RESUMEN
Rheumatoid arthritis (RA) is prevalent in many Indigenous North American First Nations (FN) and tends to be seropositive, familial, and disabling, as well as associated with highly unfavorable outcomes such as early mortality. The risk of developing RA is based on a perfect storm of gene-environment interactions underpinning this risk. The gene-environment interactions include a high frequency of shared epitope encoding HLA alleles, particularly HLA-DRB1*1402, in the background population, and prevalent predisposing environmental factors such as smoking and periodontal disease. Together, these provide a compelling rationale for an RA prevention agenda in FN communities. Our research team has worked in partnership with several FN communities to prospectively follow the first-degree relatives of FN patients with RA, with the aim of better understanding the preclinical stages of RA in this population. We have focused on specific features of the anticitrullinated protein antibodies (ACPA) and other proteomic biomarkers as predictors of future development of RA. These studies have now led us to consider interventions having a favorable risk-benefit ratio if applied at a stage prior to a hypothetical "point of no return," when the autoimmunity potentially becomes irreversible. Based on a supportive mouse model and available human studies of curcumin, omega-3, and vitamin D supplements, we are undertaking studies where we screen communities using dried blood spot technology adapted for the detection of ACPA, and then enrolling ACPA-positive individuals in studies that use a combination of these supplements. These studies are guided by shared decision-making principles.
RESUMEN
Rheumatoid arthritis (RA) is prevalent in many Indigenous North American First Nations (FN) and tends to be seropositive, familial, and disabling, as well as associated with highly unfavorable outcomes such as early mortality. The risk of developing RA is based on a perfect storm of gene-environment interactions underpinning this risk. The gene-environment interactions include a high frequency of shared epitope encoding HLA alleles, particularly HLA-DRB1*1402, in the background population, and prevalent predisposing environmental factors such as smoking and periodontal disease. Together, these provide a compelling rationale for an RA prevention agenda in FN communities. Our research team has worked in partnership with several FN communities to prospectively follow the first-degree relatives of FN patients with RA, with the aim of better understanding the preclinical stages of RA in this population. We have focused on specific features of the anticitrullinated protein antibodies (ACPA) and other proteomic biomarkers as predictors of future development of RA. These studies have now led us to consider interventions having a favorable risk-benefit ratio if applied at a stage prior to a hypothetical "point of no return," when the autoimmunity potentially becomes irreversible. Based on a supportive mouse model and available human studies of curcumin, omega-3, and vitamin D supplements, we are undertaking studies where we screen communities using dried blood spot technology adapted for the detection of ACPA, and then enrolling ACPA-positive individuals in studies that use a combination of these supplements. These studies are guided by shared decision-making principles.
Asunto(s)
Artritis Reumatoide , Humanos , Anticuerpos Antiproteína Citrulinada/sangre , Artritis Reumatoide/prevención & control , Artritis Reumatoide/genética , Artritis Reumatoide/inmunología , Biomarcadores/sangre , Interacción Gen-Ambiente , Cadenas HLA-DRB1 , Indígenas NorteamericanosRESUMEN
OBJECTIVE: There are complex and interrelated factors that lead to inequitable healthcare delivery in Canada. Many of the factors that underlie these inequities for Canada's geographically dispersed Indigenous peoples remain underexamined. METHODS: A cohort of 831 First Nations (FN) individuals from urban and remote communities were recruited into a longitudinal study of rheumatoid arthritis (RA) risk from 2005 to 2017. Data from each participant's initial enrollment visit were assessed using a survey that captured concerns with healthcare access. RESULTS: We found that remote participants with RA reported poor access compared to remote first-degree relatives (FDRs; P < 0.001); this difference was not observed for urban participants with RA. We observed substantial differences based on sex; female participants perceived access to care to be more difficult than male participants in both urban and remote cohorts (P < 0.001). We also observed that male participants with RA reported poor access to care compared to male FDRs. Importantly, access to care in remote communities appeared to improve over the duration of the study (P = 0.01). In a logistic regression analysis, female sex, remote location, and older age were independent predictors of poor access to care. Predictors of poor access in participants with RA also included female sex, remote location, and older age. CONCLUSION: FN peoples living in remote communities, particularly those with an established RA diagnosis, report more problems accessing health care. Sex-based inequities exist, with FN female individuals reporting greater difficulties in accessing appropriate health care, regardless of RA diagnosis. Addressing these sex-based inequities should be a high priority for improving healthcare delivery.
