Active Ankylosing Spondylitis Research Articles

Exploring the Effects of Ixekizumab on Pain in Patients with Ankylosing Spondylitis Based on Objective Measures of Inflammation: Post Hoc Analysis from a Large Randomized Clinical Trial.

The objective of this analysis is to evaluate the improvement in spinal pain with ixekizumab, placebo, and adalimumab based on objective measures of inflammation response in patients with ankylosing spondylitis (AS). The COAST-V 52-week, double-blind, placebo-controlled, randomized phaseIII trial examined the efficacy of ixekizumab in patients with active AS; adalimumab was used as an active reference arm. Treatment effects on reduction in pain were assessed by objective measures of controlled and persisting inflammation (defined by magnetic resonance imaging [MRI], C-reactive protein [CRP], or MRI + CRP status). Pathway analysis was used to analyze treatment effect that was not attributable to reduction in inflammation biomarkers. In patients with AS, when inflammation was controlled as assessed by MRI, patients treated with ixekizumab experienced a reduction in spinal pain at night (SP-N, numeric rating scale, ixekizumab mean = - 3.9, p < 0.001, adalimumab mean = - 2.6, p < 0.05) compared to placebo (mean = - 1.6) at week16. When inflammation was controlled as assessed by MRI + CRP, ixekizumab and adalimumab had numerically greater reductions at week16 in SP-N versus placebo. All ixekizumab groups had further improvements at week52. When inflammation was persisting as assessed by MRI + CRP, ixekizumab-treated patients had significant reduction in SP-N (mean = - 3.7, p < 0.001) versus placebo (mean = - 1.7), improvement with adalimumab did not reach significance (mean = - 2.6, p = 0.06). In the pathway analysis at week16, ixekizumab had a greater effect on pain outcomes compared to adalimumab. This post hoc analysis is supportive of the hypothesis that ixekizumab reduces pain in AS by additional mechanisms other than the reduction of measurable inflammation. NCT02696785.

Correlations of expressions of Toll-like receptor 4 and Janus kinase 3 in peripheral blood mononuclear cells with T helper 17 cell/regulatory T cell imbalance in patients with ankylosing spondylitis

Abstract Background We aimed to analyze the correlations of the expressions of Toll-like receptor 4 (TLR4) and Janus kinase 3 (JAK3) in peripheral blood mononuclear cells (PBMCs) with T helper 17 cell (Th17)/regulatory T cell (Treg) imbalance in patients with ankylosing spondylitis (AS). Methods A total of 101 AS patients were enrolled into an AS group. Based on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score, they were subdivided into a stable AS (ASS) group (BASDAI score &lt;4 points, n=42) and an active AS (ASA) group (BASDAI score ≥4 points, n=59). Meanwhile, 50 healthy volunteers who received health examination in the same time period were assigned into a healthy control (HC) group. RT-qPCR was performed to determine the mRNA expressions of TLR4 and JAK3 in PBMCs. Enzyme-linked immunosorbent assay was conducted to measure the levels of Th17/Treg-related cytokines [interleukin (IL)-10, IL-17, IL-23, and transforming growth factor-β (TGF-β)] in the serum. Results The mRNA expressions of TLR4 and JAK3 had positive correlations with IL-17 (r=0.592, 0.542) and IL-23 levels (r=0.529, 0.590) (P 0.05). The levels of TLR4 mRNA, JAK3 mRNA, IL-17, and IL-23 were all correlated with the occurrence of AS (P&lt;0.05). The areas under the receiver operating characteristic curves of TLR4, JAK3, and their combination in PBMCs for predicting the occurrence of AS were 0.912, 0.835, and 0.919, respectively. Conclusions TLR4 combined with JAK3 can effectively predict the occurrence of AS.

The Role of H3K27me3-Mediated Th17 Differentiation in Ankylosing Spondylitis.

Ankylosing spondylitis (AS) is a common chronic progressive inflammatory autoimmune disease. T helper 17 (Th17) cells are the major effector cells mediating AS inflammation. Histone 3 Lys 27 trimethylation (H3K27me3) is an inhibitory histone modification that silences gene transcription and plays an important role in Th17 differentiation. The objective of this study was to investigate the expression of H3K27me3 in patients with AS and to explore its epigenetic regulation mechanism of Th17 differentiation during AS inflammation. We collected serum samples from 45 patients with AS at various stages and 10 healthy controls to measure their Interleukin-17 (IL-17) levels using ELISA. A quantitative polymerase chain reaction was used to quantify the mRNA levels of RORc and the signaling molecules of the JAK2/STAT3 pathway, JMJD3, and EZH2. Additionally, Western blot analysis was performed to quantify the protein levels of H3K27me3, RORγt, JAK2, STAT3, JMJD3, and EZH2 in cell protein extracts. The results showed that H3K27me3 expression in peripheral blood mononuclear cells (PBMCs) was significantly lower in patients with active AS compared to both the normal control groups and those with stable AS. Moreover, a significant negative correlation was observed between H3K27me3 expression and the characteristic transcription factor of Th17 differentiation, RORγt. We also discovered that patients with active AS exhibited significantly higher levels of JMJD3, an inhibitor of H3K27 demethylase, compared to the normal control group and patients with stable AS, while the expression of H3K27 methyltransferase (EZH2) was significantly lower. These findings suggest that H3K27me3 may be a dynamic and important epigenetic modification in AS inflammation, and JMJD3/EZH2 regulates the methylation level of H3K27me3, which may be one of the key regulatory factors in the pathogenesis of AS. These findings contribute to our understanding of the role of epigenetics in AS and may have implications for the development of novel therapeutic strategies for AS.

