Background: Chronic synovial inflammation is an important hallmark of inflammatory arthritis, but the cells and mechanisms involved are incompletely understood. Previously, we have shown that CCR6+ memory T-helper (memTh) cells and synovial fibroblasts (SF) activate each other in a pro-inflammatory feedforward loop, which potentially drives persistent synovial inflammation in inflammatory arthritis. However, the CCR6+ memTh cells are a heterogeneous population, containing Th17/Th22 and Th17.1 cells. Currently, it is unclear which of these subpopulations drive SF activation and how they should be targeted. In this study, we examined the individual contribution of these CCR6+ memTh subpopulations to SF activation and examined ways to regulate their function.

Methods: Th17/Th22 (CXCR3^-CCR4⁺), Th17.1 (CXCR3⁺CCR4^-), DP (CXCR3⁺CCR4⁺), and DN (CXCR3^-CCR4^-) CCR6+ memTh, cells sorted from PBMC of healthy donors or treatment-naïve early rheumatoid arthritis (RA) patients, were cocultured with SF from RA patients with or without anti-IL17A, anti-IFNγ, or 1,25(OH)₂D₃. Cultures were analyzed by RT-PCR, ELISA, or flow cytometry.

Results: Th17/Th22, Th17.1, DP, and DN cells equally express RORC but differ in production of TBX21 and cytokines like IL-17A and IFNγ. Despite these differences, all the individual CCR6+ memTh subpopulations, both from healthy individuals and RA patients, were more potent in activating SF than the classical Th1 cells. SF activation was partially inhibited by blocking IL-17A, but not by inhibiting IFNγ or TBX21. However, active vitamin D inhibited the pathogenicity of all subpopulations leading to suppression of SF activation.

Conclusions: Human CCR6+ memTh cells contain several subpopulations that equally express RORC but differ in TBX21, IFNγ, and IL-17A expression. All individual Th17 subpopulations are more potent in activating SF than classical Th1 cells in an IFNγ-independent manner. Furthermore, our data suggest that IL-17A is not dominant in this T cell-SF activation loop but that a multiple T cell cytokine inhibitor, such as 1,25(OH)₂D₃, is able to suppress CCR6+ memTh subpopulation-driven SF activation.

Keywords: Cytokines; Inflammatory arthritis; Synovial fibroblasts; T cells; Th17; Th17.1; Transcription factors; Vitamin D.

Psoriasis is a recurrent autoimmune skin disease with aberrant regulation of keratinocytes and immunocytes. There is no universally accepted single treatment available for psoriasis, and the establishment of a common treatment option to control its signs and symptoms is urgently needed. Here, we found Ebosin, a novel exopolysaccharide isolated from Streptomyces sp. 139 by our lab, not only could ameliorate inflammation in LPS-induced keratinocytes through IKK/NF-kapaB pathway, but also attenuate psoriatic skin lesions and reduce inflammatory factors expression in imiquimod (IMQ)-mediated psoriatic mice. Except for inhibiting the expression of epidermal differentiation related proteins, Ebosin significantly increased the percentage of CD4⁺Foxp3⁺CD25⁺ Tregs and decreased CD4⁺IL17A⁺ Th17 cells in psoriatic mice. Furthermore, we demonstrate that Ebosin significantly suppressed the IL-17 signaling pathway via A20 (encoded by tnfaip3) in vivo. As the direct binding of tnfaip3 to miR-155 has been demonstrated by luciferase reporter assay, and Ebosin has been demonstrated to inhibit miR-155 level in vitro and in vivo, our study first indicates that Ebosin reduces inflammation through the miR-155-tnfaip3-IL-17 axis and T cell differentiation in a psoriasis-like model. Thus, we conclude that Ebosin can act as a promising therapeutic candidate for the treatment of psoriasis.

Keywords: ebosin; inflammation; miR-155; psoriasis; tnfaip3.