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Artritis Reumatoide , Accesibilidad a los Servicios de Salud , Humanos , Artritis Reumatoide/etnología , Masculino , Femenino , Persona de Mediana Edad , Canadá , Adulto , Estudios Longitudinales , Pueblos Indígenas , Familia , Disparidades en Atención de Salud/etnología , Anciano , Factores SexualesRESUMEN
BACKGROUND: Despite growing interest, there is no guidance or consensus on how to conduct clinical trials and observational studies in populations at risk of rheumatoid arthritis (RA). METHODS: An European League Against Rheumatism (EULAR) task force formulated four research questions to be addressed by systematic literature review (SLR). The SLR results informed consensus statements. One overarching principle, 10 points to consider (PTC) and a research agenda were proposed. Task force members rated their level of agreement (1-10) for each PTC. RESULTS: Epidemiological and demographic characteristics should be measured in all clinical trials and studies in at-risk individuals. Different at-risk populations, identified according to clinical presentation, were defined: asymptomatic, musculoskeletal symptoms without arthritis and early clinical arthritis. Study end-points should include the development of subclinical inflammation on imaging, clinical arthritis, RA and subsequent achievement of arthritis remission. Risk factors should be assessed at baseline and re-evaluated where appropriate; they include genetic markers and autoantibody profiling and additionally clinical symptoms and subclinical inflammation on imaging in those with symptoms and/or clinical arthritis. Trials should address the effect of the intervention on risk factors, as well as progression to clinical arthritis or RA. In patients with early clinical arthritis, pharmacological intervention has the potential to prevent RA development. Participants' knowledge of their RA risk may inform their decision to participate; information should be provided using an individually tailored approach. CONCLUSION: These consensus statements provide data-driven guidance for rheumatologists, health professionals and investigators conducting clinical trials and observational studies in individuals at risk of RA.
Asunto(s)
Artritis Reumatoide/prevención & control , Enfermedades Asintomáticas , Ensayos Clínicos como Asunto/métodos , Estudios Observacionales como Asunto/métodos , Antirreumáticos/uso terapéutico , Artritis Reumatoide/diagnóstico por imagen , Artritis Reumatoide/inmunología , Artritis Reumatoide/terapia , Europa (Continente) , Humanos , Reumatología , Factores de Riesgo , Índice de Severidad de la Enfermedad , Sociedades MédicasRESUMEN
OBJECTIVES: Smoking is a major risk factor for the development of both cardiovascular disease (CVD) and RA and may cause attenuated responses to anti-rheumatic treatments. Our aim was to compare disease activity, CVD risk factors and CVD event rates across smoking status in RA patients. METHODS: Disease characteristics, CVD risk factors and relevant medications were recorded in RA patients without prior CVD from 10 countries (Norway, UK, Netherlands, USA, Sweden, Greece, South Africa, Spain, Canada and Mexico). Information on CVD events was collected. Adjusted analysis of variance, logistic regression and Cox models were applied to compare RA disease activity (DAS28), CVD risk factors and event rates across categories of smoking status. RESULTS: Of the 3311 RA patients (1012 former, 887 current and 1412 never smokers), 235 experienced CVD events during a median follow-up of 3.5 years (interquartile range 2.5-6.1). At enrolment, current smokers were more likely to have moderate or high disease activity compared with former and never smokers (P < 0.001 for both). There was a gradient of worsening CVD risk factor profiles (lipoproteins and blood pressure) from never to former to current smokers. Furthermore, former and never smokers had significantly lower CVD event rates compared with current smokers [hazard ratio 0.70 (95% CI 0.51, 0.95), P = 0.02 and 0.48 (0.34, 0.69), P < 0.001, respectively]. The CVD event rates for former and never smokers were comparable. CONCLUSION: Smoking cessation in patients with RA was associated with lower disease activity and improved lipid profiles and was a predictor of reduced rates of CVD events.