Long-term efficacy and safety of netakimab in patients with active ankylosing spondylitis: results of three years of use in the international multicentre, randomized, double-blind, phase III clinical trial BCD-085-5/ASTERA

The article presents the results of the three-year use of netakimab (NTK) in patients with ankylosing spondylitis (AS) as part of the phase III BCD-085-5/ASTERA study.Objective: to evaluate the long-term efficacy and safety of NTK over a three-year period in patients with active AS.Material and methods. BCD-085-5/ASTERA – double-blind, multicenter, randomized phase III clinical trial that enrolled patients with active AS (BASDAI ≥4) and a back pain intensity ≥4 on a numeric rating scale with inefficacy or intolerance of non-steroidal anti-inflammatory drugs or biologic drugs. A total of 228 patients were randomized in a 1:1 ratio and assigned to either the NTK group or the placebo/NTK group. Starting at week 16, patients who did not achieve ASAS20 (20% improvement according to ASAS criteria) received NTK 120 mg once every 2 weeks in an open-label regimen. Patients who achieved ASAS20 response at week 52 in the NTK group and week 68 in the placebo/NTK group continued to receive NTK (120 mg every 2 weeks) until week 156 in the NTK group and until week 172 in the placebo/NTK group.Results and discussion. Over the course of three years of NTK use, most patients experienced a sustained decline in AS activity (according to ASDAS-CRP, BASDAI) with sustained response (ASAS20/40, ASAS5/6) to therapy. Most adverse events reported were mild to moderate. 36.7% of patients had adverse events, which were mainly laboratory abnormalities, blood and lymphatic system abnormalities and infectious complications.Conclusion. The clinical effect of NTK was maintained in most patients with AS over a three-year period, with no significant loss of response. NTK was well tolerated and the safety profile remained favorable.

Study on the Expression and Potential Function of LncRNA in Peripheral Blood of Patients with Ankylosing Spondylitis

Background: Ankylosing spondylitis (AS) is an autoimmune disease that has the characteristics of difficult early diagnosis and a high disability rate. Objective: The objective of this study was to further explore the possible mechanism and potential function of lncRNA in AS. Methods: We used lncRNA microarray technology to detect the expression of lncRNA and mRNA in patients with active AS, stable patients, and healthy controls (HC). Afterward, bioinformatics analysis was conducted on differentially expressed genes. Seven differentially expressed lncRNAs were screened out for real-time fluorescent quantitative PCR (RT-qPCR), combined with various clinical indicators for correlation analysis, and the receiver operating characteristic (ROC) curve was used to analyze the potential of lncRNA as a diagnostic marker for AS. Results: The results showed that the expression levels of NR-037662 and ENST00000599316 in the AS subgroups were significantly higher than those in the HC group, while the expression levels of ENST00000577914 and ENST00000579003 were lower than those in the HC group. The expression levels of NR-003542 and ENST00000512051 in the ASA group were significantly higher than those in the ASS and HC groups, while NR-026756 was just the opposite. Spearman’s correlation analysis showed that the expression level of NR-003542 was positively correlated with Bath Ankylosing Spondylitis Functional Index (BASFI), Erythrocyte Sedimentation Rate (ESR), and high sensitivity C-Reactive Protein (hsCRP). The expression level of NR-026756 was negatively correlated with the Bath Ankylosing Spine Inflammatory Disease Activity Index (BASDAI), BASFI, ESR, hsCRP, and globulin (GLOB). In addition, it was also found that the ROC curve analysis of the 4 lncRNAs between the AS group (ASA group and ASS group) and the HC group were statistically significant, and the area under the curve (AUC) of NR-037662, ENST00000599316, ENST00000577914, and ENST00000579003 was 0.804, 0.812, 0.706, and 0.698, respectively. Conclusion: It was found that these differentially expressed lncRNAs of AS may be involved in the occurrence and development of the disease. Among them, NR-037662, ENST00000599316, ENST00000577914, and ENST00000579003 might have the potential to become AS diagnostic molecular markers. Moreover, NR -003542, ENST00000512051, and NR-026756 might have the potential to be indicators of disease activity.

Relationships of Work Productivity and Activity Impairment With Patient-Reported Outcomes in Ankylosing Spondylitis: Results From Two Trials.

