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Clinical and Experimental Rheumatology Nov 2023Axial spondyloarthritides (axSpA) are a group of systemic autoimmune diseases, characterised by an inflammatory involvement of the axial skeleton, which, in the earlier... (Review)
Review
Axial spondyloarthritides (axSpA) are a group of systemic autoimmune diseases, characterised by an inflammatory involvement of the axial skeleton, which, in the earlier phases, cannot be detected by conventional radiology, but only by magnetic resonance imaging, thus defining the so-called non-radiographic axSpA (nr-axSpA). The initial osteitis then tends to complicate into bone reabsorption and aberrant bone deposition, which then determines the ankylosis of the axial skeleton in the latest phases of the disease.Peripheral joints may also be affected, enthesitis being its more characteristic manifestation. The radiographic form corresponds to ankylosing spondylitis which, with psoriatic arthritis, is the best-known subtype of SpA. AxSpA are rarely associated to laboratory abnormalities and are usually complicated by the presence of both extra-articular manifestations (particularly acute anterior uveitis, psoriasis and inflamatory bowel disease) and comorbidities, with a subsequent higher risk for patients of an impaired quality of life.In this paper we reviewed the literature on axSpA of 2021 and 2022 (Medline search of articles published from 1st January 2021 to 31st December 2022).
Topics: Humans; Spondylarthritis; Quality of Life; Spondylitis, Ankylosing; Arthritis, Psoriatic; Psoriasis
PubMed: 37965699
DOI: 10.55563/clinexprheumatol/9fhz98 -
Clinical and Translational Science Jan 2024Upadacitinib is a selective Janus kinase (JAK) inhibitor which is approved by the US Food and Drug Administration, the European Medicines Agency, as well as other... (Review)
Review
Upadacitinib is a selective Janus kinase (JAK) inhibitor which is approved by the US Food and Drug Administration, the European Medicines Agency, as well as other agencies around the world for the treatment of several chronic inflammatory diseases, including rheumatic, dermatologic, and gastrointestinal diseases. Through inhibition of JAK, upadacitinib inhibits phosphorylation of downstream effector proteins, which consequently inhibits cytokine signaling for key pathways involved in inflammatory diseases. Upadacitinib more potently inhibits JAK1 than other JAK isoforms. The pharmacokinetics, pharmacodynamics, efficacy, and safety of upadacitinib were characterized in many clinical trials, which demonstrated the superiority of upadacitinib treatment over placebo or an active comparator in rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, atopic dermatitis, Crohn's disease, and ulcerative colitis. The safety profile of upadacitinib supported a favorable benefit-risk profile across all the approved indications. In this article, we review the mechanism of action of upadacitinib and describe how the JAK-STAT (Janus kinase-signal transducers and activators of transcription) pathway is involved in the pathogenesis of several chronic and progressive immune-mediated inflammatory diseases. In addition, this review also provides an overview of key clinical trials that were conducted as well as relevant data which supported the clinical development of upadacitinib and informed the recommended dose(s) in each of the approved indications.
Topics: United States; Humans; Translational Science, Biomedical; Arthritis, Rheumatoid; Spondylitis, Ankylosing; Janus Kinase Inhibitors; Janus Kinases; Heterocyclic Compounds, 3-Ring
PubMed: 37984057
DOI: 10.1111/cts.13688 -
Arthritis Research & Therapy Sep 2023Upadacitinib, a Janus kinase inhibitor, has demonstrated efficacy and an acceptable safety profile in patients with ankylosing spondylitis (AS) in the phase III... (Randomized Controlled Trial)
Randomized Controlled Trial
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.
BACKGROUND
Upadacitinib, 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.
METHODS
Patients ≥ 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.
RESULTS
Of 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.
CONCLUSIONS
Upadacitinib 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 REGISTRATION
NCT02049138.
Topics: Humans; Antirheumatic Agents; Biological Therapy; Heterocyclic Compounds, 3-Ring; Spondylarthritis; Spondylitis, Ankylosing; Tumor Necrosis Factor Inhibitors
PubMed: 37723577
DOI: 10.1186/s13075-023-03128-1 -
Arthritis Research & Therapy Jan 2024Ankylosing spondylitis (AS) is one of several disorders known as seronegative spinal arthritis (SpA), the origin of which is unknown. Existing epidemiological data show...
BACKGROUND
Ankylosing spondylitis (AS) is one of several disorders known as seronegative spinal arthritis (SpA), the origin of which is unknown. Existing epidemiological data show that inflammatory and immunological factors are important in the development of AS. Previous research on the connection between immunological inflammation and AS, however, has shown inconclusive results.
METHODS
To evaluate the causal association between immunological characteristics and AS, a bidirectional, two-sample Mendelian randomization (MR) approach was performed in this study. We investigated the causal connection between 731 immunological feature characteristic cells and AS risk using large, publically available genome-wide association studies.
