OBJECTIVES: Our previous studies have demonstrated that the Damage Associated Molecular Pattern (DAMP) protein, S100A4, is overexpressed in the involved skin and peripheral blood of patients with SSc. It is associated with skin and lung involvement, and disease activity. By contrast, lack of S100A4 prevented the development of experimental dermal fibrosis. Herein we aimed to evaluate the effect of murine anti-S100A4 mAb 6B12 in the treatment of preestablished experimental dermal fibrosis. METHODS: The effects of 6B12 were assessed at therapeutic dosages in a modified bleomycin-induced dermal fibrosis mouse model by evaluating fibrotic (dermal thickness, proliferation of myofibroblasts, hydroxyproline content, phosphorylated Smad3-positive cell count) and inflammatory (leukocytes infiltrating the lesional skin, systemic levels of selected cytokines and chemokines) outcomes, and transcriptional profiling (RNA sequencing). RESULTS: Treatment with 7.5 mg/kg 6B12 attenuated and might even reduce pre-existing dermal fibrosis induced by bleomycin as evidenced by reduction in dermal thickness, myofibroblast count and collagen content. These antifibrotic effects were mediated by the downregulation of TGF-β/Smad signalling and partially by reducing the number of leukocytes infiltrating the lesional skin and decrease in the systemic levels of IL-1α, eotaxin, CCL2 and CCL5. Moreover, transcriptional profiling demonstrated that 7.5 mg/kg 6B12 also modulated several profibrotic and proinflammatory processes relevant to the pathogenesis of SSc. CONCLUSION: Targeting S100A4 by the 6B12 mAb demonstrated potent antifibrotic and anti-inflammatory effects on bleomycin-induced dermal fibrosis and provided further evidence for the vital role of S100A4 in the pathophysiology of SSc.
- MeSH
- alarminy * MeSH
- bleomycin toxicita MeSH
- fibróza MeSH
- kůže * patologie MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- monoklonální protilátky farmakologie MeSH
- myši MeSH
- S100 kalcium vázající protein A4 genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
OBJECTIVES: We aimed to evaluate cardiovascular (CV) risk in patients with idiopathic inflammatory myopathies (IIM) compared with healthy controls (HC) and to assess its association with disease-specific features. METHODS: Ninety IIM patients and 180 age-/sex-matched HC were included. Subjects with a history of CV disease (angina pectoris, myocardial infarction and cerebrovascular/peripheral arterial vascular events) were excluded. All participants were prospectively recruited and underwent examinations of carotid intima-media thickness (CIMT), pulse wave velocity (PWV), ankle-brachial index (ABI), and body composition. The risk of fatal CV events was evaluated by the Systematic COronary Risk Evaluation (SCORE) and its modifications. RESULTS: Compared with HC, IIM patients had a significantly higher prevalence of traditional CV risk factors, carotid artery disease (CARD), abnormal ABI and PWV. After propensity score matching (using traditional CV risk factors), the prevalence of CARD and pathological PWV remained significantly higher in IIM than HC. No significant difference in SCORE was observed. The most unfavourable CV risk profile was observed in patients with necrotizing myopathy, especially in statin-induced anti-HMGCR+ patients. The calculated CV risk scores by SCORE, SCORE2 and SCORE multiplied by the coefficient 1.5 (mSCORE) were reclassified according to CIMT and the presence of carotid plaques. SCORE was demonstrated to be most inaccurate in predicting CV risk in IIM. Age, disease activity, lipid profile, body composition parameters and blood pressure were the most significant predictors of CV risk in IIM patients. CONCLUSION: Significantly higher prevalence of traditional risk factors and subclinical atherosclerosis was observed in IIM patients compared with HC.
