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Annals of the Rheumatic Diseases Sep 2023The transition from psoriasis (PsO) to psoriatic arthritis (PsA) and the early diagnosis of PsA is of considerable scientific and clinical interest for the prevention...
BACKGROUND
The transition from psoriasis (PsO) to psoriatic arthritis (PsA) and the early diagnosis of PsA is of considerable scientific and clinical interest for the prevention and interception of PsA.
OBJECTIVE
To formulate EULAR points to consider (PtC) for the development of data-driven guidance and consensus for clinical trials and clinical practice in the field of prevention or interception of PsA and for clinical management of people with PsO at risk for PsA development.
METHODS
A multidisciplinary EULAR task force of 30 members from 13 European countries was established, and the EULAR standardised operating procedures for development for PtC were followed. Two systematic literature reviews were conducted to support the task force in formulating the PtC. Furthermore, the task force proposed nomenclature for the stages before PsA, through a nominal group process to be used in clinical trials.
RESULTS
Nomenclature for the stages preceding PsA onset, 5 overarching principles and 10 PtC were formulated. Nomenclature was proposed for three stages towards PsA development, namely people with PsO at higher risk of PsA, subclinical PsA and clinical PsA. The latter stage was defined as PsO and associated synovitis and it could be used as an outcome measure for clinical trials evaluating the transition from PsO to PsA. The overarching principles address the nature of PsA at its onset and underline the importance of collaboration of rheumatologists and dermatologists for strategies for prevention/interception of PsA. The 10 PtC highlight arthralgia and imaging abnormalities as key elements of subclinical PsA that can be used as potential short-term predictors of PsA development and useful items to design clinical trials for PsA interception. Traditional risk factors for PsA development (ie, PsO severity, obesity and nail involvement) may represent more long-term disease predictors and be less robust for short-term trials concerning the transition from PsO to PsA.
CONCLUSION
These PtC are helpful to define the clinical and imaging features of people with PsO suspicious to progress to PsA. This information will be helpful for identification of those who could benefit from a therapeutic intervention to attenuate, delay or prevent PsA development.
Topics: Humans; Arthritis, Psoriatic; Psoriasis; Nails; Risk Factors; Europe
PubMed: 37295926
DOI: 10.1136/ard-2023-224148 -
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 -
Frontiers in Immunology 2023Interleukin-17 family (IL-17s) comprises six structurally related members (IL-17A to IL-17F); sequence homology is highest between IL-17A and IL-17F, displaying certain... (Review)
Review
Interleukin-17 family (IL-17s) comprises six structurally related members (IL-17A to IL-17F); sequence homology is highest between IL-17A and IL-17F, displaying certain overlapping functions. In general, IL-17A and IL-17F play important roles in chronic inflammation and autoimmunity, controlling bacterial and fungal infections, and signaling mainly through activation of the nuclear factor-kappa B (NF-κB) pathway. The role of IL-17A and IL-17F has been established in chronic immune-mediated inflammatory diseases (IMIDs), such as psoriasis (PsO), psoriatic arthritis (PsA), axial spondylarthritis (axSpA), hidradenitis suppurativa (HS), inflammatory bowel disease (IBD), multiple sclerosis (MS), and asthma. CD4 helper T cells (Th17) activated by IL-23 are well-studied sources of IL-17A and IL-17F. However, other cellular subtypes can also produce IL-17A and IL-17F, including gamma delta (γδ) T cells, alpha beta (αβ) T cells, type 3 innate lymphoid cells (ILC3), natural killer T cells (NKT), or mucosal associated invariant T cells (MAIT). Interestingly, the production of IL-17A and IL-17F by innate and innate-like lymphocytes can take place in an IL-23 independent manner in addition to IL-23 classical pathway. This would explain the limitations of the inhibition of IL-23 in the treatment of patients with certain rheumatic immune-mediated conditions such as axSpA. Despite their coincident functions, IL-17A and IL-17F contribute independently to chronic tissue inflammation having somehow non-redundant roles. Although IL-17A has been more widely studied, both IL-17A and IL-17F are overexpressed in PsO, PsA, axSpA and HS. Therefore, dual inhibition of IL-17A and IL-17F could provide better outcomes than IL-23 or IL-17A blockade.