Asunto(s)
Artritis Reumatoide/diagnóstico , Enfermedades Cardiovasculares/etiología , Cese del Hábito de Fumar , Fumar/efectos adversos , Adulto , Anciano , Artritis Reumatoide/sangre , Artritis Reumatoide/complicaciones , Artritis Reumatoide/fisiopatología , Presión Sanguínea/fisiología , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/fisiopatología , Femenino , Humanos , Lipoproteínas/sangre , Masculino , Persona de Mediana Edad , Factores de Riesgo , Conducta de Reducción del Riesgo , Índice de Severidad de la Enfermedad , Fumar/sangre , Fumar/fisiopatologíaRESUMEN
OBJECTIVES: Patients with rheumatoid arthritis (RA) have an excess risk of cardiovascular disease (CVD). We aimed to assess the impact of CVD risk factors, including potential sex differences, and RA-specific variables on CVD outcome in a large, international cohort of patients with RA. METHODS: In 13 rheumatology centres, data on CVD risk factors and RA characteristics were collected at baseline. CVD outcomes (myocardial infarction, angina, revascularisation, stroke, peripheral vascular disease and CVD death) were collected using standardised definitions. RESULTS: 5638 patients with RA and no prior CVD were included (mean age: 55.3 (SD: 14.0) years, 76% women). During mean follow-up of 5.8 (SD: 4.4) years, 148 men and 241 women developed a CVD event (10-year cumulative incidence 20.9% and 11.1%, respectively). Men had a higher burden of CVD risk factors, including increased blood pressure, higher total cholesterol and smoking prevalence than women (all p<0.001). Among the traditional CVD risk factors, smoking and hypertension had the highest population attributable risk (PAR) overall and among both sexes, followed by total cholesterol. The PAR for Disease Activity Score and for seropositivity were comparable in magnitude to the PAR for lipids. A total of 70% of CVD events were attributable to all CVD risk factors and RA characteristics combined (separately 49% CVD risk factors and 30% RA characteristics). CONCLUSIONS: In a large, international cohort of patients with RA, 30% of CVD events were attributable to RA characteristics. This finding indicates that RA characteristics play an important role in efforts to reduce CVD risk among patients with RA.
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Artritis Reumatoide/complicaciones , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Adulto , Anciano , Colesterol/sangre , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Hipertensión/epidemiología , Hipertensión/etiología , Incidencia , Masculino , Persona de Mediana Edad , Factores de Riesgo , Índice de Severidad de la Enfermedad , Factores Sexuales , Fumar/efectos adversos , Fumar/epidemiologíaRESUMEN
OBJECTIVE: The pathogenetic mechanisms by which HLA-DRB1 alleles are associated with anticitrullinated peptide antibody (ACPA)-positive rheumatoid arthritis (RA) are incompletely understood. RA high-risk HLA-DRB1 alleles are known to share a common motif, the 'shared susceptibility epitope (SE)'. Here, the electropositive P4 pocket of HLA-DRB1 accommodates self-peptide residues containing citrulline but not arginine. HLA-DRB1 His/Phe13ß stratifies with ACPA-positive RA, while His13ßSer polymorphisms stratify with ACPA-negative RA and RA protection. Indigenous North American (INA) populations have high risk of early-onset ACPA-positive RA, whereby HLA-DRB1*04:04 and HLA-DRB1*14:02 are implicated as risk factors for RA in INA. However, HLA-DRB1*14:02 has a His13ßSer polymorphism. Therefore, we aimed to verify this association and determine its molecular mechanism. METHODS: HLA genotype was compared in 344 INA patients with RA and 352 controls. Structures of HLA-DRB1*1402-class II loaded with vimentin-64Arg59-71, vimentin-64Cit59-71 and fibrinogen ß-74Cit69-81 were solved using X-ray crystallography. Vimentin-64Cit59-71-specific and vimentin59-71-specific CD4+ T cells were characterised by flow cytometry using peptide-histocompatibility leukocyte antigen (pHLA) tetramers. After sorting of antigen-specific T cells, TCRα and ß-chains were analysed using multiplex, nested PCR and sequencing. RESULTS: ACPA+ RA in INA was independently associated with HLA-DRB1*14:02. Consequent to the His13ßSer polymorphism and altered P4 pocket of HLA-DRB1*14:02, both citrulline and arginine were accommodated in opposite orientations. Oligoclonal autoreactive CD4+ effector T cells reactive with both citrulline and arginine forms of vimentin59-71 were observed in patients with HLA-DRB1*14:02+ RA and at-risk ACPA- first-degree relatives. HLA-DRB1*14:02-vimentin59-71-specific and HLA-DRB1*14:02-vimentin-64Cit59-71-specific CD4+ memory T cells were phenotypically distinct populations. CONCLUSION: HLA-DRB1*14:02 broadens the capacity for citrullinated and native self-peptide presentation and T cell expansion, increasing risk of ACPA+ RA.
