Opening Lecture BARALIAKOS, Xenofon
Journal of clinical rheumatology and immunology (Online),
11/2023, Letnik:
23, Številka:
Supp01
Journal Article
Recenzirano
Odprti dostop
Ankylosing spondylitis (AS), also referred to as radiographic axial spondyloarthritis (r-axSpA), is a challenging, inflammatory rheumatic condition primarily impacting the sacroiliac joints and often ...extending to the spine. The prevalence of axSpA, encompassing both radiographic AS and non-radiographic axSpA, is estimated to vary between 0.2% and 0.5% among Chinese adults, depending on the classification criteria employed.
Treatment objectives for AS focus on improving the patient’s quality of life, function, and social involvement by managing inflammation and other disease symptoms. To achieve these goals, the American College of Rheumatology (ACR), the Spondylitis Association of America (SAA), and the Spondyloarthritis Research and Treatment Network (SPARTAN) advocate the use of non-steroidal anti-inflammatory drugs (NSAIDs) as the first-line treatment for AS, followed by biologic disease-modifying anti-rheumatic drugs (bDMARDs) like TNF inhibitors. While it has been common practice to initiate treatment with a TNF inhibitor or IL-17 inhibitor, the updated recommendations from the Assessment of SpondyloArthritis International Society (ASAS) and the European League Against Rheumatism (EULAR) now suggest the consideration of Janus kinase (JAK) inhibitors for patients with persistent high disease activity despite conventional therapy. Furthermore, the updated guidelines propose switching to another biologic DMARD (TNF inhibitor or IL-17 inhibitor) or JAK inhibitor if the first biologic DMARD proves ineffective.
Despite recent advancement, there remains an unmet need for effective therapies in the treatment of AS. Across various biologic studies, only 40-50% of patients achieve an ASAS40 response. Moreover, approximately one-third of patients fail to attain low disease activity according to the Ankylosing Spondylitis Disease Activity Score (ASDAS), and 65% do not achieve inactive disease status on ASDAS after one year of bDMARD therapy. There is a lack of oral treatment options for AS beyond NSAIDs, as all current biologics are administered via injection or infusion. Targeting JAK-mediated pathways with an oral option holds promise as a potential approach for treating adult AS patients.
Secukinumab is an anti-interleukin-17A monoclonal antibody that has been shown to control the symptoms of ankylosing spondylitis in a phase 2 trial. We conducted two phase 3 trials of secukinumab in ...patients with active ankylosing spondylitis.
In two double-blind trials, we randomly assigned patients to receive secukinumab or placebo. In MEASURE 1, a total of 371 patients received intravenous secukinumab (10 mg per kilogram of body weight) or matched placebo at weeks 0, 2, and 4, followed by subcutaneous secukinumab (150 mg or 75 mg) or matched placebo every 4 weeks starting at week 8. In MEASURE 2, a total of 219 patients received subcutaneous secukinumab (150 mg or 75 mg) or matched placebo at baseline; at weeks 1, 2, and 3; and every 4 weeks starting at week 4. At week 16, patients in the placebo group were randomly reassigned to subcutaneous secukinumab at a dose of 150 mg or 75 mg. The primary end point was the proportion of patients with at least 20% improvement in Assessment of Spondyloarthritis International Society (ASAS20) response criteria at week 16.
In MEASURE 1, the ASAS20 response rates at week 16 were 61%, 60%, and 29% for subcutaneous secukinumab at doses of 150 mg and 75 mg and for placebo, respectively (P<0.001 for both comparisons with placebo); in MEASURE 2, the rates were 61%, 41%, and 28% for subcutaneous secukinumab at doses of 150 mg and 75 mg and for placebo, respectively (P<0.001 for the 150-mg dose and P=0.10 for the 75-mg dose). The significant improvements were sustained through 52 weeks. Infections, including candidiasis, were more common with secukinumab than with placebo during the placebo-controlled period of MEASURE 1. During the entire treatment period, pooled exposure-adjusted incidence rates of grade 3 or 4 neutropenia, candida infections, and Crohn's disease were 0.7, 0.9, and 0.7 cases per 100 patient-years, respectively, in secukinumab-treated patients.
