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BackgroundThe interleukin-12/23p40-subunit-inhibitor ustekinumab significantly improved spondylitis-related symptoms through Week 24 in psoriatic arthritis (PsA) patients with peripheral arthritis and physician-reported spondylitis (PA-PRS) in PSUMMIT-1&2. We further evaluated ustekinumab’s effect on spondylitis-related endpoints in PSUMMIT-1&2 tumour necrosis factor-inhibitor (TNFi)-naïve patients with PA-PRS.MethodsPatients with active PsA (≥5 swollen and ≥5 tender joints, C-reactive-protein ≥ 3.0 mg/L) despite conventional (PSUMMIT-1&2) and/or prior TNFi (PSUMMIT-2) therapy received subcutaneous ustekinumab 45 mg, 90 mg or placebo (Week 0, Week 4, Week 16). Changes in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) neck/back/hip pain question (#2) and modified BASDAI (mBASDAI, excluding PA) scores and Ankylosing Spondylitis Disease Activity Score (ASDAS) responses were assessed at Weeks 12 and 24.ResultsThe pooled PSUMMIT-1&2, TNFi-naïve (n=747), PA-PRS (n=223) subset (158 with human-leucocyte-antigen (HLA)-B27 results) presented with moderate-to-severe spondylitis-related symptoms (mean BASDAI-neck/back/hip pain-6.51, mBASDAI-6.54, BASDAI-6.51, ASDAS-3.81). Mean Week 24 changes were larger among ustekinumab than placebo-treated patients for both neck/back/hip pain (−1.99 vs −0.18) and mBASDAI (−2.09 vs −0.59). Improvements in neck/back/hip pain and fatigue appeared numerically greater in HLA-B27+ than HLA-B27– patients; those for other domains were generally consistent. Greater proportions of ustekinumab versus placebo-treated patients achieved ASDAS clinically important improvement at Week 24 (decrease ≥ 1.1; 49.6% vs 12.7%; nominal p<0.05).ConclusionsImprovements in BASDAI neck/back/hip pain and mBASDAI among ustekinumab-treated, TNFi-naïve, PsA patients with PA-PRS were clinically meaningful and consistent across assessment tools. Numerically greater improvements in neck/back/hip pain in HLA-B27+ than HLA-B27– patients, noted in the context of similar overall mBASDAI improvements between the subgroups, suggest ustekinumab may improve disease activity in TNFi-naïve PsA patients likely to exhibit axial disease.Clinical trial registration numbersPSUMMIT 1, NCT01009086; PSUMMIT 2, NCT01077362.

Human leukocytic antigen-B27 heavy chain (HLA-B27 HC) has the tendency to fold slowly, in turn gradually forming a homodimer, (B27-HC)2 via a disulfide linkage to activate killer cells and T-helper 17 cells and inducing endoplasmic reticulum (ER) stress to trigger the IL-23/IL-17 axis for pro-inflammatory reactions. All these consequences lead to the pathogenesis of ankylosing spondylitis (AS). Sulfasalazine (SSA) is a common medication used for treatment of patients with AS. However, the effects of SSA treatment on (B27-HC)2 formation and on suppression of IL-23/IL-17 axis of AS patients remain to be determined. In the current study, we examine the (B27-HC)2 of peripheral blood mononuclear cells (PBMC), the mean grade of sarcoiliitis and lumbar spine Bath Ankylosing Spondylitis Radiology Index (BASRI) scores of 23 AS patients. The results indicated that AS patients without (B27-HC)2 on PBMC showed the lower levels of mean grade of sarcoiliitis and the lumbar spine BASRI scores. In addition, after treatment with SSA for four months, the levels of (B27-HC)2 on PBMCs were significantly reduced. Cytokines mRNA levels, including TNFα, IL-17A, IL-17F and IFNγ, were also significantly down-regulated in PBMCs. However, SSA treatment did not affect the levels of IL-23 and IL-23R mRNAs.

