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1.
Artigo em Inglês | MEDLINE | ID: mdl-33822898

RESUMO

OBJECTIVE: To further characterize the effect of guselkumab, a selective interleukin-23p19-subunit inhibitor approved for psoriatic arthritis (PsA), on enthesitis and assess relationships between enthesitis resolution and patient status/outcomes. METHODS: Adults with active PsA despite standard therapies in the Phase-3 DISCOVER-1 and DISCOVER-2 studies were randomized 1:1:1 to guselkumab 100 mg every-4-weeks (Q4W); guselkumab 100 mg at Week0, Week4, Q8W; or placebo through Week20 followed by guselkumab 100 mg Q4W (Placebo→Q4W). Independent assessors evaluated enthesitis using the Leeds Enthesitis Index (LEI; total score 0-6). Enthesitis findings through Week24 were prespecified to be pooled across studies; post hoc and Week52 analyses also employed pooled data. RESULTS: Among 1,118 randomized, treated patients in DISCOVER-1 and 2 who had ≥1LEI site evaluated, 65% had enthesitis at baseline. These patients exhibited numerically more swollen and tender joints, systemic inflammation, and impaired physical function than patients without enthesitis. Guselkumab Q4W and Q8W were superior to placebo in resolving pre-existing enthesitis at Week24 (45% and 50% vs 29%; both adjusted p= 0.0301). Enthesitis resolution rates continued to rise; 58% of guselkumab-randomized patients achieved resolution at Week52, including patients with mild (LEI = 1; 70-75%), moderate (LEI = 2; 69-73%), or severe (LEI = 3-6; 42-44%) enthesitis at baseline. Among guselkumab-randomized patients with resolved enthesitis at Week24, 42% achieved minimal disease activity at Week52, vs 17% of patients with unresolved enthesitis. CONCLUSION: Guselkumab resulted in higher proportions of PsA patients with resolved enthesitis by Week24, with maintenance of resolution rates through 1 year. As enthesitis confers greater disease burden, sustained resolution could portend better patient outcomes. CLINICAL TRIAL REGISTRATION: DISCOVER 1 (NCT03162796) and DISCOVER 2 (NCT03158285).

2.
Semin Immunopathol ; 43(2): 221-234, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33712923

RESUMO

Psoriatic arthritis (PsA) is a relatively common inflammatory arthritis, a spondyloarthritis (SpA), that occurs most often in patients with psoriasis, a common immune-mediated inflammatory skin disease. Both psoriasis and PsA are highly heritable. Genetic and recent genomic studies have identified variants associated with psoriasis and PsA, but variants differentiating psoriasis from PsA are few. In this review, we describe recent developments in understanding the genetic burden of PsA, linkage, association and epigenetic studies. Using pathway analysis, we provide further insights into the similarities and differences between PsA and psoriasis, as well as between PsA and other immune-mediated inflammatory diseases, particularly ankylosing spondylitis, another SpA. Environmental factors that may trigger PsA in patients with psoriasis are also reviewed. To further understand the pathogenetic differences between PsA and psoriasis as well as other SpA, larger cohort studies of well-phenotyped subjects with integrated analysis of genomic, epigenomic, transcriptomic, proteomic and metabolomic data using interomic system biology approaches are required.