RESULTS
After FDR correction, two immunophenotypes were found to be significantly associated with AS risk: CD14 - CD16 + monocyte (OR, 0.669; 95% CI, 0.544 ~ 0.823; P = 1.46 × 10; P = 0.043), CD33dim HLA DR + CD11b + (OR, 0.589; 95% CI = 0.446 ~ 0.780; P = 2.12 × 10; P = 0.043). AS had statistically significant effects on six immune traits: CD8 on HLA DR + CD8 + T cell (OR, 1.029; 95% CI, 1.015 ~ 1.043; P = 4.46 × 10; P = 0.014), IgD on IgD + CD24 + B cell (OR, 0.973; 95% CI, 0.960 ~ 0.987; P = 1.2 × 10; P = 0.021), IgD on IgD + CD38 - unswitched memory B cell (OR, 0.962; 95% CI, 0.945 ~ 0.980; P = 3.02 × 10; P = 0.014), CD8 + natural killer T %lymphocyte (OR, 0.973; 95% CI, 0.959 ~ 0.987; P = 1.92 × 10; P = 0.021), CD8 + natural killer T %T cell (OR, 0.973; 95% CI, 0.959 ~ 0.987; P = 1.65 × 10; P = 0.021).
CONCLUSION
Our findings extend genetic research into the intimate link between immune cells and AS, which can help guide future clinical and basic research.
Topics: Humans; Spondylitis, Ankylosing; Genome-Wide Association Study; Mendelian Randomization Analysis; Spondylarthritis; HLA-DR Antigens
PubMed: 38229175
DOI: 10.1186/s13075-024-03266-0 -
International Journal of Molecular... Jul 2023Fatigue is a prevalent symptom in various rheumatic diseases, such as rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. It is characterised as a... (Review)
Review
Fatigue is a prevalent symptom in various rheumatic diseases, such as rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. It is characterised as a subjective, enduring feeling of generalised tiredness or exhaustion, impacting the patient's life quality and exacerbating disability. The fatigue nature is multifaceted, encompassing physiological, psychological, and social factors, and although the exact cause of inflammatory joint diseases is not fully understood, several factors are believed to contribute to its development. Despite high prevalence and importance, the symptom is often underestimated in clinical practice. Chronic inflammation, commonly associated with rheumatic diseases, has been proposed as a potential contributor to fatigue development. While current treatments effectively target inflammation and reduce disease activity, fatigue remains a persistent problem. Clinical evaluation of rheumatic diseases primarily relies on objective criteria, whereas fatigue, being a subjective symptom, is solely experienced and reported by the patient. Managing fatigue in inflammatory joint diseases involves a multifaceted approach. Identifying and comprehensively assessing the subjective components of fatigue in individual patients is crucial for effectively managing this symptom in everyday clinical practice.
Topics: Humans; Arthritis, Rheumatoid; Spondylitis, Ankylosing; Inflammation; Rheumatic Diseases; Fatigue
PubMed: 37569413
DOI: 10.3390/ijms241512040 -
The Journal of Rheumatology Aug 2023To report safety and efficacy of ixekizumab (IXE) from the COAST program at 3 years, including 1 year from the originating studies (COAST-V, COAST-W, and COAST-X), and 2...
OBJECTIVE
To report safety and efficacy of ixekizumab (IXE) from the COAST program at 3 years, including 1 year from the originating studies (COAST-V, COAST-W, and COAST-X), and 2 years from COAST-Y.
METHODS
In COAST-Y, patients continued with the dose received at the end of the originating study at week 52: 80 mg IXE either every 4 weeks (Q4W) or every 2 weeks (Q2W). Placebo-treated patients from COAST-X received IXE Q4W in COAST-Y. Starting at week 116 (week 64 of COAST-Y), patients receiving IXE Q4W could be escalated to Q2W. Safety for patients receiving ≥ 1 dose of IXE and efficacy for patients receiving ≥ 1 dose of IXE Q4W was assessed. Data are summarized as observed.
RESULTS
For the 932 patients who received ≥ 1 dose of IXE (Q2W or Q4W) through 3 years, treatment-emergent adverse events (TEAEs) occurred at an incidence rate (IR) of 38.0 per 100 patient-years (PYs). The most frequently reported were infections (IR 25.7 per 100 PYs) and injection site reactions (IR 7.4 per 100 PYs); the majority of TEAEs were mild or moderate in severity. In total, 7.1% of TEAEs led to discontinuation (IR 3.1 per 100 PYs). All patient groups receiving IXE Q4W assessed through 3 years saw sustained improvements in Ankylosing Spondylitis Disease Activity Score, clinically important improvement, and other efficacy end points.
CONCLUSION
The 3-year safety profile of IXE in the COAST program is consistent with the previously established long-term safety profile. IXE Q4W provided sustained improvement of disease activity in patients who received treatment through 3 years. (ClinicalTrials.gov: NCT02696785 [COAST-V], NCT02696798 [COAST-W], NCT02757352 [COAST-X], and NCT03129100 [COAST-Y]).
