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1.
Sci Rep ; 11(1): 6063, 2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33727634

RESUMO

S100A11 (calgizzarin), a member of S100 family, is associated with several autoimmune diseases, including rheumatoid arthritis (RA). Neutrophil extracellular traps (NETs) are implicated in the pathogenesis of RA and in the externalization of some S100 family members. Therefore, we aimed to determine the association between S100A11 and NETs in RA. For this purpose, the levels of S100A11 and NETosis markers were detected in the RA synovial fluid by immunoassays. The expression of S100A11 by neutrophils in the RA synovial tissue was assessed. Neutrophils isolated from peripheral blood were exposed to S100A11 or stimulated to release NETs. The levels of NETosis- and inflammation-associated proteins were analysed by immunoassays. NETs were visualized by immunofluorescence. We showed that S100A11 was expressed by the neutrophils in the RA synovial tissue. Moreover, S100A11 in the RA synovial fluid correlated with several NETosis markers. In vitro, S100A11 was abundantly released by neutrophils undergoing NETosis compared to untreated cells (p < 0.001). Extracellular S100A11 increased the secretion of IL-6 (p < 0.05) and TNF (p < 0.05) by neutrophils but did not induce NETosis. This study demonstrates, for the first time, that the release of S100A11 is dependent on NETosis and that extracellular S100A11 augments the inflammatory response by inducing pro-inflammatory cytokines in neutrophils.

2.
Clin Exp Rheumatol ; 2021 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-33666159

RESUMO

OBJECTIVES: To determine the prevalence and distribution of the ultrasound (US) findings indicating cartilage and bone damage at the metacarpal head (MH) in a group of healthy subjects (HS), and their association with the clinical and US data. We also aimed to provide standard reference values of cartilage thickness. METHODS: US scans of the dorsal aspect of the metacarpophalangeal joints (MCPj) from 2nd to 5th finger of both hands were performed in 179 HS. The presence of cartilage damage, osteophytes and bone erosions was recorded. RESULTS: Cartilage damage, osteophytes and bone erosions were found in at least one MCPj in 30 (16.8%), 17 (9.5%) and 4 (2.2%) out of 179 HS, respectively. Signs of cartilage damage were found in 91 out of 1432 MHs (6.4%). Blurring of the chondrosynovial margin, minimal and severe thinning were detected in 73.7%, 26.3% and 0% of the 91 MHs, respectively. Osteophytes and bone erosions were found in 31 (2.2%) and in 4 (0.3%) MCPjs. The thickness of the MH cartilage ranged between 0.41 and 1.10 mm in males and between 0.36 and 1.03 mm in females. A significant association was found between cartilage thickness and age (r=-0.33, p<0.001), sex (rpb=0.42, p<0.001), height (r=0.39, p<0.001) and osteophytes in the same joint (v=-0.54, p<0.001) and between working condition and osteophytes (v=0.31, p=0.021). CONCLUSIONS: This cross-sectional study reports the prevalence of US findings of joint damage in a large cohort of HS. Moreover, standard reference values of the MH cartilage thickness in HS are provided.

3.
Sci Rep ; 11(1): 4719, 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33633196

RESUMO

Individuals carrying anti-citrullinated protein antibodies (ACPA) are considered at high risk of developing rheumatoid arthritis (RA). The altered expression of miRNAs contributes to the pathogenesis of RA. We aimed to identify differentially expressed miRNAs in the peripheral blood of ACPA-positive individuals with arthralgia at risk of RA compared to healthy controls (HC) and to determine their implications in the preclinical phase of RA. A comprehensive analysis of miRNAs revealed the dysregulation of miR-451 in peripheral blood mononuclear cells (PBMC) and plasma from RA-risk individuals. Higher miR-451 expression in PBMC from RA-risk individuals was further validated. Notably, miR-451 was previously shown to regulate CXCL16, a protein involved in RA pathogenesis. The expression of miR-451 in PBMC positively correlated with the CXCL16 mRNA, which could be secondary to the inflammation-induced expression of miR-451. Transfection of monocytes with pre-miR-451 in vitro resulted in the downregulation of CXCL16. Moreover, flow cytometry revealed a lower count of CXCL16-positive monocytes in RA-risk individuals. We propose that the constitutive or inflammation-induced upregulation of miR-451 in PBMC downregulates the expression of CXCL16, reduces the inflammatory milieu and thereby strives to delay the shift from the preclinical phase to the clinical manifestation of RA. This hypothesis warrants further investigation.