3.
Arthritis Res Ther ; 23(1): 59, 2021 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-33610191

RESUMO

BACKGROUND: Osteoarthritis (OA) is the most prevalent form of arthritis and the major cause of disability and overall diminution of quality of life in the elderly population. Currently there is no cure for OA, partly due to the large gaps in our understanding of its underlying molecular and cellular mechanisms. Macrophage migration inhibitory factor (MIF) is a procytokine that mediates pleiotropic inflammatory effects in inflammatory diseases such as rheumatoid arthritis (RA) and ankylosing spondylitis (AS). However, data on the role of MIF in OA is limited with conflicting results. We undertook this study to investigate the role of MIF in OA by examining MIF genotype, mRNA expression, and protein levels in the Newfoundland Osteoarthritis Study. METHODS: One hundred nineteen end-stage knee/hip OA patients, 16 RA patients, and 113 healthy controls were included in the study. Two polymorphisms in the MIF gene, rs755622, and -794 CATT5-8, were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and PCR followed by automated capillary electrophoresis, respectively. MIF mRNA levels in articular cartilage and subchondral bone were measured by quantitative polymerase chain reaction. Plasma concentrations of MIF, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1ß) were measured by enzyme-linked immunosorbent assay. RESULTS: rs755622 and -794 CATT5-8 genotypes were not associated with MIF mRNA or protein levels or OA (all p ≥ 0.19). MIF mRNA level in cartilage was lower in OA patients than in controls (p = 0.028) and RA patients (p = 0.004), while the levels in bone were comparable between OA patients and controls (p = 0.165). MIF protein level in plasma was lower in OA patients than in controls (p = 3.01 × 10-10), while the levels of TNF-α, IL-6 and IL-1ß in plasma were all significantly higher in OA patients than in controls (all p ≤ 0.0007). Multivariable logistic regression showed lower MIF and higher IL-1ß protein levels in plasma were independently associated with OA (OR per SD increase = 0.10 and 8.08; 95% CI = 0.04-0.19 and 4.42-16.82, respectively), but TNF-α and IL-6 became non-significant. CONCLUSIONS: Reduced MIF mRNA and protein expression in OA patients suggested MIF might have a protective role in OA and could serve as a biomarker to differentiate OA from other joint disorders.

4.
Rheumatol Ther ; 2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-33284423

RESUMO

INTRODUCTION: Ixekizumab, an interleukin-17A antibody, has shown efficacy in non-radiographic axial spondyloarthritis (nr-axSpA). The objectives of this analysis were (a) to measure improvement in ixekizumab-treated patients in Assessment of Spondyloarthritis International Society (ASAS) response domains and other patient-reported outcomes (PROs) and (b) to determine how ASAS responses were associated with changes in patient global disease activity (PtGA), spinal pain, function, stiffness, fatigue, and spinal pain at night. METHODS: COAST-X was a phase 3, 52-week multicenter, randomized, controlled trial investigating the efficacy and safety of 80-mg ixekizumab every 2 weeks (Q2W) and every 4 weeks (Q4W) in patients with active nr-axSpA. Changes from baseline in PROs were analyzed via mixed-effects models for repeated measures. Association analyses for ASAS responses used analysis of covariance with Scheffé's method. RESULTS: Patients treated with ixekizumab Q2W and Q4W reported significantly greater improvements in PtGA, spinal pain, function, and stiffness at week 1, when these measures were first assessed, compared with placebo (p < 0.05). ASAS40 responders, in comparison to ASAS20 non-responders, had the highest correlations with improvements in all response domains (PtGA, spinal pain, function, and stiffness) as well as fatigue and spinal pain at night (p < 0.001). ASAS40 responses were associated with 3.5- to 48.0-fold greater improvements in these PROs, with the highest values for PtGA and function, compared to ASAS20 non-achievement. CONCLUSIONS: As early as week 1, patients with nr-axSpA treated with ixekizumab reported significant improvements in PtGA, spinal pain, function, and stiffness compared with those taking placebo. ASAS40 responders reported significantly greater improvements in all ASAS response domains (PtGA, spinal pain, function, and stiffness) as well as fatigue and spinal pain at night than ASAS20 non-responders. Improvements in PtGA and function appear to be major drivers in achieving ASAS40 response in patients with nr-axSpA. TRIAL REGISTRATION: NCT02757352.