Asunto(s)
/genética , Artritis Reumatoide/etnología , Artritis Reumatoide/genética , Predisposición Genética a la Enfermedad/etnología , Cadenas HLA-DRB1/genética , Indígenas Norteamericanos/genética , Alaska/etnología , Alelos , Arginina/genética , Arginina/inmunología , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Linfocitos T CD4-Positivos/inmunología , Canadá/etnología , Estudios de Casos y Controles , Citrulina/genética , Citrulina/inmunología , Femenino , Citometría de Flujo , Genotipo , Humanos , Masculino , Péptidos Cíclicos/inmunología , Polimorfismo Genético , Factores de Riesgo , Vimentina/genéticaRESUMEN
CD20 is an attractive therapeutic target given the success of its monoclonal antibody, Rituximab, in the treatment of B-cell malignancies and B-cell-mediated autoimmune diseases. Treatment with Rituximab causes a rapid depletion of B cells and a decrease in disease symptoms. Despite the clinical efficiency of Rituximab, its mechanism of action is not completely understood. In this study, we aimed at further investigating the Rituximab-induced cell death and the factors affecting such responses. Our results indicate that Rituximab-induced cell death depends on the nature of the cells and levels of CD20 expression on the cell surface. Coexpression of CD20 with CD40, a member of the TNF receptor family that is known to be physically associated with CD20 on the cell surface, enhances the apoptotic response induced by Rituximab. Inhibiting the formation of CD40 disulfide-bound-homodimers, a process required for some CD40 signaling, further enhances Rituximab-induced cell death. Cell death induced by anti-CD40 mAb is also upregulated by the presence of CD20, suggesting a bidirectional influence of the CD20/CD40 association. Moreover, treating cells with both anti-CD20 and anti-CD40 antibodies improves the cell death response induced by a single-agent treatment. These results highlight the role of the CD20/CD40 association in triggering B-cell depletion and may pave the way for an alternative more efficient therapeutic strategy in treating B-cell-mediated disorders.
Asunto(s)
Anticuerpos Monoclonales de Origen Murino/metabolismo , Antígenos CD20/metabolismo , Antineoplásicos/metabolismo , Antígenos CD40/metabolismo , Membrana Celular/metabolismo , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales de Origen Murino/farmacología , Antígenos CD20/genética , Antineoplásicos/farmacología , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Linfocitos B/metabolismo , Antígenos CD40/antagonistas & inhibidores , Antígenos CD40/química , Antígenos CD40/genética , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Sinergismo Farmacológico , Expresión Génica , Humanos , Inmunofenotipificación , Activación de Linfocitos/inmunología , Mutación , Unión Proteica , Multimerización de Proteína , Receptores Fc/metabolismo , RituximabRESUMEN
In 2019, Health Canada established the Canadian Pain Task Force. Through this commitment, Canada joined other countries, such as the United States and Australia, in creating a national-level mechanism to support work in the area of chronic pain. This article provides a historical narrative of national and regional advocacy and efforts that led to creation of the Task Force, the broad representation of its members, as well as its mandate and goals. Subsequently it outlines the Task Force's progression through three distinct phases, each marked by extensive consultation and culminating in a comprehensive report submitted to Health Canada. A particular focus is placed on the third phase, which resulted in the formulation of An Action Plan for Pain in Canada, and we present an overview of the recommendations contained therein. Moreover, the article situates the Canadian Pain Task Force within the broader movement to transform how pain is recognized, understood, and treated in Canada. It highlights initial steps taken to address identified priorities, indicating a proactive approach toward effecting meaningful change.
