Pathogenesis Of Spondyloarthritis Research Articles

Targeted therapies for uveitis in spondyloarthritis: A narrative review

Spondyloarthritis (SpA) encompasses a group of chronic inflammatory disorders of the joints frequently associated with uveitis in almost a quarter of cases. SpA-related uveitis typically affects the eye anterior chamber with sudden onset, causing pain, redness, photophobia, and blurred vision. Ophthalmologists will describe an acute anterior unilateral uveitis. Most patients present with episodic acute anterior non-granulomatous uveitis and retain excellent visual acuity. However, systemic treatments are recommended in the event of frequent relapses (2–3/year) or in rare cases of sight-threatening with ocular complications. The improved understanding of the pathogenesis of SpA has led to the management of this disease by biologics. Here, we review the main data regarding the opportunity to target specific components in inflammatory pathways for the treatment of SpA-related uveitis. These therapies are recommended for long-term control when uveitis relapses occur too frequently despite conventional systemic treatments. Significant benefits have been obtained with the tumor necrosis factor-α inhibitors (TNFis), particularly infliximab and adalimumab. Paradoxically, a high number of uveitis occurrences have been shown on etanercept. Mixed results have been demonstrated with interleukin-17 antagonists (secukinumab) and interleukin-12/interleukin-23 antagonists (ustekinumab) in cases of failure of TNFis. JAK inhibitors seem to be a valuable class of medications for these patients in the future. Although SpA-related uveitis is typically managed with conventional local and/or systemic treatments, these biological/targeted therapies may provide avenues to control both the underlying SpA and uveitis manifestations. Thus, a close collaboration between patients, rheumatologists, internists, and ophthalmologists is needed to optimally manage ocular inflammation in SpA.

Angiotensin receptor blockers, but not angiotensin-converting enzyme inhibitors, inhibit abnormal bone changes in spondyloarthritis

Spondyloarthritis (SpA) is a chronic inflammatory disease that results in bone ankylosis. The tissue renin-angiotensin system (RAS) is an emerging pathway potentially implicated in SpA-associated bone changes. The aim of the present study was to determine the mechanisms underlying this relationship. Sakaguchi (SKG) mice injected with curdlan (SKGc), animal models for SpA, were treated with RAS modulators, angiotensin II receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEis). Disease activity was assessed using clinical scores and computed tomography scans. Mouse primary bone marrow monocytes (BMMs), osteoblast (OB) progenitor cells, peripheral blood monocytes (PBMCs), and bone-derived cells (BdCs) from patients with radiographic axial SpA (r-axSpA) were used to investigate the role of RAS in SpA pathogenesis. The expression of RAS components was significantly increased in SKGc mouse joints, and ARBs significantly reduced erosion and systemic bone loss, whereas ACEis did not. Osteoclast (OC) differentiation from primary BMMs, mediated by TRAF6, was inhibited by ARBs but promoted by ACEis; the modulators also exerted opposite effects on OB differentiation. Expression of RAS molecules was higher in PBMCs and BdCs of patients with r-axSpA than in control participants. ARBs inhibited OB differentiation in the BdCs of patients with r-axSpA, whereas ACEis did not. Neither ARBs nor ACEis affected OB differentiation in the control participants. In SpA, a condition characterized by RAS overexpression, ARBs, but not ACEis, inhibited OC and OB differentiation and bone progression. The findings should be taken into account when treating patients with SpA using RAS modulators.

Consensus on targeted drug therapy for spondyloarthritis.

Spondyloarthritis (SpA) is a group of chronic inflammatory diseases that predominantly involve the spine and/or peripheral joints. The clinical manifestations of SpA are highly heterogenous and complicated with various comorbidities. SpA is a disabling disease and adversely affects the quality of life of patients. Many new medications that target cytokines or pathways specific for the pathogenesis of SpA have been developed and they are becoming increasingly important in the treatment of SpA. However, identifying the target patient population and standardizing the usage of these drugs are critical issues in the clinical application of these "targeted therapeutic drugs". Under the leadership of National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), managed by Peking Union Medical College Hospital, the "Consensus on targeted drug therapy for spondyloarthritis" has been developed in collaboration with the Rheumatology and Immunology Physicians Committee, Chinese Medical Doctors Association, Rheumatology and Immunology Professional Committee, Chinese Association of Rehabilitation Medicine, and Chinese Research Hospital Association Rheumatology and Immunology Professional Committee. This consensus has been developed with evidence-based methodology and has followed the international standard for consensus development.

