Response In Ankylosing Spondylitis Patients Research Articles

Ankilozan Spondilit Hastalarında Hastalık Aktivitesi ve Anti-Tümör Nekroz Faktörü Alfa Ajanlar ile Tedavi Yanıtını Değerlendirmede Hematolojik Endekslerin Klinik Yararlılığı

Background: Ankylosing spondylitis (AS) is a chronic inflammatory disease which influences the proportion of immune cells. Tumor necrosis factor alpha (TNF-α) is essential in the pathogenesis of AS, and TNF inhibitors are the most effective treatment for AS patients. In recent years, routine blood parameters were reported as markers of systemic inflammation associated with the diagnosis and prognosis of numerous malignancies and chronic inflammatory diseases. This study aimed to investigate the relationship between haematological parameters and clinical parameters, disease severity and treatment response in AS patients treated with TNF inhibitors. Methods: A total of 326 participants were recruited from the rheumatology department in this study. Participants were divided into healthy controls (n = 178) and AS (n = 148). Neutrophil, lymphocyte, monocyte and platelet counts, neutrophil-lymphocyte ratio (NLR), monocyte-lymphocyte ratio (MLR), platelet-lymphocyte ratio (PLR), platelet crit (PCT), mean platelet volume (MPV), red cell distribution width (RDW), systemic inflammatory index (SII), systemic inflammatory response index (SIRI), cluster systemic inflammation index (AISI) and RPR levels were analyzed for each participant. They were compared between healthy control, AS patients during the pre-treatment phase and three months after the treatment. Results: RDW, PLR, NLR, MLR, SIRI, AISI and SII were higher than healthy controls and decreased with treatment except SIRI. The decrease in AISI and SII after treatment was significant in HLA-B27 positive patients. MPV was lower than healthy controls and increased with treatment. SII, SIRI and AISI were significantly higher in the active AS patients than in the inactive patient. Also, they were correlated with erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Conclusion: SII, AISI, and SIRI may be valuable markers for demonstrating disease activation and evaluating the effectiveness of anti‐TNF‐α therapy.

Serum interα-trypsin inhibitor heavy chain H4 may be an anti-inflammatory marker reflecting disease risk, activity and treatment outcome of ankylosing spondylitis

Interα-trypsin inhibitor heavy chain H4 (ITIH4) modulates inflammation and immunity, which take part in the pathogenesis of ankylosing spondylitis (AS). The current research intended to discover the clinical value of serum ITIH4 quantification for AS management. Serum ITIH4 among 80 AS patients before current treatment initiation (baseline) at weeks (W) 4, 8 and 12 after treatment was detected by ELISA. Serum ITIH4 from 20 disease controls (DCs) and 20 healthy controls (HCs) was detected. ITIH4 expression was lower in AS patients than in DCs (p = 0.002) and HCs (p < 0.001). Among AS patients, ITIH4 was negatively associated with C-reactive protein (CRP) (r = −0.311, p = 0.005), bath AS disease activity index (BASDAI) (r = −0.223, p = 0.047), total pack pain (r = −0.273, p = 0.014) and AS disease activity score (ASDAS) (CRP) (r = −0.265, p = 0.018). Meanwhile, ITIH4 was negatively related to tumor necrosis factor (TNF)-α (r = −0.364, p = 0.001), interleukin (IL)-1β (r = −0.251, p = 0.025), IL-6 (r = −0.292, p = 0.009) and IL-17A (r = −0.254, p = 0.023). After treatment, the assessment of the spondylitis arthritis international society 40 response rate was 28.7% at W4, 46.3% at W8 and 55.0% at W12; ITIH4 showed an increasing trend from baseline to W12 (p < 0.001). Furthermore, ITIH4 at W8 (p = 0.020) and W12 (p = 0.035), but not at baseline or W4 (both p > 0.05), was enhanced in response patients vs. nonresponse patients. Additionally, ITIH4 at W12 was increased in AS patients receiving TNF inhibitors vs. those receiving nonsteroidal anti-inflammatory drugs (NSAIDs) (p = 0.024). Serum ITIH4 increases after treatment, and its augmentation is correlated with lower disease activity, decreased inflammation and enhanced treatment response in AS patients.