- MeSH
- analýza pulzové vlny MeSH
- intimomediální šíře tepenné stěny MeSH
- kardiovaskulární nemoci * epidemiologie etiologie MeSH
- lidé MeSH
- myozitida * epidemiologie MeSH
- nemoci arterie carotis * MeSH
- rizikové faktory kardiovaskulárních chorob MeSH
- rizikové faktory MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Individuals with anti-citrullinated protein antibodies (ACPAs) and subclinical inflammatory changes in joints are at high risk of developing rheumatoid arthritis. Treatment strategies to intercept this pre-stage clinical disease remain to be developed. We aimed to assess whether 6-month treatment with abatacept improves inflammation in preclinical rheumatoid arthritis. METHODS: The abatacept reversing subclinical inflammation as measured by MRI in ACPA positive arthralgia (ARIAA) study is a randomised, international, multicentre, double-blind, placebo-controlled trial done in 14 hospitals and community centres across Europe (11 in Germany, two in Spain, and one in the Czech Republic). Adults (aged ≥18 years) with ACPA positivity, joint pain (but no swelling), and signs of osteitis, synovitis, or tenosynovitis in hand MRI were randomly assigned (1:1) to weekly subcutaneous abatacept 125 mg or placebo for 6 months followed by a double-blind, drug-free, observation phase for 12 months. The primary outcome was the proportion of participants with any reduction in inflammatory MRI lesions at 6 months. The primary efficacy analysis was done in the modified intention-to-treat population, which included participants who were randomly assigned and received study medication. Safety analyses were conducted in participants who received the study medication and had at least one post-baseline observation. The study was registered with the EUDRA-CT (2014-000555-93). FINDINGS: Between Nov 6, 2014, and June 15, 2021, 139 participants were screened. Of 100 participants, 50 were randomly assigned to abatacept 125 mg and 50 to placebo. Two participants (one from each group) were excluded due to administration failure or refusing treatment; thus, 98 were included in the modified intention-to-treat population. 70 (71%) of 98 participants were female and 28 (29%) of 98 were male. At 6 months, 28 (57%) of 49 participants in the abatacept group and 15 (31%) of 49 participants in the placebo group showed improvement in MRI subclinical inflammation (absolute difference 26·5%, 95% CI 5·9-45·6; p=0·014). Four (8%) of 49 participants in the abatacept group and 17 (35%) of 49 participants in the placebo group developed rheumatoid arthritis (hazard ratio [HR] 0·14 [0·04-0·47]; p=0·0016). Improvement of MRI inflammation (25 [51%] of 49 participants in the abatacept group, 12 [24%] of 49 in the placebo group; p=0·012) and progression to rheumatoid arthritis (17 [35%] of 49, 28 [57%] of 49; HR 0·14 [0·04-0·47]; p=0·018) remained significantly different between the two groups after 18 months, 12 months after the end of the intervention. There were 12 serious adverse events in 11 participants (four [8%] of 48 in the abatacept group and 7 [14%] of 49 in the placebo group). No deaths occurred during the study. INTERPRETATION: 6-month treatment with abatacept decreases MRI inflammation, clinical symptoms, and risk of rheumatoid arthritis development in participants at high risk. The effects of the intervention persist through a 1-year drug-free observation phase. FUNDING: Innovative Medicine Initiative.
- MeSH
- abatacept škodlivé účinky MeSH
- antirevmatika * škodlivé účinky MeSH
- artralgie chemicky indukované MeSH
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- revmatoidní artritida * diagnostické zobrazování farmakoterapie MeSH
- výsledek terapie MeSH
- zánět farmakoterapie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
Axiální spondyloartritida je chronické revmatické onemocnění postihující osový skelet, periferní klouby a mimokloubní struktury. Cílem léčby je potlačit zánětlivou aktivitu a zabránit strukturálnímu poškození, aby se minimalizovala bolest a ztuhlost a zachovala pohyblivost a dobrá kvalita života pacientů. Interleukiny (IL) 17A a 17F jsou prozánětlivé cytokiny, které hrají důležitou roli v patogenezi axiální spondyloartritidy. IL-17F je u pacientů s axiální spondyloartritidou zvýšeně exprimován, i když je biologicky méně aktivní než IL-17A. Nicméně kombinovaná inhibice obou těchto cytokinů ukázala v in vitro experimentech lepší účinnost ve snižování zánětlivé aktivity než samostatná inhibice jednoho z nich. Bimekizumab je první monoklonální protilátka, která selektivně tlumí interakci IL-17A i IL-17F s jejich receptory. V klinických hodnoceních byla prokázána jeho účinnost a bezpečnost u pacientů s axiální spondyloartritidou. Pacienti, kteří užívali bimekizumab, dosáhli signifikantně lepší klinické odpovědi podle kritérií ASAS (Assessment of SpondyloArthritis International Society) a výraznějšího zmírnění objektivních ukazatelů zánětu než pacienti užívající