Spinal Ankylosis Research Articles

Extracellular Vesicles Derived from Ligament Tissue Transport Interleukin‐17A to Mediate Ligament‐To‐Bone Crosstalk in Ankylosing Spondylitis

AbstractPathological new bone formation is a critical feature of the progression of ankylosing spondylitis (AS), and spine ankylosis is a distinctive feature of this condition. Ligaments are the primary regions of pathological new bone formation in AS. Here, it is demonstrated that ligament tissue‐derived extracellular vesicles (EVs) and their interleukin‐17A (IL‐17A) cargo mediate the communication between the tissue and other cells. The investigation revealed that IL‐17A in EVs can activate the JAK‐STAT3 pathway, thereby stimulating the expression of MMP14 in AS ligament. Overexpression of MMP14 can lead to changes in the cytoskeleton and mechanical signaling of mesenchymal stem cells and other cells. These alterations in cellular cytoskeleton and mechanical signaling at ligament sites in patients with AS or in stem cells treated with EVs can result in pathological new bone formation. Finally, inhibiting IL‐17A activity and EV endocytosis effectively controlled inflammation and pathological new bone formation. Overall, these data suggest that ligament‐derived EVs and the enclosed IL‐17A have a potential role in driving pathological new bone formation in AS, and targeting EVs may therefore emerge as a novel approach to delaying ectopic ossification in AS.

Elucidation of Factors Influencing Spinal Ankylosis in Patients with Axial Spondyloarthritis.

Spondyloarthritis encompasses conditions such as ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Advanced axial spondyloarthritis causes significant spinal fusion, affecting daily activities. Recent therapeutic agents have enhanced the control of inflammation, yet they do not consistently stop the axial progression. This study aimed to identify factors influencing the progression of axial lesions over a two-year period in Japanese patients with axial spondyloarthritis. This retrospective and cross-sectional study included 47 axial spondyloarthritis patients. Spinal lesions were assessed using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Patients were categorized into progressive and non-progressive groups based on changes in their mSASSS scores. Various clinical parameters were analyzed for correlation with ankylosis progression. The study found no significant correlation between ankylosis progression and traditional factors, including the level of inflammation or the use of biologics. However, modified Health Assessment Questionnaire (mHAQ) scores were associated with disease progression. The baseline mSASSS was another significant factor, underscoring the importance of early detection and management. This study showed that patient-reported outcomes and baseline mSASSS scores are crucial for assessing axial spondyloarthritis progression. This underscores the need for a comprehensive treatment strategy that addresses both clinical indicators and patient-reported outcomes.

The Role of Chitinase-3-like Protein 1 (YKL-40) as a Marker of Disease Activity in Ankylosing Spondylitis Patients

Abstract Background Ankylosing spondylitis is a prototype of spondyloarthritides that primarily affects the axial skeleton. Sacroiliitis is the hallmark and accompanied by inflammation of the entheses and formation of syndesmophytes, leading to spinal ankylosis in later stages. Prevalence estimates vary between 0.1% and 2% in different populations.The most utilized peripheral blood biomarkers of ankylosing spondylitis activity in clinical practice and clinical trials are ESR and CRP. However, they have low sensitivity and specificity. Objective To detect the role of YKL-40 as an objective Marker of disease activity in ankylosing Spondylitis Patients. Patient and Methods This study was a case control study, included fifteen ankylosing spondylitis patients were recruited from the outpatient clinic and inpatient department of Physical Medicine, Rheumatoloy and Rehabilitation of Ain Shams university hospitals and fifteen adult healthy volunteers as a control group. Approval of the Ain shams university research and ethical committee was obtained. Results There was no statistically significant difference between patient and control group as regard age and sex. YKL-40 showed 100% sensitivity and 100% specificity. large scale studies with follow up of patients in response to drug treatment are needed to be done to assess its uses as a disease activity marker. large scale prospective studies are needed with the assessment of comorbidities and their time of development in correlation to YKL-40 as it has an excellent potential for prediction of these comorbidities. Conclusion YKL-40 marker is a good predictor for ankylosing spondylitis disease.

Diagnosis and Treatment of Ankylosing Spondylitis.