IL-6 activates pathologic Th17 cell via STAT 3 phosphorylation in inflammatory joint of Ankylosing Spondylitis

Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease, which is characterized by inflammation of the axial skeleton and the peripheral arthritis. An increase in the number of Th17 cells in patients with AS has been reported. Although Th17 cells have been involved in the induction of inflammation, recent data suggest that not all Th17 cells are pathogenic, showing regulatory function of Th17 cell. Cells producing both interferon-gamma (IFN-γ) and interleukin (IL)-17 have been reported to be the main pathologic Th17 (pTh17) cells that induce inflammation at sites of joint. Emerging evidence demonstrated that IL-6 has a main role in regulating the balance between inflammatory and regulatory T cells. However, there is no direct study to assess pTh17 cell with IL-6 in AS. Therefore, we evaluated the effect of IL-6 on pTh17 cell activation, and it's mechanism, using ex vivo and mouse model of AS. As a result, we found that pTh17 cell is dependent on the cytokine milieu with IL-6. We confirmed pTh17 cells play a pathogenic role at sites of inflammation. As a mechanism, it was revealed that IL-6 induced STAT 3 phosphorylation contributes to the increased pTh17 responses in AS patients with peripheral arthritis. Though validation of our results is required, IL-6 inhibitor can be a promising treatment for inflammation in AS patients with peripheral arthritis.

Immunological Changes in Peripheral Blood of Ankylosing Spondylitis Patients during Anti-TNF-α Therapy and Their Correlations with Treatment Outcomes.

Tumor necrosis factor-α (TNF-α) inhibitors are the main types of biological conventional synthetic disease-modifying antirheumatic drugs and have efficacy in treating ankylosing spondylitis (AS) which is not sensitive for nonsteroidal anti-inflammatory drug. However, the impact of TNF-α inhibitors on immune cells in patients with AS is still clearly undefined, and the impact of immune cells on treatment response is also largely elusive. This study is aimed at evaluating the longitudinal changes of circulating immune cells after anti-TNF-α therapy and their associations with treatment response in AS patients. Thirty-five AS patients receiving the treatment of anti-TNF-α therapy were included into this prospective observational study. The frequencies of immune cells including Th1, Th2, Th17, regulatory T cell (Treg), T follicular helper cell (Tfh), and regulatory B cell (Breg) in the peripheral blood were measured by flow cytometry at baseline and 4 time points after therapy. The difference in the circulating immune cells between responders and nonresponders was compared. This study suggested that anti-TNF-α therapy could significantly reduce circulating proinflammatory immune cells such as Th17 and Tfh, but significantly increased the percentages of circulating Treg and Breg. Moreover, circulating Breg may be a promising predictor of response to anti-TNF-α therapy in AS patients.

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.

Altered Repertoire Diversity and Disease-Associated Clonal Expansions Revealed by T Cell Receptor Immunosequencing in Ankylosing Spondylitis Patients.