4.
Arthritis Res Ther ; 23(1): 11, 2021 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-33407803

RESUMO

BACKGROUND: Treat-to-target (T2T) is a widely accepted strategy for patients with rheumatoid arthritis (RA). It recommends attaining a goal of at least low disease activity (LDA) within 6 months; otherwise, the current therapy should be modified. We aimed to investigate whether switching a first-line targeted therapy (TT) in patients not reaching LDA within 6 months leads to a higher probability of meeting LDA at the 12-month visit in daily clinical practice using data from Czech registry ATTRA. METHODS: We included patients with RA starting the first-line TT from 1 January 2012 to 31 January 2017 with at least 1-year follow-up. We created four mutually exclusive cohorts based on (1) switching to another TT within the first year and (2) reaching a treatment target (DAS28-ESR ≤ 3.2) at the 6-month visit. The primary outcome was the comparison of odds for reaching remission (REM) or LDA at the 12-month visit between patients switching and not switching TT after not reaching treatment target at 6 months. Before using logistic regression to estimate the odds ratio, we employed the propensity score to match patients at the 6-month visit. RESULTS: A total of 1275 patients were eligible for the analysis. Sixty-two patients switched within the first 5 months of the treatment before evaluating treatment response at the 6-month visit (C1); 598 patients reached the treatment target within 6 months of therapy (C2); 124 patients did not reach treatment response at 6-month visit and switched to another therapy (C3), and 491 patients continued with the same treatment despite not reaching LDA at the 6-month visit (C4). We matched 75 patients from cohort C3 and 75 patients from C4 using the propensity score. Patients following the T2T principle (C3) showed 2.8 (95% CI 1.4-5.8; p = 0.005) times increased likelihood of achieving REM/LDA at the 12-month visit compared to patients not following the T2T strategy (C4). CONCLUSIONS: In daily clinical practice, the application of the T2T strategy is underused. Switching TT after not reaching REM/LDA within the first 6 months leads to a higher probability of achieving REM/LDA in RA patients at the 12-month visit.

5.
Biomark Med ; 15(1): 5-13, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33427496

RESUMO

Aim: Heat shock protein 90 (Hsp90) is a molecular chaperone regulating immune response. We aimed to assess systemic Hsp90 as a biomarker for spondyloarthritis (SpA). Materials & methods: Total of 80 axial SpA (axSpA) and 22 psoriatic arthritis patients and a corresponding number of age- and sex-matched healthy controls (HC) were included. Plasma Hsp90 levels were measured by ELISA. Results: Hsp90 was significantly increased in axSpA patients compared with HC (median interquartile range: 15.7 [10.5-19.8] vs 8.3 [6.6-11.8] ng/ml, p < 0.001). Moreover, Hsp90 was superior to C-reactive protein in differentiating axSpA (and both radiographic axSpA [r-axSpA] and nonradiographic-axSpA) from HC. Hsp90 levels correlated with bone marrow edema of sacroiliac joints in r-axSpA patients (r = 0.594, p = 0.019). Conclusion: Hsp90 could become a biomarker for active inflammation in r-axSpA, and can better distinguish axSpA patients from healthy subjects than C-reactive protein.