Ankylosing spondylitis (AS) is a chronic inflammatory condition primarily affecting the axial bone and sacroiliac joints. Its etiology is complicated and involves genetic variables, demographic factors (age of onset, gender, ethnicity, family history), and environmental variables. It typically manifests in males in their third decade. Galen is credited with first recognizing it, according to historical traditions, but it was not until the 19th century that specific diagnostic criteria were developed. The human leukocyte antigen B27 (HLA-B27) variation, around 20% of the genetic risk, is currently the most significant gene associated with AS susceptibility. Over 100 genes have been connected to AS susceptibility. Clinical signs of AS include stiffness and inflammation in the back, eye inflammation, aortitis (inflammation of the aorta), and spinal ankylosis that impacts posture and fatigue. The dagger sign and sacroiliitis on radiographs, in particular, are crucial for diagnosis. Early inflammatory alterations can be found using modern diagnostic tools such as MRI, and the HLA-B27 gene can help confirm the diagnosis. Overall, 80-95% of people with AS have the HLA-B27 marker. Furthermore, although non-specific, elevated inflammatory markers, such as C-reactive protein and erythrocyte sedimentation rate, offer supporting evidence. Over time, treatment paradigms have seen significant change. First-line treatments such as non-steroidal anti-inflammatory drugs are no longer the only options, even though disease-modifying anti-rheumatic drugs and biologics, especially tumor necrosis factor blockers, have been developed. Physical therapy, which emphasizes consistent exercise, stretches, and posture maintenance, is extremely helpful in managing AS. Surgical interventions can be required in extreme situations. The significance of the interleukin 23/17 axis in the disease cascade has been demonstrated by recent research. Furthermore, a deeper comprehension of the genetic landscape, mainly the functions of non-HLA-B27 loci, may open the door for more specialized therapies. Early diagnosis and interdisciplinary therapies can improve patient outcomes and quality of life as our understanding of AS grows.

Tetrahedral Framework Nuclear Acids Can Regulate Interleukin-17 Pathway to Alleviate Inflammation and Inhibit Heterotopic Ossification in Ankylosing Spondylitis.

Ankylosing spondylitis (AS) is a chronic systemic inflammatory disease that leads to serious spinal deformity and ankylosis. Persistent inflammation and progressive ankylosis lead to loss of spinal flexibility in patients with AS. Tetrahedral framework nucleic acids (tFNAs) have emerged as a one kind of nanomaterial composed of four specially designed complementary DNA single strands with outstanding biological properties. Results from in vivo experiments demonstrated that tFNAs treatment could inhibit inflammatory responses and heterotopic ossification to halt disease progression. In vitro, tFNAs were proved to influence the biological behavior of AS primary chondrocytes and inhibit the secretion of pro-inflammatory cytokines through interleukin-17 pathway. The osteogenic process of chondrocytes was as well inhibited at the transcriptional level to regulate the expression of related proteins. Therefore, we believe tFNAs had a strong therapeutic effect and could serve as a nonsurgical remedy in the future to help patients suffering from AS.

Post-traumatic spinal hematoma in diffuse idiopathic skeletal hyperostosis (DISH)

ObjectivesTo determine the incidence of spinal hematoma and its relation to neurological deficit after trauma in patients with spinal ankylosis from diffuse idiopathic skeletal hyperostosis (DISH).Materials and methodsA retrospective review of 2256 urgent or emergency MRI referrals over a period of 8 years and nine months revealed 70 DISH patients who underwent CT and MRI scans of the spine. Spinal hematoma was the primary outcome. Additional variables were spinal cord impingement, spinal cord injury (SCI), trauma mechanism, fracture type, spinal canal narrowing, treatment type, and Frankel grades during injury, before and after treatment. Two trauma radiologists reviewed MRI scans blinded to initial reports.ResultsOf 70 post-traumatic patients (54 men, median age 73, IQR 66–81) with ankylosis of the spine from DISH, 34 (49%) had spinal epidural hematoma (SEH) and 3 (4%) had spinal subdural hematoma, 47 (67%) had spinal cord impingement, and 43 (61%) had SCI. Ground-level fall (69%) was the most common trauma mechanism. A transverse, AO classification type B spine fracture (39%) through the vertebral body was the most common injury type. Spinal canal narrowing (p < .001) correlated and spinal cord impingement (p = .004) associated with Frankel grade before treatment. Of 34 patients with SEH, one, treated conservatively, developed SCI.ConclusionsSEH is a common complication after low-energy trauma in patients with spinal ankylosis from DISH. SEH causing spinal cord impingement may progress to SCI if not treated by decompression.Clinical relevance statementLow-energy trauma may cause unstable spinal fractures in patients with spinal ankylosis caused by DISH. The diagnosis of spinal cord impingement or injury requires MRI, especially for the exclusion of spinal hematoma requiring surgical evacuation.Key Points• Spinal epidural hematoma is a common complication in post-traumatic patients with spinal ankylosis from DISH.• Most fractures and associated spinal hematomas in patients with spinal ankylosis from DISH result from low-energy trauma.• Spinal hematoma can cause spinal cord impingement, which may lead to SCI if not treated by decompression.