The bone marrow side of axial spondyloarthritis.

Spondyloarthritis (SpA) is characterized by the infiltration of innate and adaptive immune cells into entheses and bone marrow. Molecular, cellular and imaging evidence demonstrates the presence of bone marrow inflammation, a hallmark of SpA. In the spine and the peripheral joints, bone marrow is critically involved in the pathogenesis of SpA. Evidence suggests that bone marrow inflammation is associated with enthesitis and that there are roles for mechano-inflammation and intestinal inflammation in bone marrow involvement in SpA. Specific cell types (including mesenchymal stem cells, innate lymphoid cells and γδ T cells) and mediators (Toll-like receptors and cytokines such as TNF, IL-17A, IL-22, IL-23, GM-CSF and TGFβ) are involved in these processes. Using this evidence to demonstrate a bone marrow rather than an entheseal origin for SpA could change our understanding of the disease pathogenesis and the relevant therapeutic approach.

Consensus on targeted drug therapy for spondyloarthritis

Spondyloarthritis (SpA) is a group of chronic inflammatory conditions that predominantly involve the spine and/or peripheral joints. The clinical manifestations of SpA are diverse and disabling, with SpA adversely affecting the quality of life of patients. Many new medications that target cytokines or pathways specific for the pathogenesis of SpA have been developed and these are becoming increasingly important in the treatment of SpA. However, establishing how to identify the target patient population and standardizing the usage of these drugs are critical issues in the clinical application of these "targeted therapies".Under the leadership of National Clinical Research Center for Dermatologic and Immunologic Diseases (Peking Union Medical College Hospital), the"Consensus on targeted drug therapy for spondyloarthritis" has been developed collaborating with the Rheumatology and Immunology Physicians Committee, Chinese Medical Doctors Association, Rheumatology and Immunology Professional Committee, Chinese Association of Rehabilitation Medicine, Chinese Research Hospital Association Rheumatology and Immunology Professional Committee. This consensus was developed with evidence-based methodology and followed the international standard for consensus development.

The Interleukine-17 Cytokine Family: Role in Development and Progression of Spondyloarthritis, Current and Potential Therapeutic Inhibitors.

Spondyloarthritis (SpA) encompasses a group of chronic inflammatory rheumatic diseases with a predilection for the spinal and sacroiliac joints, which include axial spondyloarthritis, psoriatic arthritis, reactive arthritis, arthritis associated with chronic inflammatory bowel disease, and undifferentiated spondyloarthritis. The prevalence of SpA in the population varies from 0.5 to 2%, most commonly affecting young people. Spondyloarthritis pathogenesis is related to the hyperproduction of proinflammatory cytokines (TNFα, IL-17A, IL-23, etc.). IL-17A plays a key role in the pathogenesis of spondyloarthritis (inflammation maintenance, syndesmophites formation and radiographic progression, enthesites and anterior uveitis development, etc.). Targeted anti-IL17 therapies have established themselves as the most efficient therapies in SpA treatment. The present review summarizes literature data on the role of the IL-17 family in the pathogenesis of SpA and analyzes existing therapeutic strategies for IL-17 suppression with monoclonal antibodies and Janus kinase inhibitors. We also consider alternative targeted strategies, such as the use of other small-molecule inhibitors, therapeutic nucleic acids, or affibodies. We discuss advantages and pitfalls of these approaches and the future prospects of each method.

Mucosal-associated invariant T cells in patients with axial spondyloarthritis.