6.
Sci Rep ; 11(1): 1, 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33414495

RESUMO

Our previous study demonstrated increased expression of Heat shock protein (Hsp) 90 in the skin of patients with systemic sclerosis (SSc). We aimed to evaluate plasma Hsp90 in SSc and characterize its association with SSc-related features. Ninety-two SSc patients and 92 age-/sex-matched healthy controls were recruited for the cross-sectional analysis. The longitudinal analysis comprised 30 patients with SSc associated interstitial lung disease (ILD) routinely treated with cyclophosphamide. Hsp90 was increased in SSc compared to healthy controls. Hsp90 correlated positively with C-reactive protein and negatively with pulmonary function tests: forced vital capacity and diffusing capacity for carbon monoxide (DLCO). In patients with diffuse cutaneous (dc) SSc, Hsp90 positively correlated with the modified Rodnan skin score. In SSc-ILD patients treated with cyclophosphamide, no differences in Hsp90 were found between baseline and after 1, 6, or 12 months of therapy. However, baseline Hsp90 predicts the 12-month change in DLCO. This study shows that Hsp90 plasma levels are increased in SSc patients compared to age-/sex-matched healthy controls. Elevated Hsp90 in SSc is associated with increased inflammatory activity, worse lung functions, and in dcSSc, with the extent of skin involvement. Baseline plasma Hsp90 predicts the 12-month change in DLCO in SSc-ILD patients treated with cyclophosphamide.

7.
Biomolecules ; 11(1)2020 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-33375165

RESUMO

BACKGROUND: The development of hand osteoarthritis (HOA) and its progression into the erosive subset are unclear, but inflammation is suspected to be the main source. To verify the involvement of inflammation in HOA pathogenesis, we evaluate serum inflammatory mediators and their association with HOA-related clinical features in patients. METHODS: 153 participants (50 non-erosive HOA patients, 54 erosive HOA patients, and 49 healthy control subjects) were included in this study. All patients underwent clinical examination, which included assessment of tender and swollen small hand joints, ultrasound (US) examination, and self-reported measures (e.g., AUSCAN or algofunctional indexes). Serum inflammatory mediators were quantified using human cytokine 27-plex immunoassay. We employed linear modelling, correlation analysis, and resampling statistics to evaluate the association of these mediators to HOA. RESULTS: We identified increased levels of nine inflammatory mediators (e.g., eotaxin, monocyte chemoattractant protein 1, interleukin-8, and tumour necrosis factor) in HOA patients compared to healthy controls. Increased mediators correlated with ultrasound findings as well as with clinically tender and swollen joint counts in patients with erosive HOA. However, none of the mediators distinguished between erosive and non-erosive HOA subtypes. CONCLUSION: Our findings support the hypothesis on the involvement of inflammation in HOA.

8.
Artigo em Inglês | MEDLINE | ID: mdl-33119082

RESUMO

OBJECTIVES: Individuals carrying antibodies against citrullinated proteins (ACPA) are at high risk of developing RA. EULAR provided a clinical definition of individuals with arthralgia suspicious for progression to RA (clinically suspect arthralgia, CSA). The alteration of monocyte subpopulations in patients with established RA has been previously described. We analysed peripheral blood monocyte subpopulations in individuals with arthralgia at risk of RA. METHODS: We included 70 at-risk individuals, defined as having arthralgia without arthritis and being either ACPA+ or meeting the clinical CSA definition, 23 patients with early RA (ERA) and 19 healthy controls (HCs). Monocytes classified as classical (CD14++CD16-), intermediate (CD14++CD16+/++) and nonclassical (CD14-/+CD16++) were analysed by flow cytometry. RESULTS: Of the 70 at-risk individuals, 46 were ACPA+ and 45 met the CSA definition. The at-risk individuals and, especially, ERA patients had a lower percentage of classical monocytes and a higher percentage of nonclassical monocytes than the HCs. ACPA positivity had no effect on the difference in the distribution of the monocyte subsets between at-risk individuals and ERA patients, but a difference was determined in those reaching the ERA phase. However, when compared with HCs, the shift of monocyte subsets was more significant in ACPA+ than in ACPA- individuals with arthralgia. This trend was observed in individuals who did not meet the CSA definition. This finding was, however, determined by a selection bias, as these individuals were solely ACPA+. CONCLUSION: The shift from classical to nonclassical monocyte subpopulations was observed already in individuals at risk of developing RA.