5.
J Arthroplasty ; 2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33288389

RESUMO

BACKGROUND: While total joint replacement (TJR) is the most effective treatment for end-stage osteoarthritis (OA), one-third of patients do not experience clinically important improvement in pain or function following the surgery. Thus, it is important to identify factors for nonresponders and develop strategies to improve TJR outcomes. METHODS: Study participants were patients who underwent TJR (hip/knee) due to OA and completed the WOMAC before and on average 4 years after surgery. Nonresponders (pain nonresponders, function nonresponders, pain and function nonresponders) were determined using the WOMAC change score from baseline to follow-up under two previously reported criteria. Eighty-eight self-reported factors collected by a general health questionnaire were examined for associations with nonresponders. RESULTS: A total of 601 patients (30.8% hip and 69.2% knee replacement) were included; 18% of them were found to be either pain or function nonresponders. Nine factors were identified in the univariable analyses to be associated with nonresponders, and 5 of them (clinical depression, multisite musculoskeletal pain [MSMP], younger age, golfer's elbow, and driving more than 4 hours on average per working day) remained significant in the multivariable analyses in at least one of six categories. Clinical depression, having MSMP, and younger age were the major factors to be independently associated with nonresponders across five categories. In addition, two factors (age at menopause and age at hysterectomy) were significantly associated with female nonresponders. CONCLUSION: Our data suggested potential roles of pain perception, widespread pain sensitization, patient expectations, and early menopause in females in TJR outcomes, warranting further investigation.

6.
Pain ; 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33273416

RESUMO

Metabolic dysfunction has been suggested to be involved in musculoskeletal pain; however, few studies have identified metabolic markers associated with multisite musculoskeletal pain (MSMP). This study sought to identify metabolic marker(s) for MSMP by metabolomic analysis. The Tasmanian Older Adult Cohort Study (TASOAC) provided the discovery cohort with the Newfoundland Osteoarthritis Study (NFOAS) providing the replication cohort. MSMP was assessed by a self-reported pain questionnaire and defined as painful sites ≥4 in both TASOAC and NFOAS. Further, MSMP was also defined as painful sites ≥7, while non-MSMP was defined as either painful sites <7 or ≤1 in NFOAS. Serum samples of TASOAC received metabolic profiling using The Metabolomics Innovation Centre (TMIC) Prime Metabolomics Profiling Assay. The data on the identified metabolites were retrieved from NFOAS metabolomic database for the purpose of replication. A total of 409 participants were included in TASOAC, 38% of them had MSMP. Among the 143 metabolites assessed, 129 passed quality control and were included in the analysis. Sphingomyelin (SM) C18:1 was significantly associated with MSMP (OR per log µM increase=3.96, 95%CI, 1.95-8.22; p=0.0002). The significance remained in multivariable analysis (OR per log µM increase=2.70, 95%CI, 1.25-5.95). A total of 610 participants were included in NFOAS and the association with SM C18:1 was successfully replicated with three MSMP definitions (OR ranging from 1.89 to 2.82; all p<0.03). Our findings suggest that sphingomyelin metabolism is involved in the pathogenesis of MSMP and circulating level of SM C18:1 could serve as a potential marker in the management of MSMP.

7.
BMC Rheumatol ; 4(1): 56, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-33292797

RESUMO

BACKGROUND: The objectives of this study were to describe the profile of ankylosing spondylitis (AS) patients treated with either infliximab (IFX) or subcutaneous golimumab (GLM) treatment in Canadian routine care setting along with assessing long-term effectiveness and safety. METHODS: AS patients who were eligible for treatment with IFX or subcutaneous GLM as per their respective Canadian product monographs were enrolled into the BioTRAC registry from 2005 to 2017. The study visits occurred at baseline and every 6 months thereafter. Effectiveness was assessed by changes in clinical outcomes and acute phase reactants. Safety was evaluated by assessing the incidence of adverse events (AEs) and drug survival rates. RESULTS: A total of 389 IFX- and 421 GLM-treated patients were enrolled. A significant decrease in disease duration at baseline was observed in the IFX cohort, from a median of 8.0 in 2005-2008 to 1.0 years in 2009-2015 (p < 0.001). A reduction in baseline BASFI score (p = 0.011) and proportion of patients in ASDAS very high disease activity (p = 0.004) was also observed over time. Meanwhile, in the GLM cohort, most disease parameters remained similar from 2010 to 2017. Treatment with both agents significantly improved all disease parameters over time with similar efficacy between the two agents. The incidence of AEs and SAEs were 136 and 131 events/100 PYs and 10.5 and 8.45 events/100 PYs for IFX- and GLM-treated patients, respectively. CONCLUSION: Both IFX and GLM treatment in AS significantly reduced disease activity in most outcome measures in a similar fashion and were well tolerated in Canadian routine care. TRIAL REGISTRATION: NCT00741793 .