Several studies implicate Th17-cells and its cytokine (IL-17) in disease pathogenesis of spondyloarthritis (SpA), with available evidence supporting a pathogenic role of CD8+ T-cells. However, data on the involvement of CD8+ mucosal-associated invariant T-cells (MAIT) and their phenotypic characterization and inflammatory function including IL-17 and Granzyme A production in a homogenous population of SpA-patients with primarily axial disease (axSpA) are lacking. Quantify and characterize the phenotype and function of circulating CD8+MAIT-cells in axSpA-patients with primarily axial disease. Blood samples were obtained from 41 axSpA-patients and 30 age- and sex-matched healthy controls (HC). Numbers and percentages of MAIT-cells (defined as CD3+CD8+CD161highTCRVα7.2 +) were determined, and production of IL-17 and Granzyme A (GrzA) by MAIT-cells were examined by flow cytometry upon in vitro stimulation. Serum IgG specific for CMV was measured by ELISA. No significant differences in numbers and percentages of circulating MAIT-cells were found between axSpA-patients and HCr zijn meer resultaten de centrale memory CD8 T cellen. cellen van patirculating MAIT cells.. Further phenotypic analysis revealed a significant decrease in numbers of central memory MAIT-cells of axSpA-patients compared to HC. The decrease in central memory MAIT-cells in axSpA patients was not attributed to an alteration in CD8 T-cell numbers, but correlated inversely with serum CMV-IgG titers. Production of IL-17 by MAIT-cells was comparable between axSpA-patients and HC, whereas a significant decrease in the production of GrzA by MAIT-cells from axSpA-patients was observed. The decrease in cytotoxic capability of circulating MAIT-cells in axSpA-patients might implicate that these cell types migrate to the inflamed tissue and therefore associate with the axial disease pathogenesis.

Hyaluronic Acid in Synovial Fluid Prevents Neutrophil Activation in Spondyloarthritis

Spondyloarthritis (SpA) patients suffer from joint inflammation resulting in tissue damage, characterized by the presence of numerous neutrophils in the synovium and synovial fluid (SF). As it is yet unclear to what extent neutrophils contribute to the pathogenesis of SpA, we set out to study SF neutrophils in more detail. We analyzed the functionality of SF neutrophils of 20 SpA patients and 7 disease controls, determining ROS production and degranulation in response to various stimuli. In addition, the effect of SF on neutrophil function was determined. Surprisingly, our data show that SF neutrophils in SpA patients have an inactive phenotype, despite the presence of many neutrophil-activating stimuli such as GM-CSF and TNF in SF. This was not due to exhaustion as SF neutrophils readily responded to stimulation. Therefore, this finding suggests that one or more inhibitors of neutrophil activation may be present in SF. Indeed, when blood neutrophils from healthy donors were activated in the presence of increasing concentrations of SF from SpA patients, degranulation and ROS production were dose-dependently inhibited. This effect was independent of diagnosis, gender, age, and medication in the patients from which the SF was isolated. Treatment of SF with the enzyme hyaluronidase strongly reduced the inhibitory effect of SF on neutrophil activation, indicating that hyaluronic acid that is present in SF may be an important factor in preventing SF neutrophil activation. This finding provides novel insights into the role of soluble factors in SF regulating neutrophil function and may lead to the development of novel therapeutics targeting neutrophil activation via hyaluronic acid or associated pathways.

Large-Scale Genetic Correlation Analysis between Spondyloarthritis and Human Blood Metabolites.

The aim was to study the genetic correlation and causal relationship between spondyloarthritis (SpA) and blood metabolites based on the large-scale genome-wide association study (GWAS) summary data. The GWAS summary data (3966 SpA and 448,298 control cases) of SpA were from the UK Biobank, and the GWAS summary data (486 blood metabolites) of human blood metabolites were from a published study. First, the genetic correlation between SpA and blood metabolites was analyzed by linkage disequilibrium score (LDSC) regression. Next, we used Mendelian randomization (MR) analysis to perform access causal relationship between SpA and blood metabolites. Random effects inverse variance weighted (IVW) was the main analysis method, and the MR Egger, weighted median, simple mode, and weighted mode were supplementary methods. The MR analysis results were dominated by the random effects IVW. The Cochran's Q statistic (MR-IVW) and Rucker's Q statistic (MR Egger) were used to check heterogeneity. MR Egger and MR pleiotropy residual sum and outlier (MR-PRESSO) were used to check horizontal pleiotropy. The MR-PRESSO was also used to check outliers. The "leave-one-out" analysis was used to assess whether the MR analysis results were affected by a single SNP and thus test the robustness of the MR results. Finally, we identified seven blood metabolites that are genetically related to SpA: X-10395 (correlation coefficient = -0.546, p = 0.025), pantothenate (correlation coefficient = -0.565, p = 0.038), caprylate (correlation coefficient = -0.333, p = 0.037), pelargonate (correlation coefficient = -0.339, p = 0.047), X-11317 (correlation coefficient = -0.350, p = 0.038), X-12510 (correlation coefficient = -0.399, p = 0.034), and X-13859 (Correlation coefficient = -0.458, p = 0.015). Among them, X-10395 had a positive genetic causal relationship with SpA (p = 0.014, OR = 1.011). The blood metabolites that have genetic correlation and causal relationship with SpA found in this study provide a new idea for the study of the pathogenesis of SpA and the determination of diagnostic indicators.