9.
Artigo em Inglês | MEDLINE | ID: mdl-33123205

RESUMO

Background: In the randomized, phase III, global SELECT-COMPARE study, upadacitinib 15 mg demonstrated efficacy at week 12 versus placebo and adalimumab with methotrexate (MTX) in patients with rheumatoid arthritis and inadequate response to MTX, which was maintained over 48 weeks. This post hoc analysis of SELECT-COMPARE reports the efficacy and safety of upadacitinib in Central and Eastern European (CEE) patients. Methods: Patients were randomized 2:2:1 to upadacitinib 15 mg once daily, placebo, or adalimumab 40 mg every other week, and continued MTX. Efficacy and safety were assessed through 48 weeks. Primary endpoints were the achievement of ≥20% improvement in American College of Rheumatology response criteria and Disease Activity Score in 28 joints with C-reactive protein <2.6 responses at week 12 for upadacitinib versus placebo. No statistical comparisons were conducted. Results: A total of 596 patients from 12 CEE countries were randomized. At week 12, a numerically greater proportion of patients receiving upadacitinib versus placebo or adalimumab achieved ≥20% improvement in American College of Rheumatology response criteria (72% versus 33% and 59%), Disease Activity Score in 28 joints with C-reactive protein <2.6 (26% versus 4% and 11%), low disease activity and remission, and improved physical function, with results maintained over 48 weeks. Upadacitinib treatment numerically inhibited structural progression versus placebo at week 26. Serious infection and herpes zoster rates were numerically higher with upadacitinib versus adalimumab (2.7 versus 1.7 and 2.3 versus 1.1 events/100 patient-years, respectively) over 48 weeks. Conclusion: Consistent with the global population of patients with rheumatoid arthritis and an inadequate response to MTX, in CEE patients, upadacitinib 15 mg demonstrated clinical and functional improvements versus placebo and adalimumab, radiographic improvements versus placebo, and reasonable safety, over 48 weeks.

10.
RMD Open ; 6(3)2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32950963

RESUMO

OBJECTIVES: To explore 6-month and 12-month secukinumab effectiveness in patients with axial spondyloarthritis (axSpA) overall, as well as across (1) number of previous biologic/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs), (2) time since diagnosis and (3) different European registries. METHODS: Real-life data from 13 European registries participating in the European Spondyloarthritis Research Collaboration Network were pooled. Kaplan-Meier with log-rank test, Cox regression, χ² and logistic regression analyses were performed to assess 6-month and 12-month secukinumab retention, inactive disease/low-disease-activity states (Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) <2/<4, Ankylosing Spondylitis Disease Activity Score (ASDAS) <1.3/<2.1) and response rates (BASDAI50, Assessment of Spondyloarthritis International Society (ASAS) 20/40, ASDAS clinically important improvement (ASDAS-CII) and ASDAS major improvement (ASDAS-MI)). RESULTS: We included 1860 patients initiating secukinumab as part of routine care. Overall 6-month/12-month secukinumab retention rates were 82%/72%, with significant (p<0.001) differences between the registries (6-month: 70-93%, 12-month: 53-86%) and across number of previous b/tsDMARDs (b/tsDMARD-naïve: 90%/73%, 1 prior b/tsDMARD: 83%/73%, ≥2 prior b/tsDMARDs: 78%/66%). Overall 6-month/12-month BASDAI<4 were observed in 51%/51%, ASDAS<1.3 in 9%/11%, BASDAI50 in 53%/47%, ASAS40 in 28%/22%, ASDAS-CII in 49%/46% and ASDAS-MI in 25%/26% of the patients. All rates differed significantly across number of previous b/tsDMARDs, were numerically higher for b/tsDMARD-naïve patients and varied significantly across registries. Overall, time since diagnosis was not associated with secukinumab effectiveness. CONCLUSIONS: In this study of 1860 patients from 13 European countries, we present the first comprehensive real-life data on effectiveness of secukinumab in patients with axSpA. Overall, secukinumab retention rates after 6 and 12 months of treatment were high. Secukinumab effectiveness was consistently better for bionaïve patients, independent of time since diagnosis and differed across the European countries.