Background: Small blood stem cells (SB cells), isolated from human peripheral blood, demonstrated the ability to benefit bone regeneration and osseointegration. The primary goal of our study is to examine the safety and tolerability of SB cells in dental implantation for human patients with severe bone defects.

Methods: Nine patients were enrolled and divided into three groups with SB cell treatment doses of 1 × 10⁵, 1 × 10⁶, and 1 × 10⁷ SB cells, and then evaluated by computed tomography (CT) scans to assess bone mineral density (BMD) by Hounsfield units (HU) scoring. Testing was conducted before treatment and on weeks 4, 6, 8, and 12 post dental implantation. Blood and comprehensive chemistry panel testing were also performed.

Results: No severe adverse effects were observed for up to 6-month trial. Grade 1 leukocytosis, anemia, and elevated liver function were observed, but related with the patient's condition or the implant treatment itself and not the transplantation of SB cells. The levels of cytokines and chemokines were detected by a multiplex immunological assay. Elevated levels of eotaxin, FGF2, MCP-1, MDC, and IL17a were found among patients who received SB cell treatment. This observation suggested SB cells triggered cytokines and chemokines for local tissue repair. To ensure the efficacy of SB cells in dental implantation, the BMD and maximum stresses via stress analysis model were measured through CT scanning. All patients who suffered from severe bone defect showed improvement from D3 level to D1 or D2 level. The HU score acceleration can be observed by week 2 after guided bone regeneration (GBR) and prior to dental implantation.

Conclusions: This phase I study shows that treatment of SB cells for dental implantation is well tolerated with no major adverse effects. The use of SB cells for accelerating the osseointegration in high-risk dental implant patients warrants further phase II studies.

Trial registration: Taiwan Clinical Trial Registry ( SB-GBR001 ) and clinical trial registry of the United States ( NCT04451486 ).

Keywords: Dental implantation; Guided bone regeneration; Osseointegration; SB cell therapy; Stem cells.

Our previous studies found that the C-X-C motif chemokine receptor 5 (CXCR5) loss leads to retinal pigment epithelium (RPE) dysfunction and AMD pathogenesis. The current study aimed to characterize the G protein-coupled receptor (GPCR) structure of CXCR5 and analyze its interactions with AMD-related risk genes. The sequence alignments, homology model of CXCR5 and structural assessment analysis were performed. Data and text mining were then performed to identify AMD-related risk genes and their interaction with CXCR5 using statistical and mathematical algorithms. Sequence alignment and phylogenetic tree analysis revealed that human CXCR5 was highly similar (85.4839%) to the rabbit. The least similarity (33.871%) was found to be in zebrafish compared to the other species. The CXCR5 model structural assessment and secondary structure analysis exhibited an excellent model. Network analysis revealed that IL10, TNF, ICAM1, CXCL1, CXCL8, APP, TLR4, SELL, C3, IL17A and CCR2 were the most connected genes CXCR5. These findings suggest that CXCR5 signaling may regulate the biological function of RPE and modulate AMD pathophysiology via GPCR signaling and interacting with identified AMD risk genes. In summary, the data presented here provide novel and crucial insights into the molecular mechanisms of CXCR5 involvement in AMD.Communicated by Ramaswamy H. Sarma.

Keywords: AMD; CXCR5; data mining; homology modeling; sequence analysis.

PEGylation is a promising approach to increase the residence time of antibody fragments in the lungs and sustain their therapeutic effects. However, concerns arise as to the potential pulmonary toxicity of antibody fragments conjugated to high molecular weight (HMW) polyethylene glycol (PEG), notably after repeated administrations, and the possibility of PEG accumulation in the lungs. The purpose of this proof-of-concept study is to give insights about the safety of lung administration of a Fab' anti-IL17A antibody fragment conjugated to two-armed 40 kDa PEG (PEG40). The presence of the PEG40 moiety inside alveolar macrophages remained stable for at least 24 h after intratracheal administration of PEG40-Fab' to mice. PEG40 was then progressively cleared from alveolar macrophages. Incubation of PEG40 alone with macrophages in vitro did not significantly harm macrophages and did not affect phagocytosis or the production of inflammatory markers. After acute or chronic administration of PEG40-Fab' to mice, no signs of significant pulmonary toxicity or inflammatory cell accumulation were observed. A vacuolization of alveolar macrophages not associated with any inflammation was noticed when PEG40, PEG40-Fab', or unPEGylated Fab' were administered. To conclude this preliminary proof of concept study, acute or repeated pulmonary administrations of PEGylated Fab' appear safe in rodents.