Ankylosing spondylitis (AS) is a common spondyloarthropathy primarily affecting the axial skeleton and strongly associated with HLA-B*27 carriage. Genetic evidence implicates both autoinflammatory processes and autoimmunity against an HLA-B*27-restricted autoantigen in immunopathology. In addition to articular symptoms, up to 70% of AS patients present with concurrent bowel inflammation, suggesting that adverse interactions between a genetically primed host immune system and the gut microbiome contribute to the disease. Accordingly, this study aimed to characterize adaptive immune responses to antigenic stimuli in AS. The peripheral CD4 and CD8 T cell receptor (TCR) repertoire was profiled in AS patients (n = 47) and HLA-B*27-matched healthy controls (n = 38). Repertoire diversity was estimated using the Normalized Shannon Diversity Entropy (NSDE) index, and univariate and multivariate statistical analyses were performed to characterize AS-associated clonal signatures. Furthermore, T cell proliferation and cytokine production in response to immunogenic antigen exposure were investigated in vitro in peripheral blood mononuclear cells from AS patients (n = 19) and HLA-B*27-matched healthy controls (n = 14). Based on the NSDE measure of sample diversity across CD4 and CD8 T cell repertoires, AS patients showed increased TCR diversity compared to healthy controls (for CD4 T cells, P = 7.8 × 10-6 ; for CD8 T cells, P = 9.3 × 10-4 ), which was attributed to a significant reduction in the magnitude of peripheral T cell expansions globally. Upon in vitro stimulation, fewer T cells from AS patients than from healthy controls expressed interferon-γ (for CD8 T cells, P = 0.03) and tumor necrosis factor (for CD4 T cells, P = 0.01; for CD8 T cells, P = 0.002). In addition, the CD8 TCR signature was altered in HLA-B*27+ AS patients compared to healthy controls, with significantly expanded Epstein-Barr virus-specific clonotypes (P = 0.03) and cytomegalovirus-specific clonotypes (P = 0.02). HLA-B*27+ AS patients also showed an increased incidence of "public" CD8 TCRs, representing identical clonotypes emerging in response to common antigen encounters, including homologous clonotypes matching those previously isolated from individuals with bacterial-induced reactive arthritis. The dynamics of peripheral T cell responses in AS patients are altered, suggesting that differential antigen exposure and disrupted adaptive immunity are underlying features of the disease.

AB0693 TIM-3-EXPRESSING NEUTROPHILS AS A NOVEL INDICATOR TO ASSESS DISEASE ACTIVITY AND SEVERITY IN ANKYLOSING SPONDYLITIS

Background:Ankylosing spondylitis (AS) is a type of chronic inflammatory disease that compromises the axial skeleton and sacroiliac joints. Many studies have shown that neutrophils play an important roles in the inflammatory process 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 analyzed the correlation between the level of Tim3-expressing neutrophils and the disease activity of AS.Methods:AS Patients were recruited from Guangdong Second Provincial General Hospital (n=49). 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 frequencies of Tim3-expressing neutrophils in AS patients were further analyzed for their correlation with markers of inflammation ESR and CRP, disease activity and severity of AS.Results:The expression of Tim3 on neutrophils in patients with AS was increased compared to the HC (Figure 1A). The frequency of Tim3-expressing neutrophils in patients with AS showed an positive correlation with ESR, CRP and ASAS-endorsed disease activity score (ASDAS) (Figure 1B). 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 1C).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.

Evaluation of changes in choroidal vascularity during acute anterior uveitis attack in patients with ankylosing spondylitis by using binarization of EDI-optical coherence tomography images.

To evaluate the effect of the first acute anterior uveitis (AAU) attack on the choroid by using an image binarization tool on images from enhanced depth imaging (EDI)-optical coherence tomography (OCT) scans in patients with ankylosing spondylitis (AS). In this study, three groups were formed: uveitic eyes (UE; n = 20) of patients with AS, the non-uveitic eyes (NUE; n = 20) of these patients, and the eyes of healthy controls (n = 20). EDI-OCT images were obtained during the first AAU attack and at three months after treatment in patients with AS. An image binarization tool (ImageJ software; Bethesda, MD USA) was used on EDI-OCT images to determine choroidal structures. Choroidal vascularity index (CVI) was defined as the ratio of luminal area to total subfoveal choroidal area. Compared to the convalescent period, CVI was found to be significantly increased in UE (63.2 ± 2.87 vs. 60.9 ± 5.2 %, p = 0.045) and NUE (63.8 ± 5.67 vs. 61.5 ± 4.3 %, p = 0.039), while stromal area (SA) was found to be significantly reduced only in UE (0.487 ± 0.19 vs. 0.569 ± 0.18, p = 0.012) in the attack period. Changes in the CVI values of UE and NUE groups in the first AAU attack shows that there is underlying choroidal inflammation in patients with AS. It also seems that SA is the most affected choroidal structure in eyes suffering from an attack. The present study revealed that CVI measurements can be used for follow-up and the determination of treatment response in AS patients with AAU attack.