11.
Artigo em Inglês | MEDLINE | ID: mdl-32810263

RESUMO

OBJECTIVES: RF and ACPA are used as diagnostic tools and their presence has been associated with clinical response to some biologic DMARDs (bDMARDs) in RA. This study compared the impact of seropositivity on drug discontinuation and effectiveness of bDMARDs in patients with RA, using head-to-head comparisons in a real-world setting. METHODS: We conducted a pooled analysis of 16 observational RA registries. Inclusion criteria were a diagnosis of RA, initiation of treatment with rituximab (RTX), abatacept (ABA), tocilizumab (TCZ) or TNF inhibitors (TNFis) and available information on RF and/or ACPA status. Drug discontinuation was analysed using Cox regression, including drug, seropositivity, their interaction, adjusting for concomitant and past treatments and patient and disease characteristics and accounting for country and calendar year of bDMARD initiation. Effectiveness was analysed using the Clinical Disease Activity Index evolution over time. RESULTS: Among the 27 583 eligible patients, the association of seropositivity with drug discontinuation differed across bDMARDs (P for interaction <0.001). The adjusted hazard ratios for seropositive compared with seronegative patients were 1.01 (95% CI 0.95, 1.07) for TNFis, 0.89 (0.78, 1.02)] for TCZ, 0.80 (0.72, 0.88) for ABA and 0.70 (0.59, 0.84) for RTX. Adjusted differences in remission and low disease activity rates between seropositive and seronegative patients followed the same pattern, with no difference in TNFis, a small difference in TCZ, a larger difference in ABA and the largest difference in RTX (Lundex remission difference +5.9%, low disease activity difference +11.6%). CONCLUSION: Seropositivity was associated with increased effectiveness of non-TNFi bDMARDs, especially RTX and ABA, but not TNFis.

13.
J Clin Med ; 9(8)2020 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-32759716

RESUMO

Urate transporters, which are located in the kidneys, significantly affect the level of uric acid in the body. We looked at genetic variants of genes encoding the major reabsorption proteins GLUT9 (SLC2A9) and URAT1 (SLC22A12) and their association with hyperuricemia and gout. In a cohort of 250 individuals with primary hyperuricemia and gout, we used direct sequencing to examine the SLC22A12 and SLC2A9 genes. Identified variants were evaluated in relation to clinical data, biochemical parameters, metabolic syndrome criteria, and our previous analysis of the major secretory urate transporter ABCG2. We detected seven nonsynonymous variants of SLC2A9. There were no nonsynonymous variants of SLC22A12. Eleven variants of SLC2A9 and two variants of SLC22A12 were significantly more common in our cohort than in the European population (p = 0), while variants p.V282I and c.1002+78A>G had a low frequency in our cohort (p = 0). Since the association between variants and the level of uric acid was not demonstrated, the influence of variants on the development of hyperuricemia and gout should be evaluated with caution. However, consistent with the findings of other studies, our data suggest that p.V282I and c.1002+78A>G (SLC2A9) reduce the risk of gout, while p.N82N (SLC22A12) increases the risk.

14.
RMD Open ; 6(2)2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32683326

RESUMO

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder with a global prevalence of approximately 0.5-1%. Patients with RA are at an increased risk of developing comorbidities (eg, cardiovascular disease, pulmonary disease, diabetes and depression). Despite this, there are limited recommendations for the management and implementation of associated comorbidities. This study aimed to identify good practice interventions in the care of RA and associated comorbidities. METHODS: A combination of primary research (180+ interviews with specialists across 12 European rheumatology centres) and secondary research (literature review of existing publications and guidelines/recommendations) were used to identify challenges in management and corresponding good practice interventions. Findings were prioritised and reviewed by a group of 18 rheumatology experts including rheumatologists, comorbidity experts, a patient representative and a highly specialised nurse. RESULTS: Challenges throughout the patient pathway (including delays in diagnosis and referral, shortage of rheumatologists, limited awareness of primary care professionals) and 18 good practice interventions were identified in the study. The expert group segmented and prioritised interventions according to three distinct stages of the disease: (1) suspected RA, (2) recent diagnosis of RA and (3) established RA. Examples of good practice interventions included enabling self-management (self-monitoring and disease management support, for example, lifestyle adaptations); early arthritis clinic; rapid access to care (online referral, triage, ultrasound-guided diagnosis); dedicated comorbidity specialists; enhanced communication with primary care (hotline, education sessions); and integrating patient registries into daily clinical practice. CONCLUSION: Learning from implementation of good practice interventions in centres across Europe provides an opportunity to more widely improved care for patients with RA and associated comorbidities.

