1-weighted MR image of SIJs (Figure 1c) showed a smooth thin-rimmed enhancement area extending anteriorly from the left SIJ to the iliacus muscle and extending laterally to gluteal muscles that was compatible with cold abscess. Extensive destruction of both iliac and sacral bones of the left SIJ was also visualized in the axial computed tomography (CT) images (Figure 1d) obtained during CT guided biopsy procedure. Culture of the biopsy material yielded Mycobacterium tuberculosis, and the patient was administered with a four-drug anti-tuberculous therapy. Musculoskeletal involvement is uncommon and accounts for 1%–3% of all Tb (1) cases, and SIJ Tb was reported in approximately 10% (2) of the musculoskeletal Tb cases. Early diagnosis of SIJ Tb is extremely difficult mainly because of the non-specific nature of the symptoms. Although the culture is the gold standard for the diagnosis, CT and MR may be complementary for the diagnosis. The severe joint destruction and a cold abscess with a smooth thin-rimmed enhancement may be suggestive of Tb (3).

Clinical and Electrodiagnostic Findings in Patients with Peripheral Neuropathy and Inflammatory Bowel Disease.

Several neurological diseases, especially different types of peripheral neuropathy (PN) are common in inflammatory bowel disease (IBD). We prospectively evaluated the presence of PN in 121 patients with IBD (51 with Crohn's disease [CD] and 70 with ulcerative colitis [UC]) and 50 controls (gastritis and dyspepsia) over 3.5 years. A total of 15 patients (12.4%) with small-fiber neuropathy and IBD (7 CD and 8 UC) and 24 patients (19.8%) with large-fiber PN (12 CD and 12 UC) were diagnosed. Small-fiber neuropathy affected 6% and large-fiber PN affected 4% of the control patients. Patients with CD with PN were older, had more metabolic complications and more severe motor involvement than patients with UC with PN. Carpal tunnel syndrome was more common in patients with UC. Sural and median sensory nerves were the most commonly and severely affected sensory responses. Tibial, peroneal, median, and ulnar compound muscle action potential amplitudes were also significantly decreased in patients with CD and UC. In general, sensory and motor amplitudes were a more sensitive marker for PN in patients with IBD than conduction velocities. In summary, PN is common in patients with IBD. It may be primarily related to IBD, phenotypically modified by metabolic complications. Its phenotype is diverse (most commonly small to predominantly axonal sensory large-fiber), but usually more severe in CD. It also includes ataxic and demyelinating forms. Results from our 10-year follow-up will elucidate the PN clinical course and the real impact of the comorbidities and new therapies.

Microbiota, immunoregulatory old friends and psychiatric disorders.

Regulation of the immune system is an important function of the gut microbiota. Increasing evidence suggests that modern living conditions cause the gut microbiota to deviate from the form it took during human evolution. Contributing factors include loss of helminth infections, encountering less microbial biodiversity, and modulation of the microbiota composition by diet and antibiotic use. Thus the gut microbiota is a major mediator of the hygiene hypothesis (or as we prefer, "Old Friends" mechanism), which describes the role of organisms with which we co-evolved, and that needed to be tolerated, as crucial inducers of immunoregulation. At least partly as a consequence of reduced exposure to immunoregulatory Old Friends, many but not all of which resided in the gut, high-income countries are undergoing large increases in a wide range of chronic inflammatory disorders including allergies, autoimmunity and inflammatory bowel diseases. Depression, anxiety and reduced stress resilience are comorbid with these conditions, or can occur in individuals with persistently raised circulating levels of biomarkers of inflammation in the absence of clinically apparent peripheral inflammatory disease. Moreover poorly regulated inflammation during pregnancy might contribute to brain developmental abnormalities that underlie some cases of autism spectrum disorders and schizophrenia. In this chapter we explain how the gut microbiota drives immunoregulation, how faulty immunoregulation and inflammation predispose to psychiatric disease, and how psychological stress drives further inflammation via pathways that involve the gut and microbiota. We also outline how this two-way relationship between the brain and inflammation implicates the microbiota, Old Friends and immunoregulation in the control of stress resilience.

THU0268 Local infliximab injection of sacroiliac joints in early axial spondyloarthropathies: Impact on parameters of disease activity

BackgroundSystemic administration of tumor necrosis factor-alpha (TNF-α) antagonists, such as infliximab, has been shown to be effective in the treatment of spondyloarthropathies (SpA). However, experience with the local use of...