Topics: Humans; Arthritis, Psoriatic; Chronic Disease; Hidradenitis Suppurativa; Immunity, Innate; Inflammation; Interleukin-17; Interleukin-23; Lymphocytes; Psoriasis
PubMed: 37600764
DOI: 10.3389/fimmu.2023.1191782 -
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 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 -
International Journal of Molecular... Oct 2023The mechanisms underlying the development of bone damage in the context of spondyloarthritis (SpA) are not completely understood. To date, a considerable amount of... (Review)
Review
The mechanisms underlying the development of bone damage in the context of spondyloarthritis (SpA) are not completely understood. To date, a considerable amount of evidence indicates that several developmental pathways are crucially involved in osteoimmunology. The present review explores the biological mechanisms underlying the relationship between inflammatory dysregulation, structural progression, and osteoporosis in this diverse family of conditions. We summarize the current knowledge of bone biology and balance and the foundations of bone regulation, including bone morphogenetic protein, the Wnt pathway, and Hedgehog signaling, as well as the role of cytokines in the development of bone damage in SpA. Other areas surveyed include the pathobiology of bone damage and systemic bone loss (osteoporosis) in SpA and the effects of pharmacological treatment on focal bone damage. Lastly, we present data relative to a survey of bone metabolic assessment in SpA from Italian bone specialist rheumatology centers. The results confirm that most of the attention to bone health is given to postmenopausal subjects and that the aspect of metabolic bone health may still be underrepresented. In our opinion, it may be the time for a call to action to increase the interest in and focus on the diagnosis and management of SpA.
Topics: Humans; Hedgehog Proteins; Spondylarthritis; Bone and Bones; Wnt Signaling Pathway; Osteoporosis
PubMed: 37834372
DOI: 10.3390/ijms241914924 -
International Journal of Molecular... Jul 2023Psoriasis is a chronic inflammatory skin disease with autoimmune pathological characteristics. Recent research has found a link between psoriasis, inflammation, and gut... (Clinical Trial)
Clinical Trial
Psoriasis is a chronic inflammatory skin disease with autoimmune pathological characteristics. Recent research has found a link between psoriasis, inflammation, and gut microbiota dysbiosis, and that probiotics and prebiotics provide benefits to patients. This 12-week open-label, single-center clinical trial evaluated the efficacy of probiotics ( (HU36), (HU58), (SC208), (SL307), and (SC109)) and precision prebiotics (fructooligosaccharides, xylooligosaccharides, and galactooligosaccharides) in patients with psoriasis receiving topical therapy, with an emphasis on potential metabolic, immunological, and gut microbiota changes. In total, 63 patients were evaluated, with the first 42 enrolled patients assigned to the intervention group and the next 21 assigned to the control group (2:1 ratio; non-randomized). There were between-group differences in several patient characteristics at baseline, including age, psoriasis severity (the incidence of severe psoriasis was greater in the intervention group than in the control group), the presence of nail psoriasis, and psoriatic arthritis, though it is not clear whether or how these differences may have affected the study findings. Patients with psoriasis receiving anti-psoriatic local therapy and probiotic and prebiotic supplementation performed better in measures of disease activity, including Psoriasis Area and Severity Index, Dermatology Life Quality Index, inflammatory markers, and skin thickness compared with those not receiving supplementation. Furthermore, in the 15/42 patients in the intervention group who received gut microbiota analysis, the gut microbiota changed favorably following 12 weeks of probiotic and prebiotic supplementation, with a shift towards an anti-inflammatory profile.
Topics: Humans; Arthritis, Psoriatic; Gastrointestinal Microbiome; Prebiotics; Probiotics; Psoriasis
PubMed: 37446403
DOI: 10.3390/ijms241311225 -
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 -
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