Prostaglandin E2/EP4 axis is upregulated in Spondyloarthritis and contributes to radiographic progression

Ankylosing spondylitis (AS) is an inflammatory disease leading to spine ankylosis; however, the mechanisms behind new bone formation are still not fully understood. Single Nucleotide Polymorphisms (SNPs) in PTGER4, encoding for the receptor EP4 of prostaglandin E2 (PGE2), are associated with AS. Since the PGE2-EP4 axis participates in inflammation and bone metabolism, this work aims at investigating the influence of the prostaglandin-E2 axis on radiographic progression in AS.In 185 AS (97 progressors), baseline serum PGE2 predicted progression, and PTGER4 SNP rs6896969 was more frequent in progressors. Increased EP4/PTGER4 expression was observed in AS circulating immune cells, synovial tissue, and bone marrow. CD14highEP4 + cells frequency correlated with disease activity, and when monocytes were cocultured with mesenchymal stem cells, the PGE2/EP4 axis induced bone formation.In conclusion, the Prostaglandin E2 axis is involved in bone remodelling and may contribute to the radiographic progression in AS due to genetic and environmental upregulation.

No evidence of a genetic causal relationship between ankylosing spondylitis and iron homeostasis: A two-sample Mendelian randomization study.

Ankylosing spondylitis (AS) is an immune-mediated chronic inflammatory disease that leads to bone hyperplasia and spinal ankylosis. Iron homeostasis plays a very important role in the inflammatory response and is closely related to the pathogenesis of AS. This study aimed to use large-scale genome-wide association study (GWAS) summary data to study the genetic causal relationship between AS and iron homeostasis using Mendelian randomization (MR). Genome-wide association study summary data of AS and iron homeostasis-related indicators were obtained from the FinnGen consortium and the DeCODE genetics database, respectively. We used four iron homeostasis-related indicators: ferritin, serum iron, total iron binding capacity (TIBC), and transferrin saturation (TSAT) for two-sample MR analyses to test for genetic causal association with AS using the "TwoSampleMR" package of the R software (version 4.1.2). The random-effects inverse variance weighted (IVW) method was the main analysis method used for MR. We examined the MR analysis results for heterogeneity, horizontal pleiotropy, and possible outliers. In addition, we confirmed the robustness of the MR analysis by testing whether the results were affected by a single SNP and whether they followed a normal distribution. The random-effects IVW results showed that ferritin [p = 0.225, OR 95% confidence interval (CI) = 0.836 (0.627-1.116)], serum iron [p = 0.714, OR 95% CI = 0.948 (0.714-1.260)], TIBC [p = 0.380, OR 95% CI = 0.917 (0.755-1.113)], and TSAT [p = 0.674, OR 95% CI = 0.942 (0.713-1.244)] have no genetic causal relationship with AS. We detected no heterogeneity，horizontal pleiotropy and possible outliers in our MR analysis (p > 0.05). In addition, our MR analysis results were not affected by a single SNP, and were normally distributed. Our study did not detect a genetic causal relationship between AS and iron homeostasis. Nonetheless, this does not rule out a relationship between the two at other mechanistic levels.

Vesicular traffic-mediated cell-to-cell signaling at the immune synapse in Ankylosing Spondylitis.