Consensus definitions and application guidelines for control groups in cerebrospinal fluid biomarker studies in multiple sclerosis

The choice of appropriate control group(s) is critical in cerebrospinal fluid (CSF) biomarker research in multiple sclerosis (MS). There is a lack of definitions and nomenclature of different control groups and a rationalized application of different control groups. We here propose consensus definitions and nomenclature for the following groups: healthy controls (HCs), spinal anesthesia subjects (SASs), inflammatory neurological disease controls (INDCs), peripheral inflammatory neurological disease controls (PINDCs), non-inflammatory neurological controls (NINDCs), symptomatic controls (SCs). Furthermore, we discuss the application of these control groups in specific study designs, such as for diagnostic biomarker studies, prognostic biomarker studies and therapeutic response studies. Application of these uniform definitions will lead to better comparability of biomarker studies and optimal use of available resources. This will lead to improved quality of CSF biomarker research in MS and related disorders.

Peripheral inflammatory disease associated with centrally activated IL-1 system in humans and mice

During peripheral immune activation caused by an infection or an inflammatory condition, the innate immune response signals to the brain and causes an up-regulation of central nervous system (CNS) cytokine production. Central actions of proinflammatory cytokines, in particular IL-1β, are pivotal for the induction of fever and fatigue. In the present study, the influence of peripheral chronic joint inflammatory disease in rheumatoid arthritis (RA) on CNS inflammation was investigated. Intrathecal interleukin (IL)-1β concentrations were markedly elevated in RA patients compared with controls or with patients with multiple sclerosis. Conversely, the anti-inflammatory IL-1 receptor antagonist and IL-4 were decreased in RA cerebrospinal fluid (CSF). Tumor necrosis factor and IL-6 levels in the CSF did not differ between patients and controls. Concerning IL-1β, CSF concentrations in RA patients were higher than in serum, indicating local production in the CNS, and there was a positive correlation between CSF IL-1β and fatigue assessments. Next, spinal inflammation in experimental arthritis was investigated. A marked increase of IL-1β, IL-18, and tumor necrosis factor, but not IL-6 mRNA production, in the spinal cord was observed, coinciding with increased arthritis scores in the KBxN serum transfer model. These data provide evidence that peripheral inflammation such as arthritis is associated with an immunological activation in the CNS in both humans and mice, suggesting a possible therapeutic target for centrally affecting conditions as fatigue in chronic inflammatory diseases, for which to date there are no specific treatments.

Novel acid-type cyclooxygenase-2 inhibitors: Design, synthesis, and structure–activity relationship for anti-inflammatory drug

Cyclooxygenase (COX) is a key rate-limiting enzyme for prostaglandin (PG) production cascades in the human body. The mechanisms of both the anti-inflammation effects and the side-effects of traditional COX inhibitors are associated with the existence of two COX isoforms. Thus while COX-1 is predominantly expressed ubiquitously and constitutively, and it serves a housekeeping role in processes such as gastrointestinal (GI) mucosa protection, COX-2 is absent or exhibits a low level of expression in most tissues, and is highly upregulated in response to endotoxin, virus, inflammatory or tissue-injury stimuli/signals, and tumour promoter in the various types of organs, tissues, and cells. Furthermore, COX-2 contribution to PGE2 and PGI2 production evokes and sustains systemic or peripheral inflammatory disease, but it is not involved in the COX-1-mediated GI tract events. Also, hypersensitivity of aspirin owing to its inhibitory action against COX-1 is a significant concern clinically. Consequently, highly selective COX-2 inhibitors have been needed for the treatment of inflammatory- and inflammation related-diseases that include pyrexia, inflammation, pain, rheumatoid arthritis, osteoarthritis, and cancers. In this study, a series of novel [2-{[(4-substituted or 4,5-disubstituted)-pyridin-2-yl]carbonyl}-(5- or 6-substituted or 5,6-disubstituted)-1H-indol-3-yl]acetic acid analogues was designed, synthesized, and evaluated to identify potent and selective COX-2 inhibitors as potential agents against inflammatory diseases. As significant findings, the present study clarified unique structure–activity relationship of the analogues toward potent and selective COX-2 inhibition in vitro, and identified 2-{6-fluoro-2-[4-methyl-2-pridinyl)carbonyl]-1H-indol-3-yl}acetic acid as a potent and selective COX-2 inhibitor in vitro that demonstrated orally potent anti-inflammation efficacy against carrageenan-induced oedema formation in the foot of SPF/VAF male SD rats as a peripheral inflammation model in vivo.