placebo. Léčba byla účinná nezávisle na předchozí terapii a bimekizumab byl obecně dobře snášen. Mezi nejčastější nežádoucí účinky patřily nasofaryngitida a infekce horních cest dýchacích. Plísňové infekce byly pozorovány častěji než u placeba, ale závažné infekce a kardiovaskulární příhody byly vzácné. Bimekizumab byl na podkladě těchto klinických hodnocení schválen pro léčbu ankylozující spondylitidy, neradiografické axiální spondyloartritidy a aktivní psoriatické artritidy. Pro konstatování vyšší účinnosti kombinované inhibice IL-17A a IL-17F u spondyloartritid, jako bylo prokázáno u psoriázy, zatím chybí srovnávací klinická hodnocení. Celkově lze konstatovat, že bimekizumab je účinný a dobře snášený biologický lék pro pacienty s axiální spondyloartritidou a představuje novou naději v léčbě tohoto onemocnění.
Axial spondyloarthritis is a chronic rheumatic disease affecting the axial skeleton, peripheral joints and extraarticular structures. The goal of treatment is to suppress inflammatory activity and prevent structural damage in order to minimize pain and stiffness and to preserve mobility and good quality of life of the patients. Interleukins (IL) 17A and 17F are pro-inflammatory cytokines that play an important role in the pathogenesis of axial spondyloarthritis. IL-17F is elevatedly expressed in patients with axial spondyloarthritis, although it is biologically less active than IL-17A. However, combined inhibition of both of these cytokines has shown better efficacy in reducing inflammatory activity in in vitro experiments than inhibition of either cytokine alone. Bimekizumab is the first monoclonal antibody that selectively inhibits the interaction of both IL-17A and IL-17F with their receptors. Its efficacy and safety have been demonstrated in clinical trials in patients with axial spondyloarthritis. Patients treated with bimekizumab achieved a significantly greater improvement in ASAS (Assessment of SpondyloArthritis International Society) clinical response and reduction in objective markers of inflammation than patients taking placebo. Treatment was effective independently of prior therapy and bimekizumab was generally well tolerated. The most common adverse effects were nasopharyngitis and upper respiratory tract infections. Fungal infections were seen more frequently than in placebo arm, but serious infections and cardiovascular events were rare. Based on these clinical trials, bimekizumab was approved for the treatment of ankylosing spondylitis, non-radiographic axial spondyloarthritis and active psoriatic arthritis. Comparative clinical trials are not yet available to conclude that combined IL-17A and IL-17F inhibition is more effective in spondyloarthritis, as has been demonstrated in psoriasis. Overall, bimekizumab is an effective and well-tolerated biologic for patients with axial spondyloarthritis and represents a new hope in the treatment of this disease.
OBJECTIVES: IL-37 is an anti-inflammatory cytokine involved in inflammatory and autoimmune diseases. We aimed to investigate the association between IL-37 genetic variants, IL-37 plasma levels, and various clinical phases of gout. METHODS: The study included a control group with no history of primary hyperuricemia/gout, (n = 50), asymptomatic hyperuricemia (n = 74), intercritical gout (n = 200), acute gouty flare (n = 18), and chronic tophaceous gout (n = 30). Plasma IL-37 was analysed using enzyme-linked immunosorbent assay. All coding regions and intron-exon boundaries of IL-37 and exons 1-5 were amplified and sequenced. RESULTS: Plasma levels of IL-37 were significantly higher in asymptomatic hyperuricemic (p = 0.045), intercritical gout (p = 0.001), and chronic tophaceous gout (p = 0.021) cohorts when compared to control group. The levels of IL-37 in patients with acute gouty flare were comparable to control group (p = 0.061). We identified 15 genetic variants of IL-37: eight intron (rs2708959, rs2723170, rs2708958, rs2723169 rs2466448, rs3811045, rs3811048, rs2708944) and seven non-synonymous allelic variants (rs3811046, rs3811047, rs2708943, rs2723183, rs2723187, rs2708947, rs27231927), of which rs2708959 showed an over-presentation in gouty and acute flare cohorts (p = 0.003 and 0.033, respectively) compared to European population (minor allelic frequency MAF = 0.05) but not in control and hyperuricemic cohorts (p/MAF = 0.17/0.08 and 0.71/0.05, respectively).. On the contrary, rs3811045, rs3811046, rs3811047, and rs3811048 were underrepresented among individuals with tophaceous gout (MAF = 0.57) compared to European MAF 0.70-0.71, but not compared to the control cohort (MAF = 0.67). CONCLUSIONS: We demonstrated the up-regulation of IL-37 levels across the clinical phases of gout: asymptomatic hyperuricemia, intercritical, and chronic tophaceous gout compared to control. Moreover, 15 genetic variants of IL-37 were identified and their associations with the clinical variants of gout were evaluated.