En 2019, Santé Canada a créé le Groupe de travail canadien sur la douleur. Par cet engagement, le Canada s'est joint à d'autres pays, comme les États-Unis et l'Australie, pour mettre en place un mécanisme national visant à soutenir le travail dans le domaine de la douleur chronique. Cet article présente un historique des efforts de plaidoyer nationaux et régionaux qui ont conduit à la création du Groupe de travail, la représentation diversifiée de ses membres, ainsi que son mandat et ses objectifs. Il décrit ensuite la progression du Groupe de travail en trois phases distinctes, chacune marquée par de vastes consultations et aboutissant à la présentation d'un rapport complet à Santé Canada. Une attention particulière est accordée à la troisième phase, qui a abouti à la formulation d'un Plan d'action pour la douleur au Canada. Nous présentons également un aperçu des recommandations qu'il contient. En outre, l'article situe le Groupe de travail canadien sur la douleur dans le cadre d'un mouvement plus large visant à transformer la façon dont la douleur est reconnue, comprise et traitée au Canada. Il met en lumière les premières mesures prises pour répondre aux priorités recensées, ce qui témoigne d'une approche proactive visant à apporter des changements significatifs.
RESUMEN
BACKGROUND: Rheumatoid arthritis (RA) is typically preceded by an extended preclinical period where circulating autoantibodies, particularly anti-citrullinated protein antibodies (ACPA), are detectable in the absence of clinical arthritis. Increased dietary intake of anti-inflammatory omega-3 (ω3) polyunsaturated fatty acids (PUFA) has been shown to be associated with a lower the risk of developing incident RA in large epidemiological studies. It is currently not known how changes in fatty acid (FA) metabolism may impact on the progression towards RA in at-risk individuals. To begin to address this question, we profiled serum FAs and oxylipins in an established cohort of at-risk ACPA-positive first-degree relatives (FDR) of RA patients (N = 31), some of whom developed RA (N = 4), and compared their profile to ACPA-negative FDR from the same population (N = 10). METHODS: Gas chromatography (GC) was used for FA quantitation. Oxylipins were extracted and quantified using high-performance liquid chromatography-tandem mass spectrometry (HPLC/MS/MS). RESULTS: Although we did not detect any meaningful differences in overall FA content between ACPA + and ACPA - FDR, the levels of oxylipins derived from FA metabolism demonstrated significant differences between the two groups, with the ACPA + group demonstrating enrichment in circulating arachidonic acid- and eicosapentaenoic acid-derived molecules. Compared with the ACPA - FDR group, the ACPA + FDR, including those who progressed into inflammatory arthritis, displayed higher levels of LOX-derived oxylipins. CONCLUSION: ACPA seropositivity in otherwise unaffected individuals at-risk for developing future RA based on family history (FDR) is associated with alterations in the serum oxylipin profile that suggests dysregulated LOX activity.