Background: Klebsiella pneumoniae is a common cause of antibiotic-resistant pneumonia. FSTL-1 is highly expressed in the lung and is critical for lung homeostasis. The role of FSTL-1 in immunity to bacterial pneumonia is unknown.

Methods: Wild-type (WT) and FSTL-1 Hypomorphic mice were infected with Klebsiella pneumoniae to determine infectious burden, immune cell abundance (FACS), and cytokine production. FSTL-1 Hypo/TCRδ^{-/- and} FSTL-1 Hypo/IL17ra^-/- were also generated to assess the role of γδT17 cells in this model.

Outcomes: FSTL-1 Hypo mice had reduced K. pneumoniae lung burden compared to a WT controls. FSTL-1 Hypo mice had increased Il17a/IL-17A and IL-17-dependent cytokine expression. FSTL-1 Hypo lungs also had increased IL-17A⁺ and TCRγδ⁺ cells. FSTL-1 Hypo/TCRδ^-/- displayed similar lung burden to FSTL-1 Hypo and reduced lung burden compared to the TCRδ^-/- controls. However, FSTL-1 Hypo/TCRδ^-/- mice had greater bacterial dissemination compared to FSTL-1 Hypo mice, suggesting that γδT cells are dispensible for FSTL-1 Hypo control of pulmonary infection, but required for dissemination control. Confusing these observations, FSTL-1 Hypo/TCRδ^-/- lungs had an increased percentage of IL-17A producing cells compared with TCRδ^-/- mice. Removal of IL-17A signaling in the FSTL-1 Hypo mouse resulted in an increased lung burden. These findings identify a novel role for FSTL-1 in innate lung immunity to bacterial infection, suggesting that FSTL-1 influences Type-17 pulmonary bacterial immunity.

Nitric oxide (NOx) availability in biological systems is associated with either favorable or unfavorable outcomes. In this sense, several studies bring about evidence that unbalanced NOx production may be underlying to the pathophysiology of vascular disorders. Our study investigated the possible association of clinical, biochemical and inflammatory variables with total circulating levels of NOx in elderly patients devoid of major inflammatory conditions. Clinical (demographics, lifestyle, anthropometry, pressoric traits) and biochemical characteristics (lipemic, glycemic and hormonal profiles) were assessed from 168 geriatrics outpatients eligible for primary care for age-related disorders. Furthermore, circulating levels of 10 inflammatory mediators and of NOx were measured. Correlation tests analyzed categorical or continuous traits according to serum NOx and found no association between NOx and any of the clinical or laboratory data but a negative correlation between plasma NOx concentrations and levels of the immune mediator IL17a (r = -0.236; P = 0.004). Evidence for a correlation between circulating NOx and IL17 is already present in the literature, mostly from studies conducted under inflammatory conditions. Our hypothesis is that such negative correlation can be attributed to an endogenous homeostatic system that IL17 production by the constitutively produced NOx from the vascular endothelium.

Aim: to study non-specific immune response characteristics (serum cytokine profile) in rats after subcutaneous implantation of the decellularized esophagus matrix.

Methods: Data were obtained in Wistar rats. The rats underwent subcutaneous implantation of decellularized esophagus (DE) and native allogeneic esophagus (NE). Explantation of sampling were carried out on the 7th, 14th and 21st day of the experiment. Explanted NEs and DEs were processed for histologic examination. The content of IL1α, IL2, IL4, IL17А, TNFα, IFNγ and GM-CSF in serum samples were tested by ELISA.