The chronic inflammatory disease ankylosing spondylitis (AS) is marked by back discomfort, spinal ankylosis, and extra-articular symptoms. In AS, inflammation is responsible for both pain and spinal ankylosis. However, the processes that sustain chronic inflammation remain unknown. Despite the years of research conducted to decipher the intricacy of AS, little progress has been made in identifying the signaling events that lead to the development of this disease. T cells, an immune cell type that initiates and regulates the body's response to infection, have been established to substantially impact the development of AS. T lymphocytes are regarded as a crucial part of adaptive immunity for the control of the immune system. A highly coordinated interaction involving antigen-presenting cells (APCs) and T cells that regulate T cell activation constitutes an immunological synapse (IS). This first phase leads to the controlled trafficking of receptors and signaling mediators involved in folding endosomes to the cellular interface, which allows the transfer of information from T cells to APCs through IS formation. Discrimination of self and nonself antigen is somatically learned in adaptive immunity. In an autoimmune condition such as AS, there is a disturbance of self/nonself antigen discrimination; available findings imply that the IS plays a preeminent role in the adaptive immune response. In this paper, we provide insights into the genesis of AS by evaluating recent developments in the function of vesicular trafficking in IS formation and the targeted release of exosomes enriched microRNAs (miRNA) at the synaptic region in T cells.

Assessment Tools for Pulmonary Involvement in Patients with Ankylosing Spondylitis: Is Diaphragmatic Ultrasonography Correlated to Spirometry?

Spondyloarthritis (SpA) is a chronic inflammatory rheumatic disease that can lead to spinal ankylosis and consequently, restrictive pulmonary dysfunction. Thus, the present study aimed to assess the accuracy of diaphragm ultrasound compared to spirometry in the screening of restrictive pulmonary disorders in radiographic SpA patients. We conducted a cross-sectional study of 50 patients with radiographic SpA, over six months. Sociodemographic data, clinical characteristics of the disease, as well as biological, radiological, and therapeutic data, were collected. Spirometry and diaphragm ultrasound were performed. The mean age of the study participants (N= 50) was 42.7±11 years [range: 25-66] with male predominance (N= 41). Spirometry showed a restrictive disorder in 32% of cases. The mean chest expansion (CE) value was 3.9±1.81cm [range: 1-9] with a median of 4 cm. A pathological value (<5cm) was observed in 72% of cases. A significant positive correlation was found between the right inspiratory diaphragmatic thickness and forced vital capacity (FVC) (r= 0.36; p = 0.02) and the supine FVC (r=0.29; p = 0.04). The left inspiratory diaphragmatic thickness was correlated with the percentage of the FVC decrease (r= 0.35; p = 0.01) defined as the percentage of difference between FVC and supine FVC. The right expiratory diaphragmatic thickness was associated with the FVC (r=0.32; p = 0.02). A significant positive correlation was found between the CE and the presence of B lines (r=0.32; p = 0.02), but not between the CE and the FVC. The present study showed that diaphragm ultrasonography is correlated with spirometric findings in radiographic SpA patients. Further studies are required to assess its reliability, specificity, and sensitivity in this pathology.

The impact of smoking status on radiographic progression in patients with ankylosing spondylitis on anti-tumor necrosis factor treatment.

Ankylosing spondylitis (AS) is characterized by back pain which can lead to spinal ankylosis. Anti-tumor necrosis factor (TNF) dramatically alleviates symptoms, but spinal damage can still be progressive even during anti-TNF treatment. Smoking is a one of well-known risk factors for structural damage in AS. However, it has not been confirmed that smoking can affect radiographic progression even during anti-TNF treatment. To investigate factors associated with radiographic progression during anti-TNF treatment with a focus on smoking status which is known as one of poor prognostic factors for AS. We conducted a retrospective cohort study of AS patients who began the first-line anti-TNF treatment between 2001 and 2018 according to availability of smoking data. All enrolled patients were observed until the last visit, the first-line anti-TNF discontinuation, or December 2019. Radiographic damage was assessed using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). The mSASSS progression rate (units/year) was calculated using the baseline mSASSS, the final mSASSS during observation period, and the duration between them. Univariable and multivariable logistic regression analyses were performed to identify associated factors of mSASSS progression rate > 1 unit/year. Among 459 AS patients, 185 (40.3%) patients were never smokers, 62 (13.5%) were ex-smokers and 212 (46.2%) were current smokers at baseline. Ex- and current smokers had higher mSASSS progression rates than never smokers [never smoker 0.1 (0.0-0.7), ex-smoker 0.6 (0.0-1.5), and current smoker 0.6 (0.0-1.5) units/year, P < 0.001]. In the multivariable logistic analysis, current smoking [adjusted odds ratio (OR) 1.69, 95% CI 1.01-2.82, P = 0.047] and higher baseline mSASSS [adjusted OR 1.03, 95% CI 1.01-1.04, P < 0.001] were associated with a mSASSS progression rate > 1 unit/year. Current smoking is a modifiable risk factor for radiographic progression in patients with AS on anti-TNF treatment. Quitting smoking should be strongly recommended.