15.
Artigo em Inglês | MEDLINE | ID: mdl-32521015

RESUMO

OBJECTIVE: The objective of this study was to investigate whether diacerein has comparable efficacy with celecoxib in pain reduction for treatment in symptomatic knee OA patients. METHODS: This randomized double-blind multicentre non-inferiority trial evaluated diacerein vs celecoxib treatment in patients with Kellgren-Lawrence grade 2-3 and pain scoring ≥4 (10-cm VAS). Patients were randomized to 6 months of treatment with diacerein 50 mg (n = 187) once daily for 1 month and twice daily thereafter, or celecoxib 200 mg (n = 193) once daily. The primary outcome was the change in WOMAC pain score (0-50 cm) at 6 months, and the secondary outcomes were WOMAC sub-scores, VAS pain score, and the OMERACT-OARSI responder rate. RESULTS: In the per protocol population, the adjusted mean change from baseline in the WOMAC pain score was -11.1 ( 0.9) with diacerein (n = 140) and -11.8 (0.9) with celecoxib (n = 148). The intergroup difference was 0.7 (95% CI: -1.8, 3.2; P = 0.597), meeting the non-inferiority margin. Supportive analysis of the intention-to-treat population gave similar results. Other outcomes showed no significant difference between treatment groups. The incidence of treatment-related adverse events was low and balanced between groups, but a greater incidence of diarrhoea occurred with diacerein (10.2% vs 3.7%). Diarrhoea was considered mild-to-moderate in all but one case with complete resolution. CONCLUSIONS: Diacerein was non-inferior to celecoxib in reducing knee OA pain and improving physical function. Diacerein also demonstrated a good safety profile. TRIAL REGISTRATION: A multicentre study on the effect of DIacerein on Structure and Symptoms vs Celecoxib in Osteoarthritis is a National Institutes of Health (NCT02688400) and European Clinical Trial Database (2015-002933-23) registered phase III (Canada) or IV (Europe) study.

16.
J Rheumatol ; 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32238520

RESUMO

OBJECTIVE: To investigate whether tumor necrosis factor inhibitor (TNFi) combination therapy with conventional synthetic disease-modifying antirheumatic drugs (csDMARD) is more effective for psoriatic arthritis (PsA) and/or improves TNFi drug survival compared to TNFi monotherapy. METHODS: Five PsA biologics cohorts were investigated between 2000 and 2015: the ATTRA registry (Czech Republic); the Swiss Clinical Quality Management PsA registry; the Hellenic Registry of Biologics Therapies (Greece); the University of Bari PsA biologics database (Italy); and the Bath PsA cohort (UK). Drug persistence was analyzed using Kaplan-Meier and equality of survival using log-rank tests. Comparative effectiveness was investigated using logistic regression with propensity scores. Separate analyses were performed on (1) the combined Italian/Swiss cohorts for change in rate of Disease Activity Score in 28 joints (DAS28); and (2) the combined Italian, Swiss, and Bath cohorts for change in rate of Health Assessment Questionnaire (HAQ). RESULTS: In total, 2294 patients were eligible for the drug survival analysis. In the Swiss (P = 0.002), Greek (P = 0.021), and Bath (P = 0.014) databases, patients starting TNFi in combination with methotrexate had longer drug survival compared to monotherapy, while in Italy the monotherapy group persisted longer (P = 0.030). In eligible patients from the combined Italian/Swiss dataset (n = 1056), there was no significant difference between treatment arms in rate of change of DAS28. Similarly, when also including the Bath cohort (n = 1205), there was no significant difference in rate of change of HAQ. CONCLUSION: Combination therapy of a TNFi with a csDMARD does not appear to affect improvement of disease activity or HAQ versus TNFi monotherapy, but it may improve TNFi drug survival.