Secukinumab at a subcutaneous dose of 150 mg, with either subcutaneous or intravenous loading, provided significant reductions in the signs and symptoms of ankylosing spondylitis at week 16. Secukinumab at a subcutaneous dose of 75 mg resulted in significant improvement only with a higher intravenous loading dose. (Funded by Novartis Pharma; ClinicalTrials.gov numbers, NCT01358175 and NCT01649375.).
In patients with axial spondyloarthritis (axSpA), pain, functional and structural impairments, reduced mobility and potential deformity of the axial skeleton are the most prominent health concerns. ...Limitations in physical function and spinal mobility are caused by both inflammation and structural damage, and therefore restrictions to physical function must be monitored throughout a patient's life. Consequently, the assessment of physical function is recommended as a key domain in the Assessment of Spondyloarthritis International Society-OMERACT Core Outcome Set. However, in comparison with disease activity, physical function seems to be a relatively neglected target of intervention in patients with axSpA, even though physical function is a major contributor to costs and disability in this disease. This Review aims to reacquaint rheumatologists with the targets for physical function, physical activity and performance by giving guidance on determinants of physical function and how physical function can be examined in patients with axSpA.
Editorial II Baraliakos, Xenofon
Revista argentina de reumatologiá (Buenos Aires, Argentina : 1990),
03/2020, Letnik:
31, Številka:
1
Journal Article
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La inflamación espinal es una de las más importantes características de la espondilitis anquilosante (EA), ya que determina el dolor y la disfunción espinal. Actualmente, la inflamación de la columna ...se evalúa principalmente a través de los pacientes informados resultados y puede estar sujeto a factores individuales e interferencias. Las imágenes por resonancia magnética (IRM) han demostrado su valor en la detección de edema e inflamación ósea y han sido incluidas en los nuevos criterios de Evaluación de la Sociedad Internacional de Espondiloartritis (ASAS). Poco a poco, la resonancia se impuso debido a su mayor sensibilidad en comparación con Rayos X, especialmente en lesiones tempranas y en ensayos clínicos.
Abstract
Axial SpA (axSpA) is a common rheumatic disease characterized by inflammation leading to bone formation and functional impairment. TNF-α and IL-17 represent established targets in axSpA. ...TNF-α and IL-17 inhibitors have demonstrated efficacy in clinical trials and are currently approved biologic DMARDs for all subsets of the disease. Several lines of evidence implicate a role of an IL-23–IL-17 axis in the disease pathogenesis. In this light, and given the success of IL-17 blockade in axSpA, a similar good response to IL-23 was anticipated. Nevertheless, two clinical trials of anti-IL-23 monoclonal antibodies in axSpA have clearly exhibited negative results. This failure has raised theories for a degree of IL-23 independent pathway. The Janus kinase (JAK) pathway is also a potential therapeutic target, since several cytokines, including those involved in the IL-23–IL-17 axis, signal through the JAK family of tyrosine kinases. Further studies and more extended evaluation of response to cytokine inhibition across different tissues will be required to improve our understanding of SpA pathogenesis and determine its optimal management.