Urolithiasis in ankylosing spondylitis: A meta-analysis

• Prevalence of urolithiasis in AS patients is higher than healthy controls and in other chronic inflammatory diseases. • Results suggest an association between spine ankylosis and urolithiasis. • Microscopic inflammation of the intestine in AS may contribute to the increase risk of urolithiasis. • The use of nonsteroidal anti-inflammatory drugs as treatment for AS may explain higher prevalence.

The role of LCN2 and LCN2-MMP9 in spondylitis radiographic development: gender and HLA-B27 status differences

BackgroundMale HLA-B27-positive radiographic-axial spondyloarthritis (r-axSpA) patients are prone to have severe spinal radiographic progression, but the underlying mechanisms are unclear. We recently showed that persistently elevated Lipocalin 2 (LCN2; L) reflects sacroiliac joint (SIJ) inflammation. LCN2 binds to MMP9. Concomitant elevation of L and LCN2-MMP9 (LM) was detected in many inflammatory diseases. We asked whether L and LM play similar roles in r-axSpA pathogenesis.MethodsWe analyzed 190 axSpA patients (123 radiographic and 67 non-radiographic axSpA) who had no detectable circulating Oncostatin M, to avoid complications due to cross-talk between pathways. L and LM levels from a single blood sample of each patient were measured and were correlated with MRI and modified stoke AS (mSASS) scoring. Association of elevated L (L+) or concurrent L+ and elevated LM (LM+) patterns with B27 status and gender were assessed.ResultsIn L+LM+ axSpA patients, both L and LM levels correlated with MRI SPARCC SIJ scores, but only LM levels correlated with MRI Berlin Spine Scores, suggesting LM is a biomarker for both SIJ and spinal inflammation. Among patients with minimal spinal ankylosis (mSASSS < 10), 65% of male r-axSpA patients are L+LM+, while 30% and 64% of female patients are L+LM+ and L+, respectively, supporting the role of LM with disease progression. In B27+ L+LM+ male patients, both L and LM (but not CRP) levels correlate with mSASSS. B27 positivity and maleness have additive effects on spondylitis progression, suggesting concurrent high L and LM elevations are associated with B27+ male patients having more significant radiographic damage. L+ B27-negative male patients or L+ female patients are more likely to have milder disease.ConclusionL and LM are informative biomarkers for SIJ and spinal inflammation, as well as for ankylosing development in r-axSpA patients. Distinctive L+LM+ or L+ patterns not only could distinguish clinically aggressive vs milder course of disease, respectively, but also provide an explanation for B27-positive male patients being the most susceptible to severe ankylosis.

Efficacy and Safety of Intravenous Golimumab in Patients With Ankylosing Spondylitis and Complete Spinal Ankylosis: Results Through Week 52 of the GO-ALIVE Study.

Efficacy and Safety of Intravenous Golimumab in Patients With Ankylosing Spondylitis and Complete Spinal Ankylosis: Results Through Week 52 of the GO-ALIVE Study.

Clinical efficacy and safety of adalimumab versus etanercept in patients with ankylosing spondylitis and total spinal ankylosis in Croatia: a multicentre 12-month follow-up study.

To evaluate the 12-month efficacy and safety profile of adalimumab and etanercept in patients with ankylosing spondylitis (AS) and total spinal ankylosis (TSA). Case-series follow-up study. Twenty-eight patients (26 men and 2 women) with active AS (BASDAI > 4) and TSA were treated as follows: 19 patients receiving adalimumab and 9 patients receiving etanercept. Twelve-month data related to the efficacy and safety of these two TNF-alpha inhibitors were evaluated. The primary endpoint was ASAS 20 (the ASsessment in AS International Working Group criteria for 20% improvement) at weeks 12 and 52. Other measures that were evaluated were function (BASFI), disease activity (BASDAI), patient's and physician's global disease assessment on visual analogue scale (VAS) and C-reactive protein. In both adalimumab and etanercept groups, there was a significant improvement in all observed variables (baseline compared to weeks 12 and 52). This improvement was sustained for the whole follow-up period. In the adalimumab group, at week 12, ASAS 20 was achieved in 18/19 patients and at week 52 in 17/19 patients. In the etanercept group, at week 12 ASAS 20 was achieved in all patients and at week 52 in 6/9 patients. In patients with active AS and TSA, adalimumab and etanercept treatment showed significant improvement in function and disease activity. No serious side effects or adverse effects were observed in our cohort. Key Points • TNF-alpha inhibitors can be effective treatment options for patients with AS and having total spinal ankylosis. • Patients with advanced AS should not be disregarded as good candidates for treatment with biologic disease-modifying antirheumatic drugs.