Results: In rat serum with DEs on the 7th day of the experiment it was significant increase in IL1α level in comparison with control group, IL2, TNFα, IL4 levels did not differ from the control group levels that indicates the stabilization of inflammation. The content of IL17A, IFNγ and GM-CSF significantly decreased compared to control. On the 14th day, IL17A concentration analysis showed a sharp decrease in comparison with the the 7th experimental day. We found decrease in IL1α level vs control group and decrease in IFNγ level vs 7th day. On the 21st experimental day was shown a significant decrease in the IL17A, IFNγ and IL1α content in DE rats.

Conclusions: It was found dynamic change in studied rat cytokine concentrations that correspond to favourable clinical picture in DE group in comparison with an active inflammatory reaction in NE group. IL1α, IL4, IL17A and IFNγ concentrations reflect positive dynamics of the wound healing process and the absence of local inflammation and rejection of decellularized matrices.

Keywords: decellularization; esophagus; immune response; pro-inflammatory cytokines; subcutaneous implantation.

IL-17A and IL-17F cytokines are important regulators of acute graft-versus-host-disease (GVHD). However, contrary effects of these cytokines in inflammatory diseases have been reported. To investigate the effects of donor-derived IL-17A and IL-17F on GVHD, we made use of single (Il17a-/- or Il17f-/-) and double deficient (Il17af-/-) allogeneic donor CD4+ T cells. We could demonstrate that transplantation of Il17af-/- CD4+ donor T cells led to aggravated GVHD. However, this phenotype was not observed after transplantation of single, Il17a-/- or Il17f-/-, deficient CD4+ T cells, suggesting redundant effects of IL-17A and IL-17F. Moreover, Il17af-/- cell recipients showed an increase of systemic IFNγ, indicating a heightened pro-inflammatory state, as well as infiltration of IFNγ-secreting CD4+ T cells in the recipients' intestinal tract. These recipients exhibited significant gut leakage, and markedly macrophage infiltration in the gastrointestinal epithelial layer. Moreover, we saw evidence of impaired recovery of gut epithelial cells in recipients of Il17af-/- CD4+ T cells. In this study, we show that IL-17A/F double deficiency of donor CD4+ T cells leads to accelerated GVHD and therefore highlight the importance of these cytokines. Together, IL-17 cytokines might serve as a brake to an intensified Th1 response, leading to the exacerbated gut damage in acute GVHD.

BACKGROUND

Down Syndrome is by far the most common and best known chromosomal disorder in humans. It expresses multiple systemic complications with both structural and functional defects as part of the clinical manifestation. The mechanisms of immune changes occurring in Down Syndrome are complex and include an extra gene copy of chromosome 21 and secondary dysregulation of numerous intercellular interactions. Recent studies suggest a role of interleukin 17A (IL-17A), a pro-inflammatory cytokine located on 6p12 chromosome, in the pathogenesis of inflammatory and autoimmune diseases. We aimed to analyze IL17A gene expression in peripheral white cells and IL-17A intracellular expression on CD4+ T-cells.

METHODS

The research was carried out on a group of 58 children aged 6-12 years including a group of 30 children with Down Syndrome (simple trisomy of chromosome 21 only) and a reference group of 28 healthy children. We evaluated gene IL17A expression using real-time PCR and intracellular IL-17A analyzed by flow cytometry.

RESULTS

We found significantly decreased gene expression in white cells and significantly decreased expression of IL-17A levels on CD4+ T-cells in Down Syndrome.

CONCLUSIONS

Our data indicate that decreased IL-17A expression may play a significant role in the etiology of infections in Down Syndrome. Moreover, we demonstrated that in Down Syndrome the other gene located outside the extra chromosome 21 is also affected.

Interleukin-17 receptor A (IL-17RA), encoded by the IL17RA gene, is the receptor of IL-17A cytokine and regulates the balance between promoting and inhibiting inflammation induced by IL-17A. In our previous study, three IL17A gene variations were associated with an increased osteitis risk after BCG vaccination at birth. [1,2] In cell cultures, BCG stimulation reduced IL17RA expression of human neutrophils, and the infected neutrophils or epithelial cells did not produce IL-17 cytokines. [3].