We examined the relationships of work productivity and activity impairment with key patient-reported outcomes (PROs) assessing pain, disease activity, and health-related quality of life (HRQoL) in patients with ankylosing spondylitis (AS). This post hoc analysis pooled available data from baseline to end of the double-blind phase of phase 2 and 3 placebo-controlled tofacitinib trials in patients with active AS. A repeated-measures longitudinal model assessed the relationships (linear or nonlinear) between Work Productivity and Activity Impairment questionnaire in Spondyloarthritis (WPAI:SpA) domains (absenteeism, activity impairment, presenteeism, and productivity loss) as outcomes and key PROs (total back pain, nocturnal spinal pain, Patient Global Assessment of Disease Activity, AS Quality of Life, EuroQol 5-Dimension 3-Level [EQ-5D-3L], and EQ-5D Visual Analog Scale [EQ-5D-VAS]) as predictors. Data from 330 to 475 patients were available, depending on the analysis. Relationships between WPAI:SpA domains and PROs were approximately linear. The worst PRO scores were associated with a decline in patients' work capacity (measured by activity impairment, presenteeism, and productivity loss [>65%]); the best scores were associated with improvements in WPAI:SpA domains (8%-23%). Incremental PRO improvements were associated with improvement of activity impairment, presenteeism, and productivity loss. Relationships between absenteeism and PROs were the weakest, owing to absenteeism being low in the study population. Evidence of linear relationships between work productivity and activity impairment with patient-reported pain, disease activity, and HRQoL was observed. Interventions to control pain and disease activity and improve HRQoL are therefore likely to improve work productivity and reduce activity impairment in patients with AS.

Tofacitinib Efficacy and Safety in Patients With Ankylosing Spondylitis by Prior Biologic Disease-Modifying Antirheumatic Drug Use: A Post Hoc Analysis.

To evaluate the efficacy and safety of tofacitinib in patients with ankylosing spondylitis (AS) by prior biologic disease-modifying antirheumatic drug (bDMARD) use. Data from a placebo-controlled, double-blind study of patients with active AS were analyzed. Patients received tofacitinib 5 mg twice daily (BID) or placebo to week 16; all received open-label tofacitinib 5 mg BID to week 48 and were stratified by prior treatment (bDMARD-naive or tumor necrosis factor inhibitor [TNFi]-inadequate responder [IR], including bDMARD-experienced [non-IR]). Disease activity/safety were assessed throughout. Of 269 patients, 207 (77%) were bDMARD-naive; 62(23%) were in the TNFi-IR subgroup. TNFi-IR patients had higher baseline BMI (28.0 vs. 26.1 kg/m2 ), longer symptom duration (14.4 vs. 13.2 years), and lower concomitant conventional synthetic DMARD use (14.5% vs. 30.9%) than bDMARD-naive patients. At week 16, for most outcomes, tofacitinib efficacy exceeded placebo for both subgroups and was sustained to week 48. At week 16, tofacitinib versus placebo differences were similar between bDMARD-naive and TNFi-IR patients (Assessment in Spondyloarthritis international Society 40 treatment difference [95% confidence interval]: 30.8% [19.1%-42.6%] vs. 19.4% [1.7%-37.0%]). Adverse event (AE) proportions were similar between tofacitinib-treated bDMARD-naive/TNFi-IR patients (77.5%/77.4%) at week 48 with no deaths. A numerically higher proportion of tofacitinib-treated TNFi-IR versus bDMARD-naive patients discontinued study drug (12.9% vs. 3.9%) or dose reduced/temporarily discontinued due to AEs (19.4% vs. 11.8%). Tofacitinib efficacy exceeded placebo at week 16 for bDMARD-naive/TNFi-IR patients and was sustained to week 48. The absolute magnitude of responses was generally greater in bDMARD-naive patients versus TNFi-IR patients. More TNFi-IR versus bDMARD-naive patients discontinued or dose reduced/temporarily discontinued tofacitinib due to AEs. Small sample size and sample size differences between subgroups limited the interpretation.

Elevated serum IL-36γ levels in patients with ankylosing spondylitis and its association with disease activity.

Ankylosing spondylitis (AS) is a chronic autoimmune disease. The purpose of this study was to investigate the levels of serum IL-36γ in AS patients and their association with AS. The study enrolled 131 subjects, including 45 with active AS, 46 with inactive AS, and 40 healthy controls (HCs). The basic clinical information of each participant was obtained through physical examination and relevant clinical medical records. Serum IL-36γ levels were detected through an enzyme-linked immunosorbent assay. Serum IL-36γ levels in the active AS group were significantly higher than those in the HC group (94.72 vs. 65.76pg/mL, P = 0.0087). The serum IL-36γ concentration in the inactive AS group was increased as compared to that in the HC group (100.90 vs. 65.76pg/mL, P = 0.0138). Correlation analysis indicated that serum IL-36γ was positively correlated with glutamyl transferase in the active AS group (P = 0.0172), while serum IL-36γ was positively correlated with uric acid in the inactive AS group (P = 0.0151). The area under the curve (AUC) for IL-36γ was 0.6824 (P = 0.0009), and the AUC for IL-36γ combined with the erythrocyte sedimentation rate and C-reactive protein levels was 0.8102 (P < 0.0001), according to receiver operating characteristic curve analysis. This study found that serum IL-36γ levels were elevated in AS patients and correlated with disease activity. Our results suggest that IL-36γ may be involved in the progression of AS disease and is a potential biomarker for AS.