Correlation Between Chronic Pain Acceptance and Clinical Variables in Ankylosing Spondylitis and Its Prediction Role for Biologics Treatment.

Objectives: Studies have proven that improving patients' acceptance of chronic pain could be an effective therapy for alleviating pain and other symptoms. Our objectives were to investigate the correlation between chronic pain acceptance and clinical variables in ankylosing spondylitis (AS), and the prediction role of chronic pain acceptance for biologics treatment.Methods: First, 167 AS patients were recruited to complete a series of questionnaires, including the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Chronic Pain Acceptance Questionnaire (CPAQ), Hospital Anxiety and Depression Scale (HADS), and Tampa Scale for Kinesiophobia (TSK). Bivariate correlation analysis was utilized to investigate the correlation between pain acceptance and clinical variables. Based on the level of chronic pain acceptance and serum C-reactive protein (CRP), patients were separated into four subgroups. Then, another 68 patients initiating anti-tumor necrosis factor (TNF) treatment were recruited to complete the questionnaires at baseline (T0) and 3 months after treatment (T3). The changes in clinical variables and treatment response were compared between multiple subgroups.Results: Chronic pain acceptance had strong correlations with anxiety, depression and fear of movement, and moderate correlations with BASFI and pain intensity. Both activity engagement (AE) and pain willingness (PW) had significant correlations with pain intensity, BASFI and psychological status. In addition, AE had a significant correlation with disease duration, while PW had a significant correlation with ASDAS-CRP. Subgroup analysis showed that patients with low chronic pain acceptance and high levels of serum CRP had the highest BASDAI. Among patients initiating anti-TNF treatment, those with high pain acceptance and high levels of serum CRP achieved the most obvious reduction in BASDAI after 3 months treatment.Conclusion: Pain acceptance is a new tool to assess pain in AS which may also reflect physical and psychological status. Clinicians should identify high-risk patients with low chronic pain acceptance and high levels of serum CRP, and give psychological and pharmacological intervention promptly. Moreover, the combination of baseline chronic pain acceptance and serum CRP level could be used to predict the treatment response in AS patients initiating biologics treatment.

The potent suppressive effect of β-d-mannuronic acid (M2000) on molecular expression of the TLR/NF-kB Signaling Pathway in ankylosing spondylitis patients

Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease characterized by the inflammation of sacroiliac joints and axial skeleton. A combination of genetic, environmental and immunological factors are involved in AS's pathogenesis. TLRs are type I transmembrane glycoproteins that play a crucial role in the innate immune responses against invading pathogens. Observational studies have demonstrated a possible association between TLR dysregulation and AS. The β-d-mannuronic acid (M2000), as a novel NSAID with immunosuppressive property, has shown an inhibitory effect on Toll-like receptor (TLR) 2, 4 signaling in HEK293 cells. In the present study, we investigated the gene expression of Myd88, IKB-alpha, NF-kB and MAPK14 (genes of the TLR/NF-kB Signaling Pathway) in AS patients in comparison to healthy subjects and also the effect of β-d-mannuronic acid on disease activity and mRNA expression of these molecules in affected patients. We showed for the first time that the gene expression level of Myd88, IKB-alpha, NF-kB and MAPK14 was higher in AS patients in comparison to healthy subjects. Moreover we confirmed that the β-d-mannuronic acid not just reduced significantly the disease activity of AS individuals compared to placebo, but also it could significantly decrease the expression level of genes associated with TLR/NF-kB Signaling Pathway in treated patients with M2000. These results may provide a new therapeutic approach to attenuate inflammatory responses in AS patients, (Identified; IRCT 2013062213739N1).