To update and integrate the recommendations for ankylosing spondylitis and the recommendations for the use of tumour necrosis factor inhibitors (TNFi) in axial spondyloarthritis (axSpA) into one set ...applicable to the full spectrum of patients with axSpA. Following the latest version of the European League Against Rheumatism (EULAR) Standardised Operating Procedures, two systematic literature reviews first collected the evidence regarding all treatment options (pharmacological and non-pharmacological) that were published since 2009. After a discussion of the results in the steering group and presentation to the task force, overarching principles and recommendations were formulated, and consensus was obtained by informal voting. A total of 5 overarching principles and 13 recommendations were agreed on. The first three recommendations deal with personalised medicine including treatment target and monitoring. Recommendation 4 covers non-pharmacological management. Recommendation 5 describes the central role of non-steroidal anti-inflammatory drugs (NSAIDs) as first-choice drug treatment. Recommendations 6-8 define the rather modest role of analgesics, and disprove glucocorticoids and conventional synthetic disease-modifying antirheumatic drugs (DMARDs) for axSpA patents with predominant axial involvement. Recommendation 9 refers to biological DMARDs (bDMARDs) including TNFi and IL-17 inhibitors (IL-17i) for patients with high disease activity despite the use (or intolerance/contraindication) of at least two NSAIDs. In addition, they should either have an elevated C reactive protein and/or definite inflammation on MRI and/or radiographic evidence of sacroiliitis. Current practice is to start with a TNFi. Switching to another TNFi or an IL-17i is recommended in case TNFi fails (recommendation 10). Tapering, but not stopping a bDMARD, can be considered in patients in sustained remission (recommendation 11). The final two recommendations (12, 13) deal with surgery and spinal fractures. The 2016 Assessment of SpondyloArthritis international Society-EULAR recommendations provide up-to-date guidance on the management of patients with axSpA.
Abstract
Background
Accumulating evidence supports the role of monocytes and neutrophils in radiographic axSpA (r-axSpA). Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a growth factor ...for both leukocyte lineages and a pro-inflammatory cytokine activating myeloid cells and promoting osteoclastogenesis. It acts through the JAK-STAT pathway. We measured serum GM-CSF and markers of bone metabolism in patients with r-axSpA before and after anti-TNF treatment.
Methods
Patients with active r-axSpA despite treatment with NSAIDs, all eligible for treatment with a biologic agent, were recruited. Healthy donors were sampled as controls. Serum was collected before (baseline) and after 4–6 months (follow-up) of anti-TNF treatment and the following molecules were measured with ELISA: GM-CSF, sclerostin (SOST), and dickkopf-1 (Dkk-1).
Results
Twelve r-axSpA patients (7 males, 5 females, median age 37 years) with a median disease duration of 1 year and 16 age- and sex-matched controls were included. At baseline, patients had mean BASDAI 6.3±2 and ASDAS 3.2±0.7, which decreased to 4.1±1.7 and 2.2±0.6 at follow-up, respectively. At baseline, r-axSpA patients had significantly higher mean serum levels of GM-CSF (150 vs 62pg/ml,
p
=0.049), significantly lower Dkk-1 (1228 vs 3052pg/ml,
p
=0.001), but similar levels of SOST (369 vs 544pg/ml,
p
=0.144) compared to controls. Anti-TNF treatment did not affect GM-CSF, Dkk-1, or SOST levels. Spearman correlation analysis showed that GM-CSF correlated positively with ASDAS at baseline (
r
=0.61,
p
=0.039), while no correlations were identified between bone markers (Dkk-1, SOST) on one hand and GM-CSF or disease activity indices on the other.
Conclusions
GM-CSF is increased in patients with active AS and strongly correlates with disease activity. TNF inhibition does not affect GM-SCF levels, despite improving disease activity. GM-CSF may represent an important pathway responsible for residual inflammation during TNF blockade, but also a potential target of JAK inhibitors, explaining their efficacy in r-axSpA.
To review and update the existing definition of a positive MRI for classification of axial spondyloarthritis (SpA).
The Assessment in SpondyloArthritis International Society (ASAS) MRI working group ...conducted a consensus exercise to review the definition of a positive MRI for inclusion in the ASAS classification criteria of axial SpA. Existing definitions and new data relevant to the MRI diagnosis and classification of sacroiliitis and spondylitis in axial SpA, published since the ASAS definition first appeared in print in 2009, were reviewed and discussed. The precise wording of the existing definition was examined in detail and the data and a draft proposal were presented to and voted on by the ASAS membership.