Efficacy and safety of upadacitinib in patients with ankylosing spondylitis refractory to biologic therapy: 1-year results from the open-label extension of a phase III study

BackgroundUpadacitinib, a Janus kinase inhibitor, has demonstrated efficacy and an acceptable safety profile in patients with ankylosing spondylitis (AS) in the phase III SELECT-AXIS programs. We report the 1-year efficacy and safety in patients with AS and an inadequate response to biologic disease-modifying antirheumatic drugs (bDMARD-IR) from the SELECT-AXIS 2 study.MethodsPatients ≥ 18 years with active AS who met the modified New York criteria for AS and were bDMARD-IR received double-blind upadacitinib 15 mg once daily (QD) or placebo for 14 weeks. Patients who completed 14 weeks could enter an open-label extension and receive upadacitinib 15 mg QD for up to 2 years. Efficacy endpoints included the percentage of patients achieving ≥ 40% improvement in Assessment of SpondyloArthritis international Society response (ASAS40), Ankylosing Spondylitis Disease Activity Score (ASDAS) low disease activity (LDA), and ASDAS inactive disease (ID); and change from baseline in total and nocturnal back pain, and Bath Ankylosing Spondylitis Functional Index (BASFI). Subgroup analyses (bDMARD lack of efficacy versus intolerance, and prior tumor necrosis factor inhibitor [TNFi] versus interleukin-17 inhibitor [IL-17i] exposure) were conducted. Binary and continuous efficacy endpoints were assessed using non-responder imputation with multiple imputation (NRI-MI) and as observed (AO) analyses; and mixed-effects model repeated measures (MMRM) and AO, respectively. Safety was assessed based on adverse events. Data through week 52 are reported.ResultsOf 420 randomized patients, 366 (continuous upadacitinib: n = 181; placebo to upadacitinib: n = 185) completed 52 weeks of treatment. At week 52, in the continuous upadacitinib and placebo to upadacitinib groups, ASAS40, ASDAS LDA, and ASDAS ID were achieved by 66% and 65%, 57% and 55%, and 26% and 25% (all NRI-MI); and change from baseline in total back pain, nocturnal back pain, and BASFI was -4.5 and -4.3, -4.6 and -4.4, and -3.6 and -3.5 (all MMRM), respectively. No new safety risks were identified. Subgroup analyses were consistent with the overall study population.ConclusionsUpadacitinib 15 mg QD demonstrated sustained improvement up to 52 weeks in bDMARD-IR patients with AS. Efficacy was generally similar in patients with lack of efficacy versus intolerance to bDMARDs and prior TNFi versus IL-17i exposure.Trial registrationNCT02049138.

Clinical and Economic Benefit of Advanced Therapies for the Treatment of Active Ankylosing Spondylitis.

Recent changes to treatment guidelines for ankylosing spondylitis (AS) have listed first-line advanced therapies as tumor necrosis factor (TNF), interleukin (IL)-17, and Janus kinase (JAK) inhibitors. This study sought to assess the comparative clinical and economic benefit of advanced therapies approved for AS. A systematic literature review was conducted to identify randomized clinical trials for JAK inhibitors (upadacitinib [UPA], tofacitinib [TOF]), anti-IL-17 therapies (secukinumab [SEC], ixekizumab [IXE]), and TNF inhibitors (adalimumab [ADA], etanercept [ETN], golimumab [GOL]) used for the treatment of active AS. Clinical efficacy was evaluated by Assessment of Spondyloarthritis International Society40 (ASAS40) criteria and treatment discontinuation due to adverse events (AEs) was used to generate response rates synthesized via a Bayesian network meta-analysis. Number needed to treat (NNT) was calculated as the reciprocal of incremental response rate of each treatment versus placebo. Cost per ASAS40 responder (CPR) was calculated as the 12-week treatment costs divided by ASAS40 response rates. Data were stratified by biologic treatment status (i.e., biologic naïve [bio-naïve] or inadequate response or intolerance to biologics [bio-IR]) for efficacy and CPR analyses. Among bio-naïve patients, the response rate for ASAS40 was 53.6% for UPA-treated patients, whereas most other treatments had response rates between 41% and 49%. NNTs were lowest for UPA-treated patients at 2.8 (other therapies 3.2-4.8). Estimated CPR among UPA-treated patients was lowest (UPA $39.5k vs others $44.2k-102.5k). Efficacy and CPR trends were similar among bio-IR and TNF-IR patients. Among bio-naïve and bio-IR patients, the rate of AEs leading to discontinuation was lowest among UPA and SEC-treated patients (0.0, others 0.6-3.7%). Relative to other treatments assessed in this study, UPA demonstrated numerically greater clinical and economic benefit for the treatment of AS. Head-to-head or real-world comparisons of these therapies are warranted and may inform clinical decision-making.