S100A8 alarmin supports IL-6 and metalloproteinase-9 production by fibroblasts in the synovial microenvironment of peripheral spondyloarthritis.

Spondyloarthritis (SpA) is a common autoinflammatory disease. S100A8/ S100A9 alarmin is strongly expressed in the synovial sublining layers of psoriatic arthritis. S100A8/ S100A9 is the most abundant protein in rheumatoid arthritis synovial fluid (SF) and has a key role in promoting IL-6 expression in fibroblast-like synoviocytes (FLS). The molecular mechanisms and the role of S100-alarmins in the synovial microenvironment of SpA have never been demonstrated. Here, we confirm the effect of the synovial microenvironment of peripheral SpA on interleukin-6 (IL-6) and metalloproteinase (MMP)-9 production by FLS. MMP-9 expression and activity were detected, which were reduced in the presence of anti-IL-6R. Analyzing cell signaling mechanisms, we found that stimulation with IL-6 co-triggered MMP-9 and IL-10 secretion. MMP-9 secretion depended on JNK and p38 MAPKs, whereas IL-10 secretion was dependent on the JAK pathway as a potential feedback mechanism controlling IL-6-induced MMP-9 expression. Using a proteomic approach, we identified S100A8 in the peripheral SpA SF. This presence was confirmed by immunoblotting. S100A8 increased the IL-6 secretion via ERK and p38 MAPK pathways. Furthermore, anti-S100A8/A9 reduced both IL-6 and MMP-9 production induced by SpA SF in FLS. Our data reveal a marked relationship between S100A8 alarmin with IL-6 and MMP-9 secretion by FLS in the real synovial microenvironment of peripheral SpA. These results identify a mechanism linking S100A8 to the pathogenesis of peripheral SpA.

Pro-Inflammatory Oral Microbiota in Juvenile Spondyloarthritis: A Pilot Study.

The role of the microbiota in the pathogenesis of arthritis is gaining increasing attention. While multiple studies have queried the intestinal microbiota, very few have analyzed the contents of the oral microbiota. In this pilot study, we obtained salivary and sub-gingival specimens from a cohort of six healthy controls and five children with well-controlled spondyloarthritis (SpA) and performed 16S sequencing on bacteria obtained from both habitats. The Quantitative Insight into Microbial Ecology tool suite was used to generate operational taxonomic units, Phyloseq was used for diversity analyses, and DeSeq2 was used to compare abundances while adjusting for multiple comparisons. A repeat specimen was obtained from one subject during a flare. Clustering based upon diagnosis was observed from both habitats, with decreased alpha diversity seen within the plaque obtained from the patients vs. controls. Among the differentially abundant taxa were statistically significantly increased plaque Fusobacterium and salivary Rothia mucilaginosa among the patients compared to the controls. Additionally, the abundance of plaque Fusobacterium increased in one patient at the time of a flare. Our data suggest that the oral cavity may harbor bacteria involved in the pathogenesis of spondyloarthritis; additional studies are warranted.

Targeted resequencing of the 13q13 spondyloarthritis-linked locus identifies a rare variant in FREM2 possibly associated with familial spondyloarthritis.