8.
Sci Rep ; 10(1): 21703, 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33303908

RESUMO

Biological therapies have dramatically improved the therapeutic landscape of psoriatic arthritis (PsA); however, 40-50% of patients are primary non-responders with response rates declining significantly with each successive biological therapy. Therefore, there is a pressing need to develop a coherent strategy for effective initial and subsequent selection of biologic agents. We interrogated 40 PsA patients initiating either tumour necrosis factor inhibitors (TNFi) or interleukin-17A inhibitors (17Ai) for active PsA. Patients achieving low disease activity according to the Disease Activity Index for PsA (DAPSA) at 3 months were classified as responders. Baseline and 3-month CD4+ transcript profiling were performed, and novel signaling pathways were identified using a multi-omics profiling and integrative computational analysis approach. Using transcriptomic data at initiation of therapy, we identified over 100 differentially expressed genes (DEGs) that differentiated IL-17Ai response from non-response and TNFi response from non-response. Integration of cell-type-specific DEGs with protein-protein interactions and further comprehensive pathway enrichment analysis revealed several pathways. Rho GTPase signaling pathway exhibited a strong signal specific to IL-17Ai response and the genes, RAC1 and ROCKs, are supported by results from prior research. Our detailed network and pathway analyses have identified the rewiring of Rho GTPase pathways as potential markers of response to IL17Ai but not TNFi. These results need further verification.

9.
Artigo em Inglês | MEDLINE | ID: mdl-33159799

RESUMO

OBJECTIVE: To identify endotypes of osteoarthritis (OA) by a metabolomics analysis. METHODS: Study participants included hip/knee OA patients and controls. Fasting plasma samples were metabolomically profiled. Common factor analysis and K-means clustering were applied to the metabolomics data to identify the endotypes of OA patients. Logistic regression was utilized to identify the most significant metabolites contributing to the endotypes. Clinical and epidemiological factors were examined in relation to the identified OA endotypes. RESULTS: Six hundred and fifteen primary OA patients and 237 controls were included. Among the 186 metabolites measured, 162 passed the quality control analysis. The 615 OA patients were classified in three clusters (A, 66; B, 200; and C, 349). Patients in cluster A had a significantly higher concentration of butyrylcarnitine (C4) than other clusters and controls (all P < 0.0002). Elevated C4 is thought to be related to muscle weakness and wasting. Patients in cluster B had a significantly lower arginine concentration than other clusters and controls (all P < 7.98 × 10-11). Cluster C patients had a significantly lower concentration of lysophosphatidylcholine (with palmitic acid), which is a pro-inflammatory bioactive compound, than other clusters and controls (P < 3.79 × 10-6). Further, cluster A had a higher BMI and prevalence of diabetes than other clusters (all P ≤ 0.0009), and also a higher prevalence of coronary heart disease than cluster C (P = 0.04). Cluster B had a higher prevalence of coronary heart disease than cluster C (P = 0.003) whereas cluster C had a higher prevalence of osteoporosis (P = 0.009). CONCLUSION: Our data suggest three possible clinically actionable endotypes in primary OA: muscle weakness, arginine deficit and low inflammatory OA.