The clear presence of bone marrow oedema on MRI in subchondral bone is still considered to be the defining observation that determines the presence of active sacroiliitis. Structural damage lesions seen on MRI may contribute to a decision by the observer that inflammatory lesions are genuinely due to SpA but are not required to meet the definition. The existing definition was clarified adding guidelines and images to assist in the application of the definition.
The definition of a positive MRI for classification of axial SpA should continue to primarily depend on the imaging features of 'active sacroiliitis' until more data are available regarding MRI features of structural damage in the sacroiliac joint and MRI features in the spine and their utility when used for classification purposes.
To update the evidence on efficacy and safety of biological disease-modifying antirheumatic drugs (bDMARDs) in patients with axial spondyloarthritis (axSpA) to inform the 2022 update of the ...Assessment of SpondyloArthritis international Society/European Alliance of Associations for Rheumatology (ASAS-EULAR) recommendations for the management of axSpA.
Systematic literature review (2016-2021) on efficacy and safety of bDMARDs in axSpA (radiographic axSpA (r-axSpA)/non-radiographic axSpA (nr-axSpA)). Eligible study designs included randomised controlled trials (RCTs), strategy trials and observational studies (the latter only for safety and extra-musculoskeletal manifestations). All relevant efficacy/safety outcomes were included.
In total, 148 publications were included. Efficacy of golimumab and certolizumab was confirmed. Tumour necrosis factor inhibitor (TNFi) biosimilar-originator equivalence was demonstrated. RCT (n=15) data on efficacy of interleukin-17 inhibitors (IL-17i) demonstrated clinically relevant effects (risk ratio vs placebo to achieve ASAS40 response 1.3-15.3 (r-axSpA, n=9), 1.4-2.1 (nr-axSpA, n=2)). Efficacy of secukinumab/ixekizumab was demonstrated in TNFi-naïve and TNFi-inadequate responders. IL-23 and IL-12/23 inhibitors (risankizumab/ustekinumab) failed to show relevant benefits. Tapering of TNFi by spacing was non-inferior to standard-dose treatment. The first axSpA treat-to-target trial did not meet its primary endpoint, but showed improvements in secondary outcomes. No new risks were identified with TNFi use in observational studies (data lacking for IL-17i). Secukinumab (n=1) and etanercept (n=2) were associated with increased risk of uveitis in observational studies compared to monoclonal TNFi.
New evidence supports the efficacy and safety of TNFi (originators/biosimilars) and IL-17i in r-axSpA and nr-axSpA, while IL-23i failed to show relevant effects. Observational studies are needed to confirm long-term IL-17i safety.
CRD42021257588.
Rheumatoid arthritis (RA) is a chronic rheumatic disease with a clear sex-bias. Recent data indicated a role for dopamine in RA pathogenesis, while dopaminergic pathways can be modulated by ...estrogens. As defined mechanism of action of dopamine on B cell function in RA are unclear, we aimed to elucidate this, with special focus on sex-differences. Healthy controls (HC, n = 64) and RA patients (n = 61) were recruited. Expression of D
-D
dopamine receptors (DRs) was investigated by flow cytometry on peripheral blood mononuclear cells (PBMCs). D
-like DRs were stimulated in vitro to assess effects on B cell activation and proliferation. Secretion of cytokines and dopamine content were measured by ELISA. All DRs were expressed on PBMCs of HC and RA patients. Dopamine content in PBMCs, and frequency of D
DR expressing B cells were significantly higher in RA females (p < 0.001). Expression of D
DR on RA B cells correlated positively with disease duration and severity only in women. Combined B cell and D
-like DR stimulation induced higher IL-8 and CCL-3 secretion from PBMCs of female RA patients compared to HC. These results indicate sex-specific differences in dopaminergic pathway in RA, with a proinflammatory feature of the D
DR pathway in women.
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