- MeSH
- dna (nemoc) * epidemiologie MeSH
- dnavá artritida * MeSH
- hyperurikemie * genetika MeSH
- interleukin-1beta MeSH
- kyselina močová MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Revmatologie zažívá v posledních letech významný pokrok, který je důsledkem zdůrazňování časné diagnostiky a uplatňo- vání principů léčby k cíli, stejně jako nových imunopatogenetických poznatků a dostupnosti širokého spektra biologických a cílených syntetických léčivých přípravků. V tomto sdělení přinášíme nové poznatky z oblasti diagnostiky a léčby vybraných revmatických onemocnění, a to konkrétně revmatoidní artritidy, spondyloartritid, systémového lupus erythematodes, systémové sklerodermie, idiopatických zánětlivých myopatií, systémových vaskulitid, revmatické polymyalgie a obrov- skobuněčné arteriiitidy a také osteoartrózy. Toto sdělení si klade za cíl přinést souhrn nejnovějších poznatků a trendů v diagnostice a léčbě těchto revmatických onemocnění, které mají zásadní vliv na kvalitu života pacientů.
Rheumatology has experienced significant advances in recent years as a result of the emphasis on early diagnosis and the application of treat-to-target principles, as well as new immunopathogenetic findings and the availability of a wide range of biologic and targeted synthetic drugs. In this communication, we present new findings in the diagnosis and treatment of selected rheumatic diseases, specifically rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, systemic scleroderma, idiopathic inflammatory myopathies, systemic vasculitis, rheumatic polymyalgia and giant cell arteritis, and osteoarthritis. This communication aims to provide a summary of the latest findings and trends in the diagnosis and treatment of these rheumatic diseases, which have a major impact on the quality of life of patients.
- MeSH
- ANCA-asociované vaskulitidy diagnóza farmakoterapie MeSH
- antirevmatika aplikace a dávkování farmakologie terapeutické užití MeSH
- axiální spondyloartritida diagnóza farmakoterapie komplikace MeSH
- biologická terapie metody MeSH
- imunoterapie adoptivní metody MeSH
- inhibitory Janus kinas aplikace a dávkování farmakologie terapeutické užití MeSH
- intravenózní imunoglobuliny aplikace a dávkování terapeutické užití MeSH
- methotrexát aplikace a dávkování terapeutické užití MeSH
- monoklonální protilátky aplikace a dávkování farmakologie terapeutické užití MeSH
- myozitida diagnóza farmakoterapie imunologie MeSH
- obrovskobuněčná arteritida diagnóza farmakoterapie MeSH
- osteoartróza diagnóza farmakoterapie MeSH
- polymyalgia rheumatica diagnóza terapie MeSH
- psoriatická artritida diagnóza farmakoterapie komplikace MeSH
- revmatické nemoci * diagnóza farmakoterapie komplikace MeSH
- revmatoidní artritida diagnóza farmakoterapie komplikace MeSH
- rizikové faktory MeSH
- systémová sklerodermie diagnóza farmakoterapie komplikace MeSH
- systémový lupus erythematodes diagnóza farmakoterapie komplikace MeSH