10.
Arthritis Rheumatol ; 2020 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-33043600

RESUMO

OBJECTIVE: Guselkumab, a human monoclonal antibody specific to interleukin-23p19, demonstrated efficacy and safety versus placebo through Week24 of the Phase-3 DISCOVER-2 trial in biologic-naïve psoriatic arthritis (PsA) patients. Here we report 1-year DISCOVER-2 findings. METHODS: Adults with active PsA (≥5 swollen+≥5 tender joints; C-reactive protein ≥0.6mg/dL) despite standard nonbiologic treatment were randomized to receive subcutaneous injections of guselkumab 100mg every-4-weeks (Q4W); guselkumab 100mg at Week0, Week4, Q8W; or placebo with crossover to guselkumab 100mg Q4W at Week24. We primarily evaluated clinical efficacy through Week52 by imputing missing data (nonresponse for categorical endpoints; no change/using multiple imputation for continuous endpoints). Observed radiographic scores and adverse events (AEs) were summarized. RESULTS: Of 739 randomized, treated patients, 93% completed Week52. Proportions of patients achieving ≥20% improvement from baseline in ACR criteria (ACR20) were maintained post-Week24, reaching 71% (173/245) and 75% (185/248) for Q4W- and Q8W- randomized patients, respectively, by Week52. The proportions of patients achieving ACR50/ACR70 and skin responses, minimal or very low disease activity, and dactylitis or enthesitis resolution were also maintained through Week52. Further, low levels of radiographic progression, along with improvements in physical function and health-related quality-of-life, were sustained through Week52 with continued guselkumab. Few patients experienced serious infections through Week52, with no evidence of a dosing regimen response or increase from Week0-24 (4/493 [0.8%]) to Week24-52 (3/493 [0.6%]) among guselkumab-randomized patients. No patient developed an opportunistic infection or died. CONCLUSION: In biologic-naïve PsA patients, guselkumab provided sustained improvements across diverse manifestations and maintained a favorable benefit-risk profile through Week52.

11.
BMC Rheumatol ; 4: 46, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32968710

RESUMO

Background: Long-term clinical registries are essential tools to evaluate new therapies in a patient population that differs from those in randomized clinical trials. The objectives are to describe the profile of rheumatoid arthritis (RA) patients treated with anti-TNF agents in Canadian routine care. Methods: RA patients eligible for treatment with Infliximab (IFX), golimumab (GLM) or intravenous golimumab (GLM-IV) as per their respective Canadian product monographs were enrolled into the BioTRAC registry between 2002 and 2017. Study visits occurred at baseline and every 6 months thereafter. Effectiveness was assessed by changes in disease activity. Safety was evaluated by the incidence of adverse events (AEs) and drug survival. Results: Of the 890 IFX-, 530 GLM- and 157 GLM-IV-treated patients, the proportion of females ranged from 77.0-86.6%, the mean ages from 55.8-57.7 and the mean disease duration from 6.5-8.6 years. A significant decrease in baseline disease duration and disease activity parameters (DAS, TJC, SJC, HAQ, AM stiffness, MDGA, PtGA, CRP, ESR) was observed over time. Treatment with IFX, GLM- and GLM-IV significantly improved all disease parameters over time. The incidence of AEs was 105, 113 and 82.6 /100 PYs and the incidence of SAEs was 11.7, 11.2 and 4.68 /100 PYs for IFX, GLM- and GLM-IV-treated patients, respectively. Conclusion: Differences in baseline characteristics between patients treated with an anti-TNFs over time shows the evolution of treatment modalities over time. All treatments significantly reduced disease activity and improved functionality in a similar fashion. The incidence of adverse events was consistent with the safety profiles of IFX and GLM. Trial registration: ClinicalTrials.gov Identifier: NCT00741793 (Retrospectively registered on August 26, 2008).

12.
Comput Mech ; : 1-12, 2020 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-32904431

RESUMO

A key strategy to prevent a local outbreak during the COVID-19 pandemic is to restrict incoming travel. Once a region has successfully contained the disease, it becomes critical to decide when and how to reopen the borders. Here we explore the impact of border reopening for the example of Newfoundland and Labrador, a Canadian province that has enjoyed no new cases since late April, 2020. We combine a network epidemiology model with machine learning to infer parameters and predict the COVID-19 dynamics upon partial and total airport reopening, with perfect and imperfect quarantine conditions. Our study suggests that upon full reopening, every other day, a new COVID-19 case would enter the province. Under the current conditions, banning air travel from outside Canada is more efficient in managing the pandemic than fully reopening and quarantining 95% of the incoming population. Our study provides quantitative insights of the efficacy of travel restrictions and can inform political decision making in the controversy of reopening.