Tumor Necrosis Factor-Alpha (+489 G/A) Polymorphism Can Predict the Response to Adalimumab in Chinese Han Patients With Ankylosing Spondylitis.

Studies investigating the association between single nucleotide polymorphisms (SNPs) of tumor necrosis factor-alpha (TNFα) and the efficacy of adalimumab (ADA) in ankylosing spondylitis (AS) therapy have reported conflicting results. We aimed to investigate the value of SNP typing of TNFα in predicting the efficacy of ADA in AS. Eighty patients with active AS who received ADA treatment were followed up for 24 weeks. Six known SNPs of TNFα (+489G/A, -238G/A, -308G/A, -857C/T, -863C/A, and -1031C/T) were subjected to the SNaPshot SNP typing method, which has been proven to be a reliable, efficient, and cost-effective method for detecting SNPs. The relationship between each SNP genotype and the therapeutic efficacy of ADA was analyzed. At the end of the 24-week follow-up, 58.8% of the patients with AS achieved Assessment of SpondyloArthritis International Society (ASAS) partial remission (PR), 67.5% of the patients achieved the criteria of an ASAS40response (40% improvement on indices), and 53.8% of the patients achieved Ankylosing Spondylitis Disease Activity Score (ASDAS) major improvement (MI). The univariate analysis showed that patients with AS carrying the TNFα +489 A allele were more likely to achieve ASAS-PR, ASAS40 response criteria, and ASDAS-MI after ADA treatment. In the multivariate regression analysis, the TNFα +489 A allele was an independent factor influencing the efficacy of ADA in treating AS (ASAS-PR odds ratio (OR) = 2.66, 95% confidence interval (CI) = 1.01-7.01; ASAS40 OR = 4.56, 95% CI = 1.39-15.00; ASDAS-MI OR = 3.31, 95% CI = 1.02-10.69). The patients carrying the TNFα +489 A allele may be more likely to experience better therapeutic efficacy and achieve the treatment target (ASAS-PR, ASAS40 response, or ASDAS-MI) after receiving ADA treatment. Detection of TNFα +489 G/A may predict the therapeutic efficacy of ADA, which can be used in clinical practice to tailor treatment for individual patients with AS. Further studies with larger sample sizes and longer follow-up periods with imaging evaluation are needed to verify our findings.

Tofacitinib Reduces Spinal Inflammation in Vertebral Bodies and Posterolateral Elements in Ankylosing Spondylitis: Results from a Phase 2 Trial.

This post hoc analysis of phase 2 trial data assessed the efficacy of tofacitinib on magnetic resonance imaging (MRI) outcomes with the detailed anatomy-based Canada-Denmark (CANDEN) MRI scoring system and evaluated tofacitinib suppression of spinal inflammation in patients with active ankylosing spondylitis (AS). Patients with active AS (per modified New York criteria) were randomized 1:1:1:1 to receive tofacitinib 2, 5, or 10mg twice daily (BID), or placebo, in a 16-week, phase 2, double-blind clinical trial. Spine MRI assessments were performed at baseline and week 12. For post hoc analysis, MRI images from patients receiving tofacitinib 5 or 10mg BID, or placebo, were re-evaluated by two readers blinded to time point/treatment and assessed by the CANDEN MRI scoring system. Least squares mean changes from baseline to week 12 were reported for CANDEN-specific MRI outcomes, with analysis of covariance used for comparisons of pooled tofacitinib and tofacitinib 5 or 10mg BID versus placebo. p values without multiplicity adjustment were reported. MRI data from 137 patients were analyzed. At week 12, CANDEN spine inflammation score and vertebral body, posterior elements, corner, non-corner, facet joint, and posterolateral inflammation subscores were significantly reduced with pooled tofacitinib versus placebo (p < 0.0001; except non-corner subscore, p < 0.05). Total spine fat score was numerically increased with pooled tofacitinib versus placebo. In patients with AS, tofacitinib treatment was associated with significant reductions in MRI scores of spinal inflammation versus placebo, as assessed by the CANDEN MRI scoring system. Tofacitinib reduced inflammation in posterolateral elements of the spine and facet joints, which has not been described previously. ClinicalTrials.gov registry (NCT01786668).

Effect of Intravenous Golimumab on Fatigue and the Relationship with Clinical Response in Adults with Active Ankylosing Spondylitis in the Phase 3 GO-ALIVE Study.