To determine whether rapamycin affects HLA-B27-mediated gut inflammation in experimental spondyloarthritis (SpA). HLA-B27/human β -microglobulin transgenic (B27-Tg) rats with gut inflammation were treated with rapamycin (1.5 mg/kg intraperitoneally, 3 times a week) or vehicle for 5 weeks. Healthy age-matched wild type (WT) rats were treated in parallel. Gut inflammation was evaluated via stool scoring and histological assessment. Transcriptome and microbiome analyses were performed on colon tissue and cecal luminal contents, respectively. Bulk immune cells were isolated from the colonic lamina propria of B27-Tg and WT animals, treated with rapamycin , and pro-inflammatory cytokine expression was measured using qPCR. Rapamycin treatment reduced stool and colon histological scores in B27-Tg rats compared to vehicle-treated B27-Tg controls. Transcriptome analysis revealed that rapamycin reduced expression of key pro-inflammatory cytokines like , , , , and in B27-Tg colon tissue compared to vehicle-treated B27-Tg controls. treatment of bulk immune cells isolated from B27-Tg rat colon with rapamycin reduced expression of , , and compared to vehicle-treated cells. Rapamycin treatment decreased the abundance of cecum microbiota associated with inflammation in B27-Tg rats. Rapamycin also altered the gut microbiome in WT rats, without associated changes in the tissue transcriptome. Our study demonstrates that rapamycin treatment substantially reduces HLA-B27-mediated gut inflammation in experimental SpA. Results from this pre-clinical model suggest further evaluation of rapamycin as a therapeutic strategy in HLA-B27 associated diseases is warranted.

Background Spondyloarthritis (SpA) is a chronic inflammatory disorder with axial and peripheral manifestations. A strong association between HLA-B27 and SpA has been known for more than 50 years. Remarkably, HLA-B27 and human β2-microglubulin transgenic rats (B27 rat) develop manifestations recapitulating SpA, referred to as rat SpA. Antigen-presenting cells such as dendritic cells (DC) and CD4 T cells are mandatory to develop rat SpA. Serum levels of granulocyte macrophage-colony stimulating factor (GM-CSF), a key growth factor for DC generation and functions, are significantly increased during SpA. Conventional (c)DCs can be divided in two subsets implicated either in immune tolerance (cDC1) or in adaptive immune responses induction (cDC2). In this study, we aimed to determine the influence of GM-CSF on cDC subsets functions linked to T cell activation and differentiation, in the B27 rat model. Methods cDC subsets were isolated from spleens of B27 and nontransgenic (NTG) rats, primed with GM-CSF and tested for their ability to support CD4h T cell differentiation. RNA sequencing was performed on GM-CSF-primed cDC subsets. Results GM-CSF-primed cDC2 from B27 rat were strong inducers of TNF-producing proinflammatory CD4 + T cells. In contrast, whereas control cDC1 required GM-CSF to support T cell proliferation, HLA-B27 + cDC1 primed with GM-CSF failed to do so. RNA sequencing analysis demonstrated that HLA-B27 expression promoted endoplasmic reticulum stress and unfolded protein response in both cDC subsets. In addition, HLA-B27 expression promoted inflammatory cytokine synthesis by cDC2 and a signature interfering with regulation of cell adhesion and activation in cDC1. Conclusion Altogether, our study reveals a dual role of GM-CSF during SpA. In one hand, GM-CSF promotes proinflammatory functions of cDC2. On the other hand, GM-CSF is required for cDC1 to induce T cell proliferation, and those functions are blunted by HLA-B27 expression.