13.
medRxiv ; 2020 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-32766595

RESUMO

A key strategy to prevent a local outbreak during the COVID-19 pandemic is to restrict incoming travel. Once a region has successfully contained the disease, it becomes critical to decide when and how to reopen the borders. Here we explore the impact of border reopening for the example of Newfoundland and Labrador, a Canadian province that has enjoyed no new cases since late April, 2020. We combine a network epidemiology model with machine learning to infer parameters and predict the COVID-19 dynamics upon partial and total airport reopening, with perfect and imperfect quarantine conditions. Our study suggests that upon full reopening, every other day, a new COVID-19 case would enter the province. Under the current conditions, banning air travel from outside Canada is more efficient in managing the pandemic than fully reopening and quarantining 95% of the incoming population. Our study provides quantitative insights of the efficacy of travel restrictions and can inform political decision making in the controversy of reopening.

14.
Rheumatol Ther ; 7(4): 759-774, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32814997

RESUMO

INTRODUCTION: Patients with ankylosing spondylitis (AS) are burdened with symptoms impacting work productivity measured by presenteeism, absenteeism, overall work impairment, and activity impairment. Ixekizumab, a high-affinity monoclonal antibody selectively targeting interleukin-17A, has been demonstrated to improve disease signs and symptoms in two phase 3 trials of AS. This study investigated for 52 weeks the effect of ixekizumab treatment on work productivity in patients with active AS. METHODS: COAST-V (NCT02696785) and COAST-W (NCT02696798) were phase 3, multicenter, randomized, controlled trials investigating the efficacy of ixekizumab 80 mg every 4 weeks (Q4W) and every 2 weeks (Q2W) in patients with AS naïve to biologic disease-modifying antirheumatic drugs (bDMARDs; COAST-V) or who were inadequate responders or intolerant to tumor necrosis factor inhibitors (TNFi; COAST-W). Work productivity was measured with the Work Productivity and Activity Impairment Questionnaire for Spondyloarthritis at weeks 16 and 52. Absenteeism, presenteeism, and overall work impairment were assessed for patients reporting paid work. Activity impairment was assessed regardless of work status. RESULTS: At baseline, 66.2% (434/656) of patients reported paid work. At week 16, bDMARD-naïve patients treated with both ixekizumab dose regimens and TNFi-experienced patients treated with ixekizumab Q2W reported significant improvements in activity impairment (p < 0.01 and p < 0.05, respectively). TNFi-experienced patients treated with ixekizumab showed significant improvements versus placebo in presenteeism and overall work impairment (p < 0.05); bDMARD-naïve patients had numeric improvements. After week 16, patients initially on placebo switched to ixekizumab and patients already treated with ixekizumab continued treatment. Improvements in work productivity and daily activity were sustained through week 52 for both bDMARD-experienced and -naïve patients. CONCLUSION: Both bDMARD-naïve and TNFi-experienced patients with AS had greater improvements in work productivity and activity impairment when receiving ixekizumab compared to placebo at week 16. Improvements in work productivity and activity impairment achieved at week 16 were sustained through week 52 with ixekizumab treatment.