We studied the effect of intravenous (IV)-golimumab on fatigue and the association of fatigue improvement with clinical response post hoc in adults with active ankylosing spondylitis (AS) in the GO-ALIVE trial. Patients were randomized to IV-golimumab 2mg/kg (N = 105) at week (W) 0, W4, then every 8 W (Q8W) or placebo (N = 103) at W0, W4, W12, crossover to IV-golimumab 2mg/kg at W16, W20, then Q8W through W52. Fatigue measures included Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) Question #1 (fatigue; 0 [none], 10 [worst]; decrease indicates improvement) and 36-Item Short Form HealthSurvey (SF-36) vitality subscale (0 [worst], 100 [best]; increase indicates improvement). Minimum clinically important difference is≥1 for BASDAI-fatigue and≥5 for SF-36 vitality.GO-ALIVE primary endpoint was Assessment of SpondyloArthritis international Society ≥ 20% improvement criteria (ASAS20). Other clinical outcomes assessed included other ASAS responses, Ankylosing Spondylitis Disease Activity Score, and Bath Ankylosing Spondylitis Functional Index score. The distribution-based minimally important differences (MIDs) were determined for BASDAI-fatigue and SF-36 vitality.The relationship between improvement infatigue and clinical outcomes was assessed via multivariable logistic regression. Mean changes in BASDAI-fatigue/SF-36 vitality scores were greater with IV-golimumab versus placebo at W16 (-2.74/8.46 versus -0.73/2.08, bothnominal p ≤ 0.003); by W52 (after crossover), differences between groups narrowed (-3.18/9.39 versus -3.07/9.17). BASDAI-fatigue/SF-36 vitality MIDs were achieved by greater proportions of IV-golimumab-treated versus placebo-treated patients at W16 (75.2%/71.4% versus 42.7%/35.0%). A one-point/five-point improvement in BASDAI-fatigue/SF-36 vitality scores at W16 increased likelihood of achieving ASAS20 (odds ratios [95% confidence intervals]: 3.15 [2.21, 4.50] and 2.10 [1.62, 2.71], respectively) and ASAS40 (3.04 [2.15, 4.28] and 2.24 [1.68, 3.00], respectively)responses at W16; concurrent improvements and clinical response at W52 were consistent. A one-point/five-point improvement in BASDAI-fatigue/SF-36 vitality scores at W16 predicted increased likelihood of achieving ASAS20 (1.62 [1.35, 1.95] and 1.52 [1.25, 1.86], respectively) and ASAS40 (1.62 [1.37, 1.92] and 1.44 [1.20, 1.73], respectively) responses at W52. IV-golimumab provided importantand sustained fatigue improvement in patients with AS that positively associated with achievingclinical response. ClinicalTrials.gov identifier, NCT02186873.

Upadacitinib (Rinvoq)

&#x0D; CADTH recommends that Rinvoq be reimbursed for the treatment of adults with active ankylosing spondylitis (AS) who have had an inadequate response to a biologic disease-modifying antirheumatic drug (bDMARD) or when use of those therapies is inadvisable only if certain conditions are met.&#x0D; Eligibility for Rinvoq should be based on the criteria used by each of the public drug plans for reimbursement of bDMARDs for the treatment of adult with active AS who have had an inadequate response to a bDMARD, are intolerant, or who have contraindications to bDMARDs.&#x0D; Rinvoq should only be reimbursed if it is prescribed by a rheumatologist. For patients with other manifestations, an ophthalmologist, gastroenterologist, or dermatologist may be consulted. Rinvoq should not be reimbursed when used in combination with bDMARDs or other Janus kinase (JAK) inhibitor treatments for active AS. The cost of Rinvoq should not exceed the drug program cost of treatment with the least expensive bDMARD reimbursed for the treatment of AS.&#x0D;

A Randomized, Double-Blind, Placebo-Controlled Phase 2a Study of Tildrakizumab Efficacy and Safety in Patients With Active Ankylosing Spondylitis.

Tildrakizumab is an anti-interleukin-23p19 monoclonal antibody approved to treat moderate to severe plaque psoriasis. This study evaluated the efficacy and safety of tildrakizumab in patients with ankylosing spondylitis (AS). In this randomized, double-blind, parallel-group, multinational trial (clinicaltrials.gov NCT02980705), patients with active AS, according to modified New York criteria and Bath Ankylosing Spondylitis Disease Activity Index Score ≥4, were randomized 1:1 to tildrakizumab 200 mg or placebo every 4 weeks until week 24. Thereafter, all patients received tildrakizumab 200 mg every 4 weeks until week 48. The primary outcome was proportion of patients achieving 20% improvement from baseline by Assessment in SpondyloArthritis International Society criteria (ASAS20) at week 24. This outcome was analyzed in subgroups defined by prior treatment experience, weight, age, and sex using the full analysis set. Safety was assessed through treatment-emergent adverse events. From December 5, 2017-September 3, 2019, 101 patients (76.2% male, 97% White) enrolled and were randomized to treatment. At week 24, the ASAS20 response rate was 74.0% in patients receiving tildrakizumab 200 mg (n = 50) versus 80.4% in placebo-treated patients (n = 51; treatment difference, -6.31%; 95% confidence interval, -22.34 to 9.71; p = 0.44). No difference in treatment effect by subgroups was observed. Tildrakizumab treatment was generally well tolerated, with no unexpected safety findings. The study was terminated after the week 24 interim analysis due to lack of efficacy. Tildrakizumab treatment was generally well tolerated but did not improve ASAS20 response rate versus placebo in patients with AS.