Ethnic Influence in Clinical and Functional Measures of Brazilian Patients with Spondyloarthritis

Spondyloarthritides (SpA) can present different disease spectra according to ethnic background. The Brazilian Registry of Spondyloarthritis (RBE) is a nationwide registry that comprises a large databank on clinical, functional, and treatment data on Brazilian patients with SpA. The aim of our study was to analyze the influence of ethnic background in SpA disease patterns in a large series of Brazilian patients. A common protocol of investigation was prospectively applied to 1318 SpA patients in 29 centers distributed through the main geographical regions in Brazil. The group comprised whites (65%), African Brazilians (31.3%), and people of mixed origins (3.7%). Clinical and demographic variables and various disease index scores were compiled. Ankylosing spondylitis (AS) was the most frequent disease in the group (65.1%); others were psoriatic arthritis (18.3%), undifferentiated SpA (6.8%), enteropathic arthritis (3.7%), and reactive arthritis (3.4%). White patients were significantly associated with psoriasis (p = 0.002), positive HLA-B27 (p = 0.014), and use of corticosteroids (p < 0.0001). Hip involvement (p = 0.02), axial inflammatory pain (p = 0.04), and radiographic sacroiliitis (p = 0.025) were associated with African Brazilian descent. Sex distribution, family history, and presence of peripheral arthritis, uveitis, dactylitis, urethritis, and inflammatory bowel disease were similar in the 3 groups, as well as age at disease onset, time from first symptom until diagnosis, and use of anti-tumor necrosis factor-α agents (p > 0.05). Schober test and thoracic expansion were similar in the 3 groups, whereas African Brazilians had higher Maastricht Ankylosing Spondylitis Enthesitis Scores (p = 0.005) and decreased lateral lumbar flexion (p = 0.003), while whites had a higher occiput-to-wall distance (p = 0.02). African Brazilians reported a worse patient global assessment of disease (p = 0.011). Other index scores and prevalence of work incapacity were similar in the 3 groups, although African Brazilians had worse performance in the Ankylosing Spondylitis Quality of Life questionnaire (p < 0.001). Ethnic background is associated with distinct clinical aspects of SpA in Brazilian patients. African Brazilian patients with SpA have a poorer quality of life and report worse disease compared to whites.

Autoreactive T Cells Escaping Thymic Deletion in REL-B Deficient Mice Depend on Dendritic Cell-encoded REL-B for Control of Autoimmunity

In humans and mice, autoimmunity is associated with mutations that attenuate T cell receptor (TCR) signaling capacity, which alter thymic selection, and signaling of the peripheral T cell repertoire. The RelB transcription factor controls maturation of antigen presenting cell function by dendritic cells (DCs). Similar to TCR signaling mutants, RelB-/- mice have severe T cell-dependent autoimmune disease and relative lymphopenia, but normal numbers of FoxP3+ regulatory T cells. By analysis of effector and regulatory T cell phenotype and function, distribution and function of antigen presenting cells (APCs) and DC transfer studies in RelB knockout and RelB-/- bone marrow chimeras, we addressed whether reduced capacity of thymic and peripheral APCs to signal T cells drives autoimmunity in RelB-/-mice. Th2-type RelB-/- CD44hi effector T cells, which escape thymic negative selection due to medullary atrophy and APC deficiency, are susceptible to RelB-/- Treg suppression only when signalled by wild type DCs, with enhanced costimulatory activity. Transfer of RelB-sufficient DCs, to RelB-/- mice reversed peripheral organ inflammatory disease, Th2 cytokine over-production, thymic atrophy and lymphopenia, and rendered effector T cells susceptible to suppression by Treg cells. Thus, similar to defects in TCR signaling, autoimmunity may also result from defects in APC function. In the absence of DC-encoded RelB, progressive T cell and myeloid cell-mediated inflammation, uncontrolled by Treg cells, destroys thymus and other organs. Genetic and environmental factors control the level of RelB expression, and reduced expression is predicted to exacerbate the effect of mutations, such as PTPN22R620W that attenuate TCR signaling capacity. Copyright © 2010 Published by Elsevier Inc.