BackgroundDysbiosis has been recently demonstrated in patients with ankylosing spondylitis (AS) but its implications in the modulation of intestinal immune responses have never been studied. The aim of this study was to investigate the role of ileal bacteria in modulating local and systemic immune responses in AS.MethodsIleal biopsies were obtained from 50 HLA-B27+ patients with AS and 20 normal subjects. Silver stain was used to visualise bacteria. Ileal expression of tight and adherens junction proteins was investigated by TaqMan real-time (RT)-PCR and immunohistochemistry. Serum levels of lipopolysaccharide (LPS), LPS-binding protein (LPS-BP), intestinal fatty acid-BP (iFABP) and zonulin were assayed by ELISA. Monocyte immunological functions were studied in in vitro experiments. In addition the effects of antibiotics on tight junctions in human leukocyte antigen (HLA)-B27 transgenic (TG) rats were assessed.ResultsAdherent and invasive bacteria were observed in the gut of patients with AS with the bacterial scores significantly correlated with gut inflammation. Impairment of the gut vascular barrier (GVB) was also present in AS, accompanied by significant upregulation of zonulin, and associated with high serum levels of LPS, LPS-BP, iFABP and zonulin. In in vitro studies zonulin altered endothelial tight junctions while its epithelial release was modulated by isolated AS ileal bacteria. AS circulating monocytes displayed an anergic phenotype partially restored by ex vivo stimulation with LPS+sCD14 and their stimulation with recombinant zonulin induced a clear M2 phenotype. Antibiotics restored tight junction function in HLA-B27 TG rats.ConclusionsBacterial ileitis, increased zonulin expression and damaged intestinal mucosal barrier and GVB, characterises the gut of patients with AS and are associated with increased blood levels of zonulin, and bacterial products. Bacterial products and zonulin influence monocyte behaviour.

Introduction/Aim HLA-B27/human β2m transgenic rats (B27-rats) develop an inflammatory disorder resembling spondyloarthritis (SpA) with dysregulated IL-10/IL-17 production by regulatory T cells (Treg). Treg plays a major role in controlling pathogenic inflammatory processes. Interleukin 2 (IL-2), a cytokine which promotes Treg cell survival and function, may thus have therapeutic efficacy in SpA. Here, we tested this hypothesis using a low dose of IL-2 treatment in B27-rat. Material and methods B27-rats aged 4 weeks (before disease onset) and nontransgenic (NTG) littermates were administered intraperitoneally recombinant human IL-2 (Sanofi®; 2,000IU/injection) or PBS, 3 days per week during 6 weeks. Assessment of treatment effect was performed, based on clinical (weight, diarrhea, arthritis), histological (proximal and distal colon, caecum, ileum and tarsal/ankle joint) scores, and frequency of Treg in the spleen and lymph nodes (LN). Results IL-2 administration had no effect on weight gain, either in B27- or NTG-rats. Over the 6 weeks of treatment, the clinical disease score worsened similarly in both IL-2-treated and control groups of B27-rats. The macroscopic and histological evaluation of gut and joints showed marked inflammation in B27-rats; however, no change related to IL-2 treatment was observed. In the B27-rats, the percentage of Treg was moderately increased after IL-2 treatment in the spleen, but neither in mesenteric nor peripheral LN in those rats. Conclusion Our data demonstrate that a low dose of IL-2 administered before disease onset was moderately effective for boosting Treg but failed to prevent SpA development in B27-rat.

In this study, we aimed to evaluate HLA-B subtypes in cases developing TB while using anti-TNF agents and to compare with the HLA-B subtypes of three different groups including community-acquired TB cases, anti-TNF patients without TB and healthy controls. The study consisted of four groups. Group 1: 35 community-acquired TB patients, group 2; 47 anti-TNF-TB patients, group 3; 61 anti-TNF (non TB) patients and group 4; 40 healthy controls. HLA-B subgroups were studied genetically from blood samples taken from the patients. Approval was received from the ethics committee. HLA-B typing was performed by using the LIFECODES HLA-B eRES SSO Typing SSO typing kit (Immucor, Stamford, CT, USA). Among HLA-B subtypes, significant differences between the four groups were found only for HLA-B5, HLA-B8, HLA-B27 and HLA-B38. Although frequency of HLA-B8 was highest in patients developing TB during anti-TNF treatment, significance was lost after Bonferoni correction. HLA-B27 was significantly higher in both anti-TNF groups, with and without TB, due to presence of patients with ankylosing spondylitis in those groups. To our knowledge, this is the first study analyzing HLA-B subtypes in anti-TNF patients developing TB. Although in literature HLA-B8 positivity was suggested to associate with or to confer a risk for community-acquired TB, we could not confirm this association in anti-TNF patients developing TB. However, further studies with larger number of patients from different ethnic groups are clearly needed to get the final word in this topic.