15.
BMJ Open ; 10(8): e036245, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32792436

RESUMO

OBJECTIVES: The objectives of this study were to describe the demographic profile and baseline disease characteristics of patients with psoriatic arthritis (PsA) treated with either infliximab (IFX), subcutaneous golimumab (GLM) or ustekinumab (UST) treatment in Canadian routine care setting along with assessing long-term effectiveness and safety. METHODS: Patients with PsA were enrolled into the Biologic Treatment Registry Across Canada registry (ClinicalTrials.gov Identifier: NCT00741793) from 2005 to 2017. The study visits occurred at study enrolment (baseline) and every 6 months thereafter. Effectiveness was assessed by changes in disease parameters (joint counts, Psoriasis Area Severity Index (PASI), Health Assessment Questionnaire, patient/physician global, minimal disease activity, enthesitis, dactylitis, erythrocyte sedimentation rate, C reactive protein). Improvements from baseline were explored with the paired t-test and the McNemar's test. Safety was evaluated by assessing the incidence of adverse events (AEs) and drug survival rates. RESULTS: A total of 111 IFX-treated, 281 GLM-treated and 70 UST-treated patients were enrolled. Most baseline disease parameters remained similar over time in all three cohorts. UST-treated patients had lower mean baseline Disease Activity Score in 28 joints CRP, swollen joint based on 28 joints and higher PASI compared with patients treated with GLM. Treatment with IFX, GLM and UST was associated with significant improvements in all disease parameters over time (p<0.001) from baseline up to 84, 84 and 40 months, respectively.AEs were reported for 74.8%, 69.8% and 52.9% (138, 114 and 115 events/100 patient-years (PYs)) covering 325, 567 and 87 years of exposure for IFX-treated, GLM-treated and UST-treated patients, respectively. Severe AEs were reported in 19.8%, 8.5% and 5.7% (8.8, 7.2 and 8.0 events/100 PYs) in IFX-treated, GLM-treated and UST-treated patients, respectively. The proportion of patients who discontinued treatment were 63.1%, 50.9% and 50.0%, respectively. CONCLUSIONS: IFX, GLM and UST treatment significantly reduced disease activity and improved functionality in patients with PsA followed by routine clinical practice and had a safety profile similar to that previously reported in the literature. TRIAL REGISTRATION NUMBER: NCT00741793.

16.
Pain ; 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32833795

RESUMO

Musculoskeletal pain often occurs simultaneously at multiple anatomical sites. The aim of the study was to identify metabolic biomarkers for multisite musculoskeletal pain (MSMP) by metabolomics with an extreme phenotype sampling strategy. The study participants (n = 610) were derived from the Newfoundland Osteoarthritis Study. Musculoskeletal pain was assessed using a self-reported pain questionnaire where painful sites were circled on a manikin by participants and the total number of painful sites were calculated. Targeted metabolomic profiling on fasting plasma samples was performed using the Biocrates AbsoluteIDQ p180 kit. Plasma cytokine concentrations including tumor necrosis factor-α, interleukin-6, interleukin-1ß, and macrophage migration inhibitory factor were assessed by enzyme-linked immunosorbent assay. Data on blood cholesterol profiles were retrieved from participants' medical records. Demographic, anthropological, and clinical information was self-reported. The number of reported painful sites ranged between 0 and 21. Two hundred and five participants were included in the analysis comprising 83 who had ≥7 painful sites and 122 who had ≤1 painful site. Women and younger people were more likely to have MSMP (P ≤ 0.02). Multisite musculoskeletal pain was associated with a higher risk of having incontinence, worse functional status and longer period of pain, and higher levels of low-density lipoprotein and non-high-density lipoprotein cholesterol (all P ≤ 0.03). Among the 186 metabolites measured, 2 lysophosphatidylcholines, 1 with 26 carbons with no double bond and 1 with 28 carbons with 1 double bond, were significantly and positively associated with MSMP after adjusting for multiple testing with the Bonferroni method (P ≤ 0.0001) and could be considered as novel metabolic markers for MSMP.

17.
Per Med ; 17(4): 283-293, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32589098

RESUMO

Aim: To survey the general public about whole genome sequencing interest, including pharmacogenomic testing, and to identify information important for sequencing decisions. Patients & methods: An online survey of 901 members of the general public in an eastern Canadian province. Results: Interest in whole genome sequencing, including pharmacogenomic testing, was high with few differences among demographic variables. Issues identified as very important to sequencing decisions included familial implications of testing, whether treatment was available for conditions tested and knowing who could access genomic information. Most respondents would value support when interpreting sequencing results. Conclusion: Findings reveal the kind of information and support users of sequencing services would value and could inform the implementation of sequencing into care in ways that accord with public preferences and needs.