Treatment of neuroinflammation by soluble tumor necrosis factor receptor Type II fused to a thermally responsive carrier

Biochemical irritation of the dorsal root ganglion (DRG) after intervertebral disc herniation contributes to radiculopathy through tumor necrosis factor-alpha (TNFalpha)-mediated inflammation. Soluble TNF receptor Type II (sTNFRII) sequesters this cytokine, providing clinical benefit. Previous work involving conjugation of sTNFRII with thermally responsive elastin-like polypeptide (ELP) yielded a chimeric protein (ELP-sTNFRII) with in vitro anti-TNFalpha bioactivity. Furthermore, temperature-triggered ELP aggregation into a "depot" prolongs protein residence time following perineural injection. In this study the authors evaluated the inflammatory phenotype of DRG explants after TNFalpha stimulation, and assessed the abilities of sTNFRII or ELP-sTNFRII to attenuate these neuro-inflammatory changes. Rat lumbar DRGs (35 animals) were treated in 6 groups, as follows: control; TNFalpha (25 ng/ml); TNFalpha with low-(0.2 microg/ml) or high-dose (1 microg/ml) sTNFRII; and TNFalpha with low-(52.5 microg/ml) or high-dose (262.5 microg/ml) ELP-sTNFRII. After 24 hours, supernatant was evaluated for inflammatory cytokines (interleukin [IL]-1, IL-6, and IL-10); prostaglandin E2; and metabolites (glutamate, lactate, and pyruvate). Single-factor analysis of variance with post hoc Dunn analysis (alpha = 0.05) was used to assess treatment differences. Incubation of explants with TNFalpha caused metabolic stress reflected by an increased lactate/pyruvate ratio (1.8 +/- 0.5-fold) and extracellular glutamate (79 +/- 8% increase). Inflammatory activation was observed with heightened IL-6 release (5.2 +/- 1.4-fold) and prostaglandin E2 production (14 +/- 3-fold). An autoregulatory response occurred with an 11.8 +/- 0.6-fold increase in sTNFRI shedding. Treatment with high doses of sTNFRII or ELP-sTNFRII reversed all changes. Values are expressed as the mean +/- standard deviation. These results demonstrate that TNFalpha stimulation of DRG explants yields a phenotype of neurotoxic metabolite release and inflammatory mediator expression. Coincubation with either sTNFRII or ELP-sTNFRII antagonizes TNFalpha activity to abrogate these changes, suggesting potential for therapeutic intervention to treat peripheral nerve inflammatory disease.

Bronchial asthma as neurogenic paroxysmal inflammatory disease: Do some antiepileptic drugs have antiasthmatic properties?

Bronchial asthma is an inflammatory disease, and neurogenic inflammation may play important role in asthma mechanisms. But asthma also is an inflammatory disease with paroxysmal clinical picture. It is known that migraine and trigeminal neuralgia also are inflammatory diseases with paroxysmal clinical picture, and neurogenic inflammation plays important role in their mechanisms. Antiepileptic drugs are highly effective in pharmacotherapy of migraine and trigeminal neuralgia, and these drugs completely prevent attacks of migraine and trigeminal pain in great majority of cases. Due to this it is possible that some antiepileptic drugs may be highly effective in pharmacotherapy of asthma. Bronchial asthma can be considered as peripheral paroxysmal and inflammatory disease with definite central neurogenic mechanism. It is also possible that some antiepileptic drugs can suppress inflammatory processes in asthma through the central neural influence, like in therapy of migraine and trigeminal neuralgia.

Macrophage migration inhibitory factor (MIF) seems crucially involved in Guillain–Barré syndrome and experimental allergic neuritis

Macrophage migration inhibitory factor (MIF) is a proinflammatory type 1 cytokine that plays a pathogenic role in several inflammatory and autoimmune diseases. The role of this cytokine in peripheral nerve inflammatory disease has not been evaluated. Therefore, to evaluate the role of macrophage migration inhibitory factor (MIF) in Guillain–Barré syndrome (GBS) and experimental allergic neuritis (EAN), we determined MIF circulating levels in a series of patients with GBS and healthy subjects with ELISA and evaluated the effect of two specific inhibitors of MIF, a neutralizing monoclonal antibody or a chemical inhibitor ISO1 on the course of murine EAN. The data show increased MIF plasma levels in GBS patients as compared to healthy controls ( p < 0.0001) and a progressive increase of MIF circulating concentration with patient's disability ( p < 0.0001). Both anti-MIF mAb and ISO1 favorably influenced the course of EAN. Treated mice had a lower cumulative severity score ( p = 0.001) and reduced disease duration than the control mice ( p < 0.03). MIF may promote immune reaction in GBS. Therapeutic effects of both anti-MIF mAb and ISO1 in EAN suggest that MIF could be a promising therapeutic target in inflammatory demyelinating peripheral nerve disorders.