Immunogenicity, adalimumab levels and clinical response in ankylosing spondylitis patients during 24 weeks of follow-up

BackgroundImmunogenicity influences adalimumab levels and therefore clinical response in patients with rheumatic diseases.ObjectivesTo study the relationship between clinical response, adalimumab levels and antidrug antibodies (ADAb) in ankylosing spondylitis (AS).MethodsObservational cohort...

FRI0426 Immunogenicity, adalimumab levels and clinical response in ankylosing spondylitis patients during 24 weeks of follow-up.

BackgroundImmunogenicity influences adalimumab levels and therefore clinical response in patients with rheumatic diseases.ObjectivesTo study the relation between clinical response, adalimumab levels and anti-drug antibodies (ADA) in ankylosing spondylitis (AS) patients.MethodsObservational...

FRI0418 How important is the assessment of asdas in the long-term evaluation of disease activity in ankylosing spondylitis? a comparison with currently used clinical parameters

BackgroundMeasures for disease activity (BASDAI) or response to therapy (ASAS partial remission (PR)) are widely used in the assessment of patients with ankylosing spondylitis (AS). The recently developed ASDAS is...

Induction of arthritis and uveitis in Lewis rats by antigenic mimicry of peptides from HLA-B27 and cytokeratin.

Ankylosing spondylitis (AS) is highly associated with HLA-B27. We have previously shown that peripheral blood lymphocytes from AS patients respond to stimulation with a peptide from the sequence of HLA-B27. Here we report on molecular mimicry of peptides from HLA-B27 and cytokeratin, the latter being specifically expressed in synovial membranes and eyes, the main targets of the autoaggressive immune response in AS patients. Immunization of rats with these peptides induced an inflammatory response in joints, spine and eyes, resembling the symptoms in AS. Furthermore, both HLA-B27- and cytokeratin-derived peptides, are effective oral tolerogens: feeding these peptides ameliorated arthritis and uveitis induced with the cytokeratin peptide. Our model might elucidate the role of peptides from the sequence of HLA-B27 as an antigen of the immune response in AS, introducing a new aspect of antigenic mimicry between HLA-B27 and tissue-specific antigens. We propose this as a mechanism directing a systemic autoimmune response to specific target organs by antigenic mimicry of T cell epitopes.

Characterization of the humoral immune response to Klebsiella species in inflammatory bowel disease and ankylosing spondylitis.

This study was carried out to characterize the antibody class response by ELISA to seven Klebsiella pneumoniae serotypes (K2, K3, K17, K21, K26, K36, K50) in five different groups, 40 HLA-B27-positive ankylosing spondylitis (AS) patients, 46 patients with Crohn's disease (CD), 38 patients with ulcerative colitis (UC), 50 patients with active anti-endomysial antibody-positive coeliac disease and 40 healthy controls, using whole bacteria and capsular polysaccharide. IgG antibody levels were significantly elevated in AS patients to K17, K36, K50; IgA to K2, K3, K21, K26, K36 and K50; and IgM to serotype K21 when compared to normal controls. Furthermore, IgG antibody levels were significantly elevated in CD patients to K2, K17, K21, K26, K36 and K50; IgA to K2, K3, K21, K26, K36 and K50; and IgM to K2, K3, K17, K21 and K50. Increased IgG antibody levels in the UC group were limited only to K17, K36 and K50. No antibody class was increased to any of the K. pneumoniae serotypes in the coeliac disease group. The immune responses in AS patients also involve Klebsiella bacteria having capsular serotypes other than K26, K36 and K50. The similarity in the immune responses between CD and AS groups suggests that many AS patients may have occult bowel inflammation.

Hla-d locus typing in ankylosing spondylitis and reiter's syndrome

HLA-D typing of 44 patients with ankylosing spondylitis (AS) and 31 patients with Reiter's syndrome (RS) did not show increased frequency of any particular Dw allele in either population of patients as compared to controls. Such studies also allowed each patient's general response to be compared with other general responses within each experiment. Contrary to reports of diminished lymphocyte responses in AS patients, hyperresponsiveness in both AS and RS patients was found.