Interleukin 17A (IL17A) is reported to be involved in many inflammatory processes, but its role in aortic valve diseases remains unknown. We examined the role of IL17A based on an ApoE^-/- mouse model with strategies as fed with high-fat diet or treated with IL17A monoclonal antibody (mAb). 12 weeks of high-fat diet feeding can elevate cytokines secretion, inflammatory cells infiltration and myofibroblastic transition of valvular interstitial cells (VICs) in aortic valve. Moreover, diet-induction accelerated interleukin 17 receptor A (IL17RA) activation in VICs. In an IL17A inhibition model, the treatment group was intra-peritoneally injected with anti-IL17A mAb while controls received irrelevant antibody. Functional blockade of IL17A markedly reduced cellular infiltration and transition in aortic valve. To investigate potential mechanisms, NF-κB was co-stained in IL17RA⁺ VICs and IL17RA⁺ macrophages, and further confirmed by Western blotting in VICs. High-fat diet could activate NF-κB nuclear translocation in IL17RA⁺ VICs and IL17RA⁺ macrophages and this process was depressed after IL17A mAb-treatment. In conclusion, high-fat diet can lead to IL17A upregulation, VICs myofibroblastic transition and inflammatory cells infiltration in the aortic value of ApoE^-/- mice. Blocking IL17A with IL17A mAb can alleviate aortic valve inflammatory states.

Keywords: NF-κB pathway; aortic valve inflammation; colocalization; intensity correlation analysis; interleukin 17A.

IL23 receptor (IL23R) binding by IL23 is required for the maturation of CD4⁺ cells into Th17 cells and subsequent generation of IL17A and TNF. As IL23R variations contribute to AS susceptibility, we investigated the effect of IL23R variants on cytokine levels and disease measures in an AS cohort.

This was a cross-sectional study of AS patients (n = 334, 90% B27⁺, age 45 years). IL23R genotyping for three non-synonymous single-nucleotide polymorphisms (rs11209026, protective allele A; rs10489629, protective allele A; and rs11209032, risk allele A) was done by Taqman RT-PCR. IL23, IL17A, TNF and IL6 concentrations were determined by sandwich ELISA. Genotypic associations were analysed with non-parametric methods.

Twenty-two AS patients (6.6%) carried the protective rs11209026 A allele, whereas 206 (61.7%) carried the rs11209032A risk allele (P = 0.03). Two patients homozygous for rs11209026A had late onset, no co-morbidity and undetectable cytokine levels. IL23R genotypes and five common haplotypes were unrelated with age at onset, BASFI or co-morbidity (all P >0.2). There was no overall difference in the concentration of IL17A (184 vs 233 pg/ml, P > 0.2) or IL23 (276 vs 262 pg/ml, P > 0.4) between AS patients and controls, but a global haplotype association (P = 0.01) was observed for IL23 concentrations.

Homozygosity for rs11209026A is rare in AS patients, but may ameliorate the clinical presentation. IL17A and IL23 levels are similar in controls and AS patients. IL23R variants influence IL23 levels but not IL17A levels in AS patients, suggesting that IL23R impacts more on cell types other than Th17 cells.

Introduction. With the advent of targeted drugs, a correct identification of patients with neuromyelitis optica spectrum disorders (NMOSD) is fundamental. Moreover, to assess treatment efficacy, sensitive biomarkers for monitoring disease activity are needed.Areas covered. In this review, the authors provide an up-to-date guide to NMOSD biomarkers, starting from the pathogenetic mechanisms and moving to clinical findings, focusing on their diagnostic meaning, their possible application for disease monitoring and their correlation with clinical features.Expert opinion. Beside anti-AQP4-IgG, other emerging biomarkers for NMOSD have been proposed. Elements supporting antibody production, such as T Helper 17 and T Follicular Helper cells, plasmablasts, and their related cytokines, can be supportive criteria for NMOSD diagnosis since their levels are related to disease activity. Similarly, indices of granulocyte and complement activation, associated with markers of astrocyte damage, reflect disease status and correlate with clinical features. Among all cytokines, IL6 and IL17a represent the bridge between innate and acquired immunity and between cellular and humoral arms of the immune system, therefore being useful for both diagnosis and disease monitoring. Paraclinical tools, such as magnetic resonance imaging and optical coherence tomography, can provide useful diagnostic information, especially in double-seronegative patients.