CXCL12/CXCR4-Rac1-mediated migration of osteogenic precursor cells contributes to pathological new bone formation in ankylosing spondylitis.

Ankylosing spondylitis (AS) is a chronic inflammatory disease characterized by inflammatory back pain and spinal ankylosis due to pathological new bone formation. Here, we identified CXCL12 as a critical contributor to pathological new bone formation through recruitment of osteogenic precursor cells (OPCs). CXCL12 was found highly expressed in the regions that would potentially develop pathological new bone. OPCs were recruited to the regions where CXCL12 was up-regulated. Inhibition of CXCL12/CXCR4 axis with AMD3100 or conditional knockout of CXCR4 attenuated OPCs migration and subsequent pathological new bone formation in animal models of AS. By contrast, a genetically engineered animal model with CXCL12 overexpression developed a joint ankylosis phenotype. Furthermore, Rac1 was found essential for OPCs migration and pathological new bone formation. These findings ravel the novel role of CXCL12 in AS and indicate a potential strategy for targeting the CXCL12/CXCR4-Rac1 axis to prevent progression of axial skeleton ankylosis.

SOX9+ enthesis cells are associated with spinal ankylosis in ankylosing spondylitis

Although cartilage degeneration and invasion of the subchondral bone plate in entheseal lesion has been considered to consequently lead bony ankylosis in ankylosing spondylitis (AS), no evident mechanisms are known. To identify histopathological and physiological changes in enthesitis-related ankylosis in AS, we performed molecular characterization of transcription factors and surface markers, and transcriptome analysis with human tissues. Entheseal tissue containing subchondral bone was obtained from the facet joints of 9 patients with AS and 10 disease controls, and assessed by using differential staining techniques. Enthesis cells were isolated, characterized, stimulated with TNF and/or IL-17A, and analysed by cell-based experimental tools. We found diffusely distributed granular tissue and cartilage in the subchondral bone in AS. Co-expression of SOX9, a specific transcription factor in cartilage, and matrix metalloproteinase 13 (MMP13) was found in the granular tissues within the subchondral bone from AS patients. Intriguingly, SOX9 expression was significantly higher in AS enthesis cells than controls and correlated with TNFR1 and IL-17RA expressions, which is important for high reactivity to TNF and IL-17A cytokines. Co-stimulation by TNF and IL-17A resulted in accelerated mineralization/calcification features, and increased OCN expression in AS enthesis cells. Furthermore, SOX9 overexpression in enthesis leads to promoting mineralization feature by TNF and IL-17A stimuli. Finally, OCN expression is elevated in the destructive enthesis of advanced AS. These findings provide insight into the links between inflammation and the mineralization of entheseal tissue as the initiation of spinal ankylosis, emphasizing the importance of SOX9+ enthesis cells.

Diffuse Idiopathic Skeletal Hyperostosis of the Spine: Pathophysiology, Diagnosis, and Management.

Diffuse idiopathic skeletal hyperostosis (DISH) is an ankylosing condition affecting up to 32.5% of the general cohort. Although often asymptomatic, affected individuals may present with back pain, stiffness, dysphagia, functional decline, and neurologic deficits. Radiographically, DISH is characterized by flowing ossifications along the anterior spine spanning ≥4 vertebral bodies. Although the etiology of DISH remains unknown, diabetes mellitus and other metabolic derangements are strongly associated with DISH. Importantly, spinal ankylosis in DISH predisposes patients to unstable spine fractures from low-energy trauma, and careful consideration must be taken in managing these patients. This article reviews the epidemiology and pathophysiology of DISH, and its clinical findings, diagnostic criteria, and management.

Targeting the Interleukin-23/Interleukin-17 Inflammatory Pathway: Successes and Failures in the Treatment of Axial Spondyloarthritis.