Rickettsia rickettsii, a tick borne disease, is the pathogen responsible for inducing Rocky Mountain Spotted Fever (RMSF), an illness that can progress to fulminant multiorgan failure and death. We present a case where R. rickettsii, acquired on a camping trip, precipitated a flare of peripheral arthritis and episcleritis in an HLA-B27 positive patient. Although Yersinia, Salmonella, Mycobacteria, Chlamydia, Shigella, Campylobacter, and Brucella have been previously associated with HLA-B27 spondyloarthritis, this unusual case demonstrates that obligate intracellular rickettsial organisms, and specifically, R. rickettsii, can also induce flares of HLA-B27 spondyloarthritis. Rickettsial infections in general can rapidly become fatal in both healthy and immunosuppressed patients, and thus, prompt diagnosis and therapy are required.

Enteropathic arthritis (EA) is a spondyloarthritis (SpA) which occurs in patients with inflammatory bowel diseases (IBDs) and other gastrointestinal diseases. Diagnosis is generally established on the medical history and physical examination. It was, generally, made according to the European Spondyloarthropathy Study Group (ESSG) criteria. Rheumatic manifestations are the most frequent extraintestinal findings of IBD with a prevalence between 17% and 39%, and IBD is associated, less frequently, with other rheumatic disease such as rheumatoid arthritis, Sjogren syndrome, Takayasu arteritis, and fibromyalgia. Although the pathogenesis of EA has not been plainly clarified, the most popular theory supposes that joint inflammation occurs in genetically predisposed subjects with bacterial gut infections, provided an important evidence for a possible relationship between inflammation of the gut mucosa and arthritis. The management of patients with EA requires an active cooperation between the gastroenterologist and rheumatologist.

Spondyloarthritis (SpA) is characterized by inflammation, articular bone erosions and pathologic new bone formation. Targeting TNFα or IL-17A with current available therapies reduces inflammation in SpA, however, treatment of the bone pathology in SpA remains an unmet clinical need. Activation of the mammalian target Of rapamycin (mTOR) promotes IL-17A expression and osteogenesis. Therefore, the inhibition of mTOR (with rapamycin) could be a promising therapeutic avenue in SpA. To investigate the effect of blocking mTOR on inflammation, bone erosions and new bone formation in SpA. Peripheral blood mononuclear cells (PBMCs) from patients with SpA were stimulated with anti-CD3/CD28 in the presence or absence of rapamycin and the resulting cytokine expression was assessed. Fibroblast-like synoviocytes (FLS) from SpA patients were assessed for osteogenic differentiation potential in conditions with TNFα, IL-17A, or TNFα plus IL-17A, in the presence or absence of rapamycin. HLA-B27/Huβ2m transgenic rats were immunized with low dose heat-inactivated , treated with 1.5 mg/kg rapamycin prophylactically or therapeutically and monitored for arthritis and spondylitis. Histology and mRNA analysis were performed after 5 weeks of treatment to assess inflammation and bone pathology. TNFα and IL-17A protein production by SpA PBMCs was inhibited in the presence of rapamycin. Rapamycin also inhibited osteogenic differentiation of human SpA FLS. analysis of SpA synovial biopsies indicated activation of the mTOR pathway in the synovial tissue of SpA patients. , prophylactic treatment of HLA-B27/Huβ2m transgenic rats with rapamycin significantly inhibited the development and severity of inflammation in peripheral joints and spine (arthritis and spondylitis), with histological evidence of reduced bone erosions and new bone formation around peripheral joints. In addition, therapeutic treatment with rapamycin significantly decreased severity of arthritis and spondylitis, with peripheral joint histology showing reduced inflammation, bone erosions and new bone formation. mRNA expression was decreased in the metacarpophalangeal joints after rapamycin treatment. mTOR blockade inhibits IL-17A and TNFα production by PBMCs, and osteogenic differentiation of FLS from patients with SpA . In the HLA-B27 transgenic rat model of SpA, rapamycin inhibits arthritis and spondylitis development and severity, reduces articular bone erosions, decreases pathologic new bone formation and suppresses IL-17A expression. These results may support efforts to evaluate the efficacy of targeting the mTOR pathway in SpA patients.