Association between air pollutants and initiation of biological therapy in patients with ankylosing spondylitis: a nationwide, population-based, nested case–control study

BackgroundOutdoor air pollution has been found to trigger systemic inflammatory responses and aggravate the activity of certain rheumatic diseases. However, few studies have explored the influence of air pollution on the activity of ankylosing spondylitis (AS). As patients with active AS in Taiwan can be reimbursed through the National Health Insurance programme for biological therapy, we investigated the association between air pollutants and the initiation of reimbursed biologics for active AS.MethodsSince 2011, hourly concentrations of ambient air pollutants, including PM2.5, PM10, NO2, CO, SO2, and O3, have been estimated in Taiwan. Using Taiwanese National Health Insurance Research Database, we identified patients with newly diagnosed AS from 2003 to 2013. We selected 584 patients initiating biologics from 2012 to 2013 and 2336 gender-, age at biologic initiation-, year of AS diagnosis- and disease duration-matched controls. We examined the associations of biologics initiation with air pollutants exposure within 1 year prior to biologic use whilst adjusting for potential confounders, including disease duration, urbanisation level, monthly income, Charlson comorbidity index (CCI), uveitis, psoriasis and the use of medications for AS. Results are shown as adjusted odds ratio (aOR) with 95% confidence intervals (CIs).ResultsThe initiation of biologics was associated with exposure to CO (per 1 ppm) (aOR, 8.57; 95% CI, 2.02–36.32) and NO2 (per 10 ppb) (aOR, 0.23; 95% CI, 0.11–0.50). Other independent predictors included disease duration (incremental year, aOR, 8.95), CCI (aOR, 1.31), psoriasis (aOR, 25.19), use of non-steroidal anti-inflammatory drugs (aOR, 23.66), methotrexate use (aOR, 4.50; 95% CI, 2.93–7.00), sulfasalazine use (aOR, 12.16; 95% CI, 8.98–15.45) and prednisolone equivalent dosages (mg/day, aOR, 1.12).ConclusionsThis nationwide, population-based study revealed the initiation of reimbursed biologics was positively associated with CO levels, but negatively associated with NO2 levels. Major limitations included lack of information on individual smoking status and multicollinearity amongst air pollutants.

Analysis of Single-Cell Transcriptome and Surface Protein Expression in Ankylosing Spondylitis Identifies OX40-Positive and Glucocorticoid-Induced Tumor Necrosis Factor Receptor-Positive Pathogenic Th17 Cells.

To demonstrate the immune landscape of blood and synovial cells in the setting of ankylosing spondylitis (AS) through the analysis of both single-cell transcriptome and surface protein expression, and to unveil the molecular characteristics of pathogenic Th17 cells. This study included 40 individuals with active AS, 20 individuals with stable AS, 40 patients with active rheumatoid arthritis, and 20 healthy controls. Surface phenotype and intracellular staining were assessed using flow cytometry after peripheral blood mononuclear cells and synovial fluid mononuclear cells were stimulated with T cell receptor. Single-cell transcriptomes of 6 patients with active AS were studied along with cellular indexing of transcriptomes and epitopes by sequencing. We also assessed the outcome of targeting OX40 and glucocorticoid-induced tumor necrosis factor receptor (GITR) on the surface of Th17 cells in a mouse model of curdlan-injected SKG mice in which anti-GITR ligand and/or anti-OX40 ligand were used. We identified pathogenic Th17 cells as polyfunctional interleukin-17A (IL-17A)- and interferon-γ (IFNγ)-producing memory CD4+ T cells, with clinically supportive evidence for their pathogenic roles at sites of inflammation in AS. Transcriptome and flow cytometric analyses revealed that the coexpression of TNFRSF4 (OX40) and TNFRSF18 (GITR) is increased in pathogenic Th17 cells. Suppression of ligand receptor interactions in vivo through OX40 and GITR effectively suppressed clinical arthritis and decreased pathogenic Th17 cells in the curdlan-injected SKG mouse model. Our results have implications for the understanding of pathogenic Th17 cells in AS patients and suggest potential therapeutic targets.

The Long-Term Effects of Short-Period Adalimumab Biosimilar Usage in Ankylosing Spondylitis.