Asunto(s)
Anticuerpos Antiproteína Citrulinada , Artritis Reumatoide , Humanos , Oxilipinas , Espectrometría de Masas en Tándem , Autoanticuerpos , LipooxigenasasRESUMEN
OBJECTIVES: Chronic inflammation promotes cardiovascular risk in rheumatoid arthritis (RA). Biological disease-modifying antirheumatic drugs (bDMARDs) improve disease activity and cardiovascular disease outcomes. We explored whether bDMARDs influence the impact of disease activity and inflammatory markers on long-term cardiovascular risk in RA. METHODS: We studied 4370 participants without cardiovascular disease in a 10-country observational cohort of patients with RA. Endpoints were (1) major adverse cardiovascular events (MACE) encompassing myocardial infarction, stroke and cardiovascular death; and (2) any ischaemic cardiovascular events (iCVE) including MACE plus revascularisation, angina, transient ischaemic attack and peripheral arterial disease. RESULTS: Over 26 534 patient-years, 239 MACE and 362 iCVE occurred. The interaction between 28-joint Disease Activity Score with C-reactive protein (DAS28-CRP) and bDMARD use was significant for MACE (p=0.017), suggesting the effect of DAS28-CRP on MACE risk differed among bDMARD users (n=515) and non-users (n=3855). DAS28-CRP (per unit increase) is associated with MACE risk in bDMARD non-users (HR 1.21 (95% CI 1.07 to 1.37)) but not users (HR 0.69 (95% CI 0.40 to 1.20)). The interaction between CRP (per log unit increase) and bDMARD use was also significant for MACE (p=0.011). CRP associated with MACE risk in bDMARD non-users (HR 1.16 (95% CI 1.04 to 1.30)), but not users (HR 0.65 (95% CI 0.36 to 1.17)). No interaction was observed between bDMARD use and DAS28-CRP (p=0.167) or CRP (p=0.237) for iCVE risk. CONCLUSIONS: RA activity and inflammatory markers associated with risk of MACE in bDMARD non-users but not users suggesting the possibility of biological-specific benefits locally on arterial wall independently of effects on systemic inflammation.
Asunto(s)
Antirreumáticos , Artritis Reumatoide , Enfermedades Cardiovasculares , Inflamación , Humanos , Artritis Reumatoide/complicaciones , Artritis Reumatoide/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Antirreumáticos/uso terapéutico , Antirreumáticos/efectos adversos , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/mortalidad , Anciano , Biomarcadores , Proteína C-Reactiva/metabolismo , Proteína C-Reactiva/análisis , Factores de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
The impact of cigarette smoke (CS), a risk factor for rheumatoid arthritis (RA), on sauto-antibody production was studied in humans and mice with and without chronic lung disease (LD). Rheumatoid factor (RF), anti-cyclic citrullinated peptides (CCPs), and anti-HSP70 autoantibodies were measured in several mouse strains and in cohorts of smokers and nonsmokers with and without autoimmune disease. Chronic smoking-induced RFs in AKR/J mice, which are most susceptible to LD. RFs were identified in human smokers, preferentially in those with LD. Anti-HSP70 auto-antibodies were identified in CS-exposed AKR/J mice but not in ambient air exposed AKR/J controls. Whereas inflammation could induce anti-HSP70 IgM, smoke exposure promoted the switch to anti-HSP70 IgG autoantibodies. Elevated anti-CCP autoantibodies were not detected in CS-exposed mice or smokers. AKR/J splenocytes stimulated in vitro by immune complexes (ICs) of HSP70/anti-HSP70 antibodies produced RFs. The CD91 scavenger pathway was required as anti-CD91 blocked the HSP70-IC-induced RF response. Blocking Toll-like receptors did not influence the HSP70-IC-induced RFs. These studies identify both anti-HSP70 and RFs as serological markers of smoke-related LD in humans and mice. Identification of these autoantibodies could suggest a common environmental insult, namely CS, in a number of different disease settings.