18.
Mol Genet Genomic Med ; 8(8): e1344, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32558308

RESUMO

BACKGROUND: There appears to be large regional variation for susceptibility, severity, and mortality for COVID-19 infections. Numerous potential factors could explain the wide variability in the number of infections and death among the countries. We examined genetic differences in the human angiotensin-converting enzyme 2 (hACE2) gene, as its receptor serves as a cellular entry for SARS-CoV-2. At present, there is a paucity of data regarding the differences for ACE2 polymorphisms and expression levels between ethnicities. METHODS: We compared the allele frequency of mutations between European and East Asians. Molecular dynamic simulation were performed to investigate the influences of significant mutant on protein structure. The binding free energies were calculated between S protein and hACE2. We also examined hACE2 gene expression in eight global populations from HapMap3. RESULTS: Four missense mutations showed significant minor allele frequency difference between Asians and Caucasians. Molecular dynamic demonstrated that two of these variants (K26R and I468V) may affect binding characteristics between S protein of the virus and hACE2 receptor. We also noted marginal differences in gene expression for some populations in HapMap3 as compared to the Chinese population. CONCLUSION: Our studies reveal subtle changes in the genetics of hACE2 between human populations, but the magnitude of the difference was small and the significance is not clear in the absence of further in vitro and functional studies.


Assuntos
Peptidil Dipeptidase A/genética , Polimorfismo Genético , Grupo com Ancestrais do Continente Asiático/genética , Betacoronavirus/isolamento & purificação , Betacoronavirus/metabolismo , Sítios de Ligação , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Grupo com Ancestrais do Continente Europeu/genética , Frequência do Gene , Humanos , Simulação de Dinâmica Molecular , Mutação de Sentido Incorreto , Pandemias , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Ligação Proteica , Estrutura Terciária de Proteína , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo
19.
J Rheumatol ; 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32358162

RESUMO

OBJECTIVE: To identify plasma markers associated with an increased risk of radiographic knee osteoarthritis (OA) progression using a metabolomics approach. METHODS: Study participants were from the Multicenter Osteoarthritis Study (MOST) and were categorized into 2 groups based on the presence of baseline radiographic OA. Subjects in group 1 had unilateral knee OA and subjects in group 2 had bilateral knee OA. Progression was defined as a half-grade or greater worsening in joint space width at 30-month follow-up. For group 1, a participant progressed when their OA knee showed radiographic progression and the contralateral knee developed OA; for group 2, a participant progressed when both knees with OA showed radiographic progression. Metabolomic profiling was performed on plasma samples collected at baseline and logistic regression was performed to test the association between each metabolite and knee OA progression after adjustment for age, sex, BMI, and clinic site. Significance was defined as P ≤ 0.0003 in the combined analysis. RESULTS: There were 234 progressors (57 in group 1 and 177 in group 2) and 322 nonprogressors (206 in group 1 and 116 in group 2) included in the analyses. Among 157 metabolites studied, we found that odds of progression were 1.46 times higher per SD increase of phenylalanine level (95% CI 1.20-1.77, P = 0.0001) in the combined analysis. Sex-specific analysis showed that an association was seen in women (P = 0.0002) but not in men. CONCLUSION: Our data suggest that phenylalanine might be a novel plasma marker for higher risk of bilateral radiographic knee OA progression in women.

20.
Metabolomics ; 16(5): 61, 2020 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-32335722

RESUMO

INTRODUCTION: Up to one third of total joint replacement patients (TJR) experience poor surgical outcome. OBJECTIVES: To identify metabolomic signatures for non-responders to TJR in primary osteoarthritis (OA) patients. METHODS: A newly developed differential correlation network analysis method was applied to our previously published metabolomic dataset to identify metabolomic network signatures for non-responders to TJR. RESULTS: Differential correlation networks involving 12 metabolites and 23 metabolites were identified for pain non-responders and function non-responders, respectively. CONCLUSION: The differential networks suggest that inflammation, muscle breakdown, wound healing, and metabolic syndrome may all play roles in TJR response, warranting further investigation.

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