The strong heritability of spondyloarthritis remains poorly explained, despite several large-scale association studies. A recent linkage analysis identified a new region linked to SpA on 13q13. Here we searched for variants potentially explaining this linkage signal by deep-sequencing of the region. Re-sequencing of the 1.4 Mb target interval was performed in 92 subjects from the 43 best-linked multicases families (71 spondyloarthritis and 21 unaffected relatives), using hybridization capture-based protocol (Illumina Nextera®). Variants of interest were then genotyped by TaqMan and high resolution melting to check their co-segregation with disease in the same families and to test their association with spondyloarthritis in an independent cohort of 1,091 unrelated cases and 399 controls. Expression of FREM2 was assessed by immunostaining. Of the 7,563 variants identified, 24 were non-synonymous coding single-nucleotide variants. Two of them were located in the FREM2 gene on a haplotype co-segregating with the disease, including one common variant (R1840W, minor allele frequency=0.11) and one rare variant (R727H, minor allele frequency=0.0001). In the case-control analysis, there was no significant association between R1840W and spondyloarthritis (P-value=0.21), whereas R727H was not detected in any of the genotyped individuals. Immunostaining experiments revealed that FREM2 is expressed in synovial membrane, cartilage and colon. Targeted re-sequencing of a spondyloarthritis-linked region allowed us to identify a rare non-synonymous coding variant in FREM2, co-segregating with spondyloarthritis in a large family. This gene is expressed in several tissues relevant to spondyloarthritis pathogenesis, supporting its putative implication in spondyloarthritis.

TCR repertoire profiling revealed antigen-driven CD8+ T cell clonal groups shared in synovial fluid of patients with spondyloarthritis.

Spondyloarthritis (SpA) comprises a number of inflammatory rheumatic diseases with overlapping clinical manifestations. Strong association with several HLA-I alleles and T cell infiltration into an inflamed joint suggest involvement of T cells in SpA pathogenesis. In this study, we performed high-throughput T cell repertoire profiling of synovial fluid (SF) and peripheral blood (PB) samples collected from a large cohort of SpA patients. We showed that synovial fluid is enriched with expanded T cell clones that are shared between patients with similar HLA genotypes and persist during recurrent synovitis. Using an algorithm for identification of TCRs involved in immune response we discovered several antigen-driven CD8+ clonal groups associated with risk HLA-B*27 or HLA-B*38 alleles. We further show that these clonal groups were enriched in SF and had higher frequency in PB of SpA patients vs healthy donors, implying their relevance to SpA pathogenesis. Several of the groups were shared among patients with different SpAs that suggests a common immunopathological mechanism of the diseases. In summary, our results provide evidence for the role of specific CD8+ T cell clones in pathogenesis of SpA.

Management of Axial Spondyloarthritis - Insights into Upadacitinib.

Although the pathogenesis of spondyloarthritis (SpA) has still not been elucidated our options to treat SpA have definitely improved in the last decades. There are two main types of SpA: (i) axial spondyloarthritis (axSpA), also covering the classical ankylosing spondylitis (AS) which is largely equivalent to radiographic (r)-axSpA but different from non-radiographic (nr)-axSpA, and (ii) peripheral SpA (pSpA) also covering psoriatic arthritis (PsA) as the main subtype. The subtype nr-axSpA has historically developed because the approval of drugs for AS did not cover forms without structural changes in the sacroiliac joints which is mandatory in the 1984 New York criteria. The definitions for axSpA are based on the 2009 Assessments in AxSpA International Society (ASAS) classification criteria. Several biologic disease modifying anti-rheumatic drugs (bDMARDs) such as the tumor necrosis factor alpha inhibitors (TNFi) and the interleukin-17-inhibitors (IL-17i) are approved mostly for the whole spectrum of SpA including axSpA and PsA but L-17i does not work in inflammatory bowel disease (IBD). Targeted synthetic (ts) DMARDs cover mainly the janus kinase (JAK)-inhibitors which have recently been developed to inhibit inflammation in several rheumatic and other immune mediated diseases such as IBD. Indeed, the physiologic mechanism of JAK-mediated signal transduction has been recognized as an important target because the inhibition of its actions was shown to successfully work as a therapeutic mechanism. There are now 4 small molecule JAK inhibitors (JAKi) that currently play a role in rheumatology with variable selectivity for the four different JAK isoforms: tofacitinib, baricitinib, upadacitinib and filgotinib. In this review, we summarize current clinical trial data and evaluate the use of the JAK1 selective inhibitor upadacitinib in the treatment of axSpA, including nr-axSpA and r-axSpA. Even though the efficacy and safety of upadacitinib over shorter periods of time has been convincing to date, long-term trials are needed to fully establish its performance and also evaluate the safety at higher doses, and its use in PsA.