Background Cost and drug toxicity frequently deter the long-term use of anti-tumor necrosis factor (TNF) agents in ankylosing spondylitis (AS). Therefore, this study was conducted to observe long-term relief after the short-term administration of an anti-TNF agent. Methodology A one-year, prospective, interventional, uncontrolled, single-center trial was conducted. There were 50 patients with symptomatic active chronic AS who received rheumatology therapy and were anti-TNF naive. Every two weeks, 40 mg of standard biosimilar adalimumab (Bs-ADA, Exemptia™) was administered subcutaneously for six injections (10 weeks) or to continue with standard follow-up if they did not achieve an Assessment in Ankylosing Spondylitis Response Criteria (ASAS 20) index response by week 12. Standard indicators (Assessment Spondyloarthritis International Society/ASAS and Bath) were used to evaluate progress. In addition, TNF-alpha, interleukin (IL)-6, and IL-17 were tested using a commercially available enzyme-linked immunosorbent assay kit from Bio Legend (Bengaluru, India). Results Patients experienced early and significant improvement in pain, non-steroidal anti-inflammatory drugs (NSAIDs) requirement, function, and several indices (ASAS 20 and 40, ASAS partial remission, Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, Ankylosing Spondylitis Disease Activity Score) after discontinuing injections. At weeks 12 and 48, 84% and 52% of patients showed ASAS 20 improvement, with 34% and 24% showing ASAS partial remission. Over half of the patients continued to improve and provided proof of concept. Conclusions In difficult-to-treat AS, a 10-week course of biosimilar adalimumab demonstrated significant early improvement that often lasted for 24 weeks. This unconventional method proved to be economically appealing. It merits further confirmation and acceptance, especially in resource-constrained contexts.

Effect of Upadacitinib on Disease Activity, Pain, Fatigue, Function, Health-Related Quality of Life and Work Productivity for Biologic Refractory Ankylosing Spondylitis.

Patients with ankylosing spondylitis (AS) have significant unmet treatment needs, despite advancements in biologic therapies. This study evaluated the impact of upadacitinib on clinically meaningful improvement in patient-reported outcomes (PROs) assessing disease activity, pain, fatigue, function, health-related quality of life (HRQoL), and work productivity in patients with AS with inadequate responses or intolerance to biologic disease-modifying antirheumatic drugs (bDMARD-IR). Patients enrolled in the phase 3 SELECT-AXIS 2 AS bDMARD-IR study received blinded once-daily oral upadacitinib 15mg or placebo for 14weeks. The percentage of patients achieving improvements ≥ minimum clinically important differences (MCID) at week 14 were compared between treatment groups for disease activity (Bath Ankylosing Spondylitis Disease Activity Index, BASDAI), patient global assessment of disease activity (PtGA), total and nocturnal back pain, fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue, FACIT-F), physical function (Bath Ankylosing Spondylitis Functional Index, BASFI), HRQoL (Assessment of SpondyloArthritis international Society Health Index [ASAS HI], Ankylosing Spondylitis Quality of Life [ASQoL], Short form-36 [SF-36] physical [PCS] and mental [MCS] component summary scores), and work productivity (Work Productivity and Activity Impairment [WPAI] Questionnaire). Mean changes from baseline through week 14 in fatigue and HRQoL were compared between treatment groups. A total of 420 patients with active AS who were bDMARD-IR were included. A higher proportion of patients reported MCIDs at week 14 across all PROs with upadacitinib compared with placebo (nominal p ≤ 0.05). Greater improvements in mean change from baseline through week 14 were reported with upadacitinib compared with placebo across FACIT-F, HRQoL, and WPAI, with improvements differentiated as early as week 1 for ASAS HI, ASQoL and SF-36 PCS and week 4 for SF-36 MCS. Upadacitinib 15mg demonstrated rapid and clinically meaningful improvements in disease activity, pain, FACIT-F, function, HRQoL, and WPAI among bDMARD-IR patients with active AS. Clinical Registration number: NCT04169373, SELECT-AXIS 2.

Patient registry data on the efficacy and tolerability of adalimumab biosimilar in ankylosing spondylitis: A retrospective multicenter observational study

Abstract: BACKGROUND: Adalimumab, a tumor necrosis factor-α inhibitor, is an approved treatment for ankylosing spondylitis (AS). In Iraq, a biosimilar of adalimumab (ABP 501; Amgevita®) has been licensed for prescription since 2021. However, there have been no previous studies on its efficacy and safety in Iraqi AS patients. Multiple studies have shown that adalimumab biosimilars are effective and well tolerated, with comparable rates of clinical response, adverse events (AEs), and immunogenicity to the reference product. OBJECTIVES: To evaluate the efficacy and safety of Amgevita in Iraqi patients with AS. PATIENTS AND METHODS: A retrospective multi-center observational study involving 72 patients with active AS for whom Amgevita 40 mg was prescribed every 2 weeks The data were collected from Amgevita registry data across multiple centers in Iraq. Patients’ entire data sets were retrieved and examined for disease activity parameters and recorded adverse reactions up to 12 months of Amgevita medication. RESULTS: The cumulative percentage of response in active AS patients treated with Amgevita was 82% after 3 months (the baseline) and 61% after 12 months. The mean change from the baseline in the Bath AS Disease Activity Index was statistically significant (−0.5 [P = 0.033; 95% confidence interval (CI): −0.87 to −0.04] and −1.14 [P = 0.0001; 95% CI: −1.68 to −0.60]) at 3 months and 12 months, respectively. On multivariate Cox regression modeling, disease activity was a predictor of a decreased response to treatment by 49%. There were no new, significant AEs. CONCLUSIONS: Adalimumab biosimilar (ABP501; Amgevita®) is clinically effective and tolerable over 12 months of follow-up in Iraqi patients with AS.