Background: Chagas disease caused by Trypanosoma cruzi (T. cruzi) affects approximately six million individuals worldwide. Clinical manifestations are expected to occur due to the parasite persistence and host immune response. Herein we investigated potential associations between IL1B, IL6, IL17A, or IL18 polymorphism profiles and cardiomyopathy or T. cruzi parasitemia, as well as the impact of HIV infection on cardiopathy.

Methods: Two hundred twenty-six patients and 90 control individuals were analyzed. IL1B rs1143627 T>C, IL6 rs1800795 C>G, IL17A rs2275913 G>A, IL18 rs187238 C>G, and IL18 rs1946518 C>A SNVs were analyzed by real-time PCR and T. cruzi parasitemia by PCR.

Results: Our data revealed association between a cytokine gene polymorphism and parasitemia never previously reported. The IL6 rs1800795 CG genotype lowered the risk of positive parasitemia (OR = 0.45, 95% CI 0.24-0.86, P = 0.015). Original findings included associations between IL17A rs2275913 AA and IL18 s1946518 AA genotypes with decreased risk of developing cardiomyopathy (OR = 0.27, 95% CI 0.07-0.97, P = 0.044; and OR = 0.35, 95% CI 0.14-0.87, P = 0.023, respectively). IL18 rs1946518 AA and IL1B rs1143627 TC were associated with reduced risk for cardiomyopathy severity, including NYHA (New York Heart Association) class ≥ 2 (OR = 0.21, 95% CI 0.06-0.68, P = 0.009; and OR = 0.48, 95% CI 0.24-0.95, P = 0.036, respectively) and LVEF (left ventricular ejection fraction) <45% for IL18 rs1946518 AA (OR = 0.22, 95% CI 0.05-0.89, P = 0.034). A novel, unexpected protective effect of HIV infection against development/progression of cardiomyopathy was identified, based on a lower risk of developing cardiopathy (OR = 0.48, 95% CI 0.23-0.96, P = 0.039), NYHA class ≥ 2 (OR = 0.15, 95% CI 0.06-0.39, P < 0.001), and LVEF < 45% (OR = 0.03, 95% CI 0.00-0.25, P = 0.001). Digestive involvement was negatively associated with NYHA ≥ 2 and LVEF < 45% (OR = 0.20, 95% CI 0.09-0.47, P < 0.001; and OR = 0.24, 95% CI 0.09-0.62, P = 0.004, respectively).

Conclusions: Our data support a protective role of IL17A AA, IL18 AA, and IL1B TC genotypes against development/progression of cardiomyopathy and a modulatory effect of the IL6 CG genotype on the risk of parasitemia in Chagas disease. Notably, HIV infection was shown to protect against development/progression of cardiopathy, potentially associated with a synergistic effect of HIV and highly active antiretroviral therapy (HAART), attenuating a Th1-mediated response in the myocardium. This proposed hypothesis requires confirmation, however, in larger and more comprehensive future studies.

Keywords: Chagas disease; HIV; IL1 B; IL17 A and IL18 polymorphisms; IL6; T. cruzi parasitemia; cardiomyopathy.

Background: Vitamin D treatment may reduce Crohn's disease (CD) activity by modulating the mucosal immune function. We investigated if high-dose vitamin D +/- infliximab modulated the mucosal cytokine expression in active CD.