Asunto(s)
Proteínas HSP70 de Choque Térmico/inmunología , Inmunoglobulina G/inmunología , Inmunoglobulina M/inmunología , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Factor Reumatoide/inmunología , Contaminación por Humo de Tabaco/efectos adversos , Anciano , Biomarcadores/sangre , Estudios de Cohortes , Femenino , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/antagonistas & inhibidores , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/sangre , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/inmunología , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/sangre , Enfermedad Pulmonar Obstructiva Crónica/inducido químicamente , Enfermedad Pulmonar Obstructiva Crónica/patología , Factor Reumatoide/sangreRESUMEN
OBJECTIVE: To update estimates of cancer risk in SLE relative to the general population. METHODS: A multisite international SLE cohort was linked with regional tumor registries. Standardized incidence ratios (SIRs) were calculated as the ratio of observed to expected cancers. RESULTS: Across 30 centres, 16,409 patients were observed for 121,283 (average 7.4) person-years. In total, 644 cancers occurred. Some cancers, notably hematologic malignancies, were substantially increased (SIR 3.02, 95% confidence interval, CI, 2.48, 3.63), particularly non-Hodgkin's lymphoma, NHL (SIR 4.39, 95% CI 3.46, 5.49) and leukemia. In addition, increased risks of cancer of the vulva (SIR 3.78, 95% CI 1.52, 7.78), lung (SIR 1.30, 95% CI 1.04, 1.60), thyroid (SIR 1.76, 95% CI 1.13, 2.61) and possibly liver (SIR 1.87, 95% CI 0.97, 3.27) were suggested. However, a decreased risk was estimated for breast (SIR 0.73, 95% CI 0.61-0.88), endometrial (SIR 0.44, 95% CI 0.23-0.77), and possibly ovarian cancers (0.64, 95% CI 0.34-1.10). The variability of comparative rates across different cancers meant that only a small increased risk was estimated across all cancers (SIR 1.14, 95% CI 1.05, 1.23). CONCLUSION: These data estimate only a small increased risk in SLE (versus the general population) for cancer over-all. However, there is clearly an increased risk of NHL, and cancers of the vulva, lung, thyroid, and possibly liver. It remains unclear to what extent the association with NHL is mediated by innate versus exogenous factors. Similarly, the etiology of the decreased breast, endometrial, and possibly ovarian cancer risk is uncertain, though investigations are ongoing.
Asunto(s)
Lupus Eritematoso Sistémico/epidemiología , Neoplasias/epidemiología , Adulto , Asia/epidemiología , Neoplasias de la Mama/epidemiología , Canadá/epidemiología , Estudios de Cohortes , Europa (Continente)/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Cooperación Internacional , Linfoma no Hodgkin/epidemiología , Masculino , Neoplasias Ováricas/epidemiología , Riesgo , Estados Unidos/epidemiologíaRESUMEN
OBJECTIVE: Rheumatoid arthritis (RA) is prevalent in North American Native populations, with a high frequency of multicase families and seropositivity in first-degree relatives. This study was undertaken to determine whether the serum cytokine profile of first-degree relatives of North American Native patients with RA differed from that of individuals with no family history of autoimmunity and whether there was an association with RA autoantibodies. METHODS: North American Native patients with RA (n = 105), their first-degree relatives (n = 273), healthy North American Native controls (n = 200), and Caucasian controls (n = 150) were studied. Serum levels of 42 cytokines were tested using a multiplex laser bead assay. Rheumatoid factor (RF), anti-cyclic citrullinated peptide 2 (anti-CCP-2), monocyte chemotactic protein 1 (MCP-l), and high-sensitivity C-reactive protein (hsCRP) were tested by enzyme-linked immunosorbent assay, and HLA-DRB1 alleles by specific primers. Discriminant analysis and logistic regression classified individuals based on their cytokine profile. RESULTS: The prevalence of RF (cutoff level predetermined to include 5% of Caucasian controls) and anti-CCP (cutoff level of ≥40 units) was, respectively, 88% and 81% in the RA patients, 34% and 9% in first-degree relatives, and 9% and 4% in North American Native controls; the prevalence of anti-CCP was 0% in Caucasian controls. Levels of most cytokines were highest in RA patients; 17 of 40 cytokines (43%) were significantly higher in first-degree relatives than in controls, including multiple proinflammatory cytokines. Discriminant analysis showed a notable distinction between the groups, with 85% classification accuracy. First-degree relatives had markedly higher MCP-1 and hsCRP levels than North American Native controls, but there was no consistent association with RA autoantibodies. CONCLUSION: Our findings indicate that levels of multiple cytokines and hsCRP are higher in first-degree relatives of North American Native patients with RA compared to individuals from a nonautoimmune background. These data suggest that elevated baseline cytokine levels may be part of the risk profile