Characterization of Blood Mucosal-Associated Invariant T Cells in Patients With Axial Spondyloarthritis and of Resident Mucosal-Associated Invariant T Cells From the Axial Entheses of Non-Axial Spondyloarthritis Control Patients.

The importance of interleukin-17A (IL-17A) in the pathogenesis of axial spondyloarthritis (SpA) has been demonstrated by the success of IL-17A blockade. However, the nature of the cell populations that produce this important proinflammatory cytokine remains poorly defined. We undertook this study to characterize the major IL-17A-producing blood cell populations in the peripheral blood of patients with axial SpA, with a focus on mucosal-associated invariant T (MAIT) cells, a population known to be capable of producing IL-17. We evaluated IL-17A production from 5 sorted peripheral blood cell populations, namely, MAIT cells, γδ T cells, CD4+ T cells, CD8+ T cells, and neutrophils, before and after stimulation with phorbol myristate acetate, the calcium ionophore A23187, and β-1,3-glucan. Expression of IL-17A transcripts and protein were determined using nCounter and ultra-sensitive Simoa technology, respectively. MAIT cells from the axial entheses of non-axial SpA control patients (n=5) were further characterized using flow cytometric immunophenotyping and quantitative polymerase chain reaction, and the production of IL-17 was assessed following stimulation. On a per-cell basis, MAIT cells from peripheral blood produced the most IL-17A compared to CD4+ T cells (P < 0.01), CD8+ T cells (P < 0.0001), and γδ T cells (P < 0.0001). IL-17A was not produced by neutrophils. Gene expression analysis also revealed significantly higher expression of IL17A and IL23R in MAIT cells. Stimulation of peripheral blood MAIT cells with anti-CD3/CD28 and IL-7 and/or IL-18 induced strong expression of IL17F. MAIT cells were present in the normal, unaffected entheses of control patients who did not have axial SpA and showed elevated AHR, JAK1, STAT4, and TGFB1 transcript expression with inducible IL-17A protein. IL-18 protein expression was evident in spinal enthesis digests. Both peripheral blood MAIT cells and resident MAIT cells in normal axial entheses contribute to the production of IL-17 and may play important roles in the pathogenesis of axial SpA.

Antigen-specific immune reactions by expanded CD8+ T cell clones from HLA-B*27-positive patients with spondyloarthritis

Spondyloarthritis (SpA) is a chronic inflammatory disease that is tightly linked to HLA-B*27 but the pathophysiological basis of this link is still unknown. It is discussed whether either the instability of HLA-B*27 molecules triggers predominantly innate immune reactions or yet unknown antigenic peptides presented by HLA-B*27 induce adaptive autoimmune reactions by CD8+ T cells. To analyze the pathogenesis of SpA, we here investigated the T cell receptor (TCR) usage and whole transcriptomes of CD8+ single cells from synovial fluid of HLA-B*27-positive SpA patients and HLA-B*27-negative controls. In HLA-B*27-positive patients, we confirmed preferential expression of several TCR β-chain families, found even more restricted usage of particular TCR α-chains, assigned matching TCR αβ-chain pairs with homologous CDR3-sequences, and detected identical TCR-chains in different patients. Gene expression analyses by single cell mRNAseq revealed that genes specific for the tissue resident memory phenotype, exhaustion, and apoptosis were particularly highly expressed in expanded clonotypes from HLA-B*27-positive SpA patients. Together, several independent lines of evidence argue in favor of an (auto)antigenic peptide related pathogenesis.

Metabolomic analysis in spondyloarthritis: A systematic review.