Topics: Humans; Treatment Outcome; Double-Blind Method; Dermatologic Agents; Spondylitis, Ankylosing
PubMed: 36792107
DOI: 10.3899/jrheum.221022 -
Frontiers in Immunology 2023The impact of inflammatory factors on the development of Ankylosing Spondylitis (AS) is widely recognized, but the exact causal relationship remains unclear.
BACKGROUND
The impact of inflammatory factors on the development of Ankylosing Spondylitis (AS) is widely recognized, but the exact causal relationship remains unclear.
METHODS
The bidirectional mendelian-randomization study utilized genetic data from a genome-wide association study (GWAS) of 186 AS cases and 456,162 controls of European ancestry. Inflammatory cytokines were obtained from a GWAS summary of 8,293 healthy participants. Causal associations were primarily investigated using the inverse variance-weighted method, supplemented by MR Egger, weighted median and weighted mode analyses. Heterogeneity in the results was assessed using the Cochrane Q test. Horizontal pleiotropy was evaluated through the MR-Egger intercept test and the MR pleiotropy residual sum and outliers (MR-PRESSO) test. Sensitivity analysis was conducted through leave-one-out analysis.
RESULTS
The results suggest a genetically predicted potential association between beta-nerve growth factor (βNGF), Interleukin-1-beta (IL-1β), and TNF-related apoptosis inducing ligand (TRAIL) with the risk of AS (OR: 2.17, 95% CI: 1.13-4.16; OR: 0.41, 95% CI: 0.18-0.95,; OR: 1.47, 95% CI: 1.02-2.13).Additionally, Interleukin-12p70 (IL-12p70), Interleukin-17 (IL-17), Interleukin-6 (IL-6), Interleukin-4 (IL-4), Stromal-cell-derived factor 1 alpha (SDF-1α), Macrophage inflammatory protein 1β (MIP1β), Monocyte chemoattractant protein-3 (MCP-3), Platelet-derived growth factor bb (PDGFbb), Granulocyte-colony stimulating factor (GCSF), Fibroblast growth factor basic (bFGF), TNF-related apoptosis inducing ligand (TRAIL), and Interferon-gamma (IFN -γ) are suggested as consequences of AS in genetically prediction.No evidence of horizontal pleiotropy or heterogeneity between the genetic variants was found (P>0.05), and a leave-one-out test confirmed the stability and robustness of this association.
CONCLUSION
These findings suggest that βNGF, IL-1β, and TRAIL may play a crucial role in the pathogenesis of AS. Additionally, AS may impact the expression of cytokines such as IL-12p70, IL-17, IL-6, IL-4, SDF-1α, MIP1β, MCP-3, PDGFbb,GCSF, bFGF,TRAIL,and IFN-γ. Further investigations are warranted to determine whether these biomarkers can be utilized for the prevention or treatment of AS.
Topics: Humans; Cytokines; Interleukin-17; Interleukin-4; Interleukin-6; Chemokine CXCL12; Genome-Wide Association Study; Ligands; Random Allocation; Spondylitis, Ankylosing; Interleukin-12; Granulocyte Colony-Stimulating Factor; Interferon-gamma; Becaplermin
PubMed: 38054001
DOI: 10.3389/fimmu.2023.1285106 -
Nature Medicine Nov 2023Autoimmunity is intrinsically driven by memory T and B cell clones inappropriately targeted at self-antigens. Selective depletion or suppression of self-reactive T cells...
Autoimmunity is intrinsically driven by memory T and B cell clones inappropriately targeted at self-antigens. Selective depletion or suppression of self-reactive T cells remains a holy grail of autoimmune therapy, but disease-associated T cell receptors (TCRs) and cognate antigenic epitopes remained elusive. A TRBV9-containing CD8 TCR motif was recently associated with the pathogenesis of ankylosing spondylitis, psoriatic arthritis and acute anterior uveitis, and cognate HLA-B*27-presented epitopes were identified. Following successful testing in nonhuman primate models, here we report human TRBV9 T cell elimination in ankylosing spondylitis. The patient achieved remission within 3 months and ceased anti-TNF therapy after 5 years of continuous use. Complete remission has now persisted for 4 years, with three doses of anti-TRBV9 administered per year. We also observed a profound improvement in spinal mobility metrics and the Bath Ankylosing Spondylitis Metrology Index (BASMI). This represents a possibly curative therapy of an autoimmune disease via selective depletion of a TRBV-defined group of T cells. The anti-TRBV9 therapy could potentially be applicable to other HLA-B*27-associated spondyloarthropathies. Such targeted elimination of the underlying cause of the disease without systemic immunosuppression could offer a new generation of safe and efficient therapies for autoimmunity.
Topics: Humans; Epitopes; HLA-B Antigens; Immunotherapy; Receptors, Antigen, T-Cell; Spondylitis, Ankylosing; T-Lymphocytes; Tumor Necrosis Factor Inhibitors
PubMed: 37872223
DOI: 10.1038/s41591-023-02613-z