The IL-23/IL-17 pathway has been implicated in the etiopathogenesis of axial spondyloarthritis through studies of genetic polymorphisms associated with disease, an animal model with over-expression of IL-23 that resembles human disease, and observations that cytokines in this pathway can be found at the site of disease in both humans and animal models. However, the most direct evidence has emerged from clinical trials of agents targeting cytokines in this pathway. Monoclonal antibodies targeting IL-17A have been shown to ameliorate signs and symptoms, as well as MRI inflammation in the spine and sacroiliac joints, in patients with radiographic and non-radiographic axial spondyloarthritis. This was evident in patients refractory to non-steroidal anti-inflammatory agents as well as patients failing treatment with tumor necrosis factor inhibitor therapies. Treatment with a bispecific antibody targeting both IL-17A and IL-17F was also effective in a phase II study. Post-hoc analyses have even suggested a potential disease-modifying effect in reducing development of spinal ankylosis. However, benefits for extra-articular manifestations were limited to psoriasis and did not extend to colitis and uveitis. Conversely, trials of therapies targeting IL-23 did not demonstrate any significant impact on signs, symptoms, and MRI inflammation in axial spondyloarthritis. These developments coincide with recent observations that expression of these cytokines is evident in many different cell types with roles in innate as well as adaptive immunity. Moreover, evidence has emerged for the existence of both IL-23-dependent and IL-23-independent pathways regulating expression of IL-17, potentially associated with different roles in intestinal and axial skeletal inflammation.

POS0369 ELEVATED EXPRESSION OF TIM-3 ON NEUTROPHILS CORRELATES WITH DISEASE ACTIVITY AND SEVERITY OF ANKYLOSING SPONDYLITIS

Background:Ankylosing spondylitis (AS) is a type of common, chronic inflammatory disease that compromises the axial skeleton and sacroiliac joints, causing inflammatory low back pain and progressive spinal stiffness, over time some patients develop spinal immobility and ankylosis which can lead to a decrease in quality of life. The last few decades, evidence has clearly indicated that neutrophil also plays key roles in the progression of AS. However, the immunomodulatory roles and mechanisms of neutrophils in AS are poorly understood. T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) has been reported as an important regulatory molecule, expressed and regulated on different innate immune cells, plays a pivotal role in several autoimmunity diseases. Recent study indicates that Tim3 is also expressed on neutrophils. However, the frequency and roles of Tim3-expressing neutrophils in AS was not clear.Objectives:In this study, we investigated the expression of Tim3 on neutrophils in AS patients and explored the correlation between the level of Tim3-expressing neutrophils and the disease activity and severity of AS.Methods:Patients with AS were recruited from Guangdong Second Provincial General Hospital (n=62). Age/sex-matched volunteers as Healthy controls (HC) (n=39). The medical history, clinical manifestations, physical examination, laboratory measurements were recorded. The expression of costimulatory molecules including programmed death 1 (PD-1), Tim-3 on neutrophils were determined by flow cytometry. The mRNA expression of PD-1 and Tim-3 was determined by real-time PCR. The levels of Tim3-expressing neutrophils in AS patients were further analyzed for their correlation with the markers of inflammation such as ESR,CRP,WBC and neutrophil count(NE), as well as disease activity and severity of AS. The expression of Tim3 on neutrophils was monitored during the course of treatment (4 weeks).Results:The expression of Tim3 on neutrophils in patients with AS was increased compared to the HC (Figure 1A). However, significant difference was observed in the frequency of PD-1-expressing neutrophils between AS patients and HC (Figure 1B). The expression analysis of Tim-3 mRNA, but not PD-1, confirmed the results obtained from flow cytometry (Figure 1C). The level of Tim3-expressing neutrophils in patients with AS showed an positive correlation with ESR, CRP and ASAS-endorsed disease activity score (ASDAS) (Figure 1D). Moreover, the frequency of Tim3-expressing neutrophils in active patients(ASDAS≥1.3) was increased as compare with the inactive patients (ASDAS&lt;1.3) (Figure 1E). As shown in Figure 1F, the frequency of Tim3-expressing neutrophils decreased after the treatment.Conclusion:Increased Tim-3 expression on neutrophils may be a novel indicator to assess disease activity and severity in AS, which may serves as a negative feedback mechanism preventing potential tissue damage caused by excessive inflammatory responses in AS patients.