Spondyloarthritis (SpA) is a group of rheumatic diseases that cause joint inflammation. Accumulating studies have focused on the metabolomic profiling of SpA in recent years. We conducted a systematic review to provide a collective summary of previous findings on metabolomic profiling associated with SpA. We systematically searched PubMed, Medline, Embase and Web of Science for studies on comparisons of the metabolomic analysis of SpA patients and non-SpA controls. The Newcastle–Ottawa Scale (NOS) was used to assess the quality of the included articles. From 482 records identified, 31 studies were included in the analysis. A number of metabolites were differentially distributed between SpA and non-SpA cases. SpA patients showed higher levels of glucose, succinic acid, malic acid and lactate in carbohydrate metabolism, higher glycerol levels and lower fatty acid (especially unsaturated fatty acid) levels in lipid metabolism, and lower levels of tryptophan and glutamine in amino acid metabolism than healthy controls. Both conventional and biological therapy of SpA can insufficiently reverse the aberrant metabolism state toward that of the controls. However, the differences in the results of metabolic profiling between patients with SpA and other inflammatory diseases as well as among patients with several subtypes of SpA are inconsistent across studies. Studies on metabolomics have provided insights into etiological factors and biomarkers for SpA. Supplementation with the metabolites that exhibit decreased levels, such as short-chain fatty acids (SCFAs), has good treatment prospects for modulating immunity. Further studies are needed to elucidate the role of disordered metabolic molecules in the pathogenesis of SpA.

New therapeutic options for the treatment of ankylosing spondylitis.

The pathogenesis of spondyloarthritis (SpA) is multifactorial and involves multiple immune cells and cytokines that are signaled by Janus kinase (JAK). Inhibition of JAK signaling pathways has emerged as a new therapeutic option for patients with inflammatory joint diseases. Despite the proven effect of treatment with anti-IL-17, as well as TNFα inhibitors, some patients with ankylosing spondylitis cannot reach minimal disease activity or remission. This necessitated the development of a new class of molecules, and in recent years more and more clinical studies have proven their role in the treatment of both rheumatoid arthritis and ankylosing spondylitis. JAK inhibition is a promising therapeutic strategy for the treatment of SpA and its application has potential in patients with axial, polyarticular, or extraarticular manifestations of the disease in psoriatic arthritis and ankylosing spondylitis.&#x0D; The present literature review aims to highlight the new therapeutic options offered by this class of target synthetic disease-modifying antirheumatic drugs and to summarize the clinical trial data for tofacitinib, upadacitinib and filgotinib reported to date.

Deep Insight into the Role of MIF in Spondyloarthritis.

Pathological roles of macrophage migration inhibitory factor (MIF) have recently been demonstrated in spondyloarthritis (SpA) preclinical models, identifying MIF as a new treatment target for SpA. However, the specific contribution of MIF and therapeutic potential of MIF-targeted therapies to various tissue types affected by SpA are not well delineated. MIF and its cognate receptor CD74 are extensively involved in the pathogenesis of SpA including inflammation in the spine, joint, eyes, skin, and gut. The majority of the current evidence has consistently shown that MIF drives the inflammation in these distinct anatomical sites. In preclinical models, genetic deletion or blockade of MIF reduces the severity of inflammation. Although MIF is generally an upstream cytokine which regulates downstream effector cytokines, MIF also intensifies type 3 immunity by promoting helper T 17 (Th17) plasticity. MIF- or CD74-targeted therapies have also reported to be well tolerated in clinical trials for other diseases. Recent findings suggest that MIF-CD74 axis is a new therapeutic target for SpA to improve various clinical features. Clinical trials for MIF- or CD74-targeted therapies for SpA patients are warranted.

Enthesitis – a review on the ultrasonographic assessment

The potential benefit gained from ultrasonography examination of the enthesis been extensively studied. Enthesitis plays a key role in pathogenesis of spondyloarthritis and thus, understanding the diagnostic and therapeutic implications has shaped the way clinicians view its importance in clinical practice. The development of high-quality imaging technologies offered a great opportunity to obtain more detailed analysis of the enthesis structure and also differentiate acute from chronic lesions. Several taskforce groups, including OMERACT, highlighted the diagnostic performance of ultrasonography for the detection of enthesitis. Panels of experts have also provided consensus-based definitions of elementary lesions in order to standardize the approach of US-defined enthesitis. Enthesitis is considered one of the main clinical domains in psoriatic arthritis patients and several trials have adopted its use as a potential outcome measure, although research carried out until now, still lacks uniformity between methods used to assess enthesitis. Multiple semiquantitative scoring systems of enthesitis using ultrasonography have been developed in the last two decades and these may provide a more standardized approach in future research.