17.
BMC Rheumatol ; 4: 13, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32021963

RESUMO

Background: S100A4 is a member of calcium binding S100 protein family well known for its role in cancer progression and metastasis. Nevertheless, S100A4 also serves as a negative regulator of bone formation. Dickkopf-1 (DKK-1), marker of bone remodelling, is also implicated in the process of syndesmophyte formation in ankylosing spondylitis. The aim of our study was to evaluate plasma levels of S100A4 in patients with axial spondyloarthritis and to determine the potential association of S100A4 with disease severity, clinical manifestations and with bone changes in a cross-sectional study. Methods: Fifty-eight patients with axial spondyloarthritis and 40 healthy controls were studied. Biological samples were analysed for S100A4 and Dickkopf-1. Disease activity was assessed according to the Bath Ankylosing Spondylitis Disease Activity Index. C-reactive protein (CRP) was used as a marker of inflammation. Radiographic damage was assessed using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). Results: The plasma levels of S100A4 were significantly higher in patients with axial spondyloarthritis compared to heathy controls (p < 0.0001). The levels of S100A4 were higher in early stages of the disease and lower in patients with the presence of syndesmophytes (p = 0.009). Furthermore, we found weak but significant inverse correlation of plasma S100A4 with the mSASSS (r = - 0.363, p = 0.030). Levels of S100A4 were negatively associated with disease duration (r = - 0.404, p = 0.002) and positively with Dickkopf-1 binding capacity (r = 0.312, p = 0.023). Conclusions: This is the first study showing elevated circulating levels of S100A4 in patients with axial spondyloarthritis, particularly in early stages of the disease prior to spinal involvement, and its significantly lower levels in patients with syndesmophytes. The role of S100A4 in the pathogenesis of axial spondyloarthritis can be suggested.

18.
Rheumatology (Oxford) ; 59(9): 2455-2461, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31960053

RESUMO

OBJECTIVES: To assess the impact of 'patient's minus evaluator's global assessment of disease activity' (ΔPEG) at treatment initiation on retention and remission rates of TNF inhibitors (TNFi) in psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) patients across Europe. METHODS: Real-life data from PsA and axSpA patients starting their first TNFi from 11 countries in the European Spondyloarthritis Research Collaboration Network were pooled. Retention rates were compared by Kaplan-Meier analyses with log-rank test and by Cox regression, and remission rates by χ2 test and by logistic regression across quartiles of baseline ΔPEG, separately in female and male PsA and axSpA patients. RESULTS: We included 14 868 spondyloarthritis (5855 PsA, 9013 axSpA) patients. Baseline ΔPEG was negatively associated with 6/12/24-months' TNFi retention rates in female and male PsA and axSpA patients (P <0.001), with 6/12/24-months' BASDAI < 2 (P ≤0.002) and ASDAS < 1.3 (P ≤0.005) in axSpA patients, and with DAS28CRP(4)<2.6 (P ≤0.04) and DAPSA28 ≤ 4 (P ≤0.01), but not DAS28CRP(3)<2.6 (P ≥0.13) in PsA patients, with few exceptions on remission rates. Retention and remission rates were overall lower in female than male patients. CONCLUSION: High baseline patient's compared with evaluator's global assessment was associated with lower 6/12/24-months' remission as well as retention rates of first TNFi in both PsA and axSpA patients. These results highlight the importance of discordance between patient's and evaluator's perspective on disease outcomes.