Methods: Forty CD patients were randomized into: infliximab + vitamin D; infliximab + placebo-vitamin D; placebo-infliximab + vitamin D or placebo-infliximab + placebo-vitamin D. Infliximab (5 mg/kg) and placebo-infliximab were administered at weeks 0, 2 and 6. Oral vitamin D was administered as bolus 200,000 international units (IU) per week 0 followed by 20,000 IU/day for 7 weeks or placebo. Endoscopy with biopsies was performed at weeks 0 and 7 where endoscopic activity was measured and mucosal mRNA cytokine expression was examined. C-reactive protein (CRP), fecal calprotectin and Harvey-Bradshaw Index (HBI) were measured at weeks 0, 2 and 6.

Results: High-dose vitamin D treatment alone and combined with infliximab decreased the IL17A, IFNγ and IL10 expression. High-dose vitamin D alone did not significantly decrease the disease activity, CRP or calprotectin. Combined infliximab and vitamin D treatment was not clinically significantly superior to monotherapy with infliximab.

Conclusions: High-dose vitamin D as monotherapy and combined with infliximab decreases IL17A, IFNγ and IL-10 expression in mucosa within treatment groups. This did not induce a statistically significant decreased disease activity. EudraCT no.2013-000971-34.

Keywords: Crohn’s disease; infliximab; vitamin D treatment.

Switching of biologic agents in treatment of plaque psoriasis is a common strategy. Only a few studies are available on switching between IL17A-blockers. In a retrospective study, we identified 22 psoriasis patients who, after failing secukinumab as a first IL17A-blocker received ixekizumab with an observation period of at least 24 weeks. At last observation 10/22 patients had a good response (PASI75 or PASI&lt;3) using ixekizumab therapy. None of five patients with primary non-response to secukinumab reached a good, durable response to ixekizumab. In conclusion, ixekizumab appears to be a therapeutic option as a second IL17A-blocker in psoriasis patients who did not show a primary non-response to secukinumab.

Knowledge regarding the mechanisms of the IL17-IL23 pathway and its role in spondyloarthritis (SpA) has been pivotal to the development of IL-17 blockade in patients with axial SpA. Previously, only anti-TNF has proven to be clinically efficacious in patients with active disease, despite non-steroidal anti-inflammatory drugs and physiotherapy. However, up to 50% fail to achieve a clinically significant response. Secukinumab, a fully humanized monoclonal antibody targeting IL-17A, has recently been approved for use in patients with active ankylosing spondylitis. Clinical studies and current issues surrounding the use of secukinumab will be discussed.

This paper is to assess the efficacy of different biologic DMARDs (bDMARDs) on several patient-reported outcomes (PROs) in randomized controlled trials (RCT) in axial spondyloarthritis (axSpA). A systematic literature review (SLR) was performed. MEDLINE (May 1, 2018) was used with the filters "published in the last 10 years" and "humans." The PICO criteria used were Patients: adults with radiographic axSpA (r-axSpA) or non-radiographic axSpA (nr-axSpA); Intervention: any bDMARD; Compararator: placebo (PBO)/any different drug; Outcome: the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Bath Ankylosing Spondylitis Functional Index (BASFI), the Ankylosing Spondylitis Quality of Life (ASQoL), the EuroQol-5D (EQ-5D), the Short Form 36 Health Survey physical component summary (SF36-PCS), the Short Form 36 Health Survey mental component summary (SF36-MCS), and the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F). After screening 84 initial references and manually selecting other 9, 24 publications, assessing TNF inhibitors (TNFi) or IL17A inhibitors (IL17Ai) were selected. Four RCTs quantified the minimal clinical important difference (MCID) between treatment arms. Most of the RCTs compared the mean difference of PROs between different timepoints. Overall, the treatment arm was superior to the comparator. PROs were often underreported or highly heterogeneously presented. MCID was seldom mentioned. There is a need to raise the standard of care on SpA by aiming at remission and PRO associated improvements. In order to achieve this goal, the target must be clearly defined, reported, and tested.

Keywords: PROs; Patient-reported outcomes; RCTs; Spondyloarthritis; bDMARDs.