19.
ACR Open Rheumatol ; 2(2): 119-127, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31957970

RESUMO

OBJECTIVE: Secukinumab 150 mg has demonstrated significant improvement in signs and symptoms of ankylosing spondylitis (AS), with response rates sustained for up to 5 years. Here, we report end-of-study 3-year efficacy and safety results of secukinumab 150 and 300 mg from the MEASURE 3 study. METHODS: A total of 226 patients was randomized to intravenous secukinumab 10 mg/kg (baseline, weeks 2 and 4) followed by subcutaneous (s.c.) secukinumab 300/150 mg every 4 weeks or a matched placebo. At week 16, placebo patients were re-randomized to s.c. secukinumab 300/150 mg. Analysis at week 156 included patients initially randomized to secukinumab and those who switched from placebo to secukinumab at week 16 (any secukinumab 300/150 mg). Outcome measures at week 156 included Assessment of Spondyloarthritis International Society (ASAS) 20/40, Bath Ankylosing Spondylitis Disease Activity Index, ASAS partial remission (PR), ASAS 5/6, and Ankylosing Spondylitis Disease Activity Score-C-reactive protein inactive disease. RESULTS: The retention rates from weeks 16 to 156 were 80.5% and 80.9% in secukinumab 300 and 150 mg, respectively. ASAS 20/40 response rates at week 156 were 75.0%/56.5% and 68.2%/47.7% for secukinumab 300 and 150 mg, respectively. At week 156, response rates on more stringent clinical end points (eg, ASAS 40, ASAS-PR) were higher with the 300-mg dose, particularly in tumor necrosis factor (TNF)-inadequate responder (IR) patients. No new safety findings were observed. CONCLUSION: Secukinumab (300 and 150 mg) provided sustained improvements through 3 years in the signs and symptoms of active AS. Improvements with secukinumab 300 mg were numerically higher compared with the 150-mg dose for some higher hurdle end points and in TNF-IR patients. The safety profile of secukinumab was consistent with previous reports.

20.
Expert Opin Biol Ther ; 20(2): 183-192, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31736377

RESUMO

Objectives: To assess the role of short-term response to first anti-TNF in long-term prediction of disability.Methods: In nationwide registry ATTRA, we identified ankylosing spondylitis patients starting anti-TNF between 01/2003 and 12/2016. Full disability and work impairment (WI; WPAI questionnaire) were predicted via the Cox- and lagged-parameter mixed-effect regression.Results: 2,274 biologicals-naïve patients newly indicated to anti-TNF were prospectively followed (6,333 patient-years; median follow-up 1.9 years). Reaching BASDAI < 4 (77.4%) and ASDAS-CRP < 2.1 (61.1%) after 3 months of anti-TNF both decreased the risk of future disability by ≈2.5-fold. ASDAS-CRP < 2.1 predicted non-disability better than BASDAI < 4 & CRP < 5 mg/L (p = 0.032). BASDAI < 4 & CRP < 5 mg/L was comparable to BASDAI < 4 (p = 0.941) and to BASDAI change by >50% or by >2 points (p = 0.902). ASDAS-CRP change >1.1 and >2.0 both failed to predict non-disability. Once on anti-TNF therapy, the strongest predictor of WI was Pain (SF36). Yearly increase in indirect costs remains below €3,000 in those reaching ASDAS-CRP < 2.1.Conclusions: Low disease activity measured by ASDAS-CRP ≤ 2.1 should be used to measure the outcome of new anti-TNF therapy. Continuous WI could be decreased through pain management.


Assuntos
Produtos Biológicos/uso terapêutico , Eficiência , Espondilite Anquilosante/diagnóstico , Espondilite Anquilosante/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Absenteísmo , Adulto , Estudos de Coortes , República Tcheca/epidemiologia , Avaliação da Deficiência , Pessoas com Deficiência/estatística & dados numéricos , Eficiência/efeitos dos fármacos , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prognóstico , Sistema de Registros/estatística & dados numéricos , Índice de Gravidade de Doença , Espondilite Anquilosante/complicações , Espondilite Anquilosante/epidemiologia , Inquéritos e Questionários , Fatores de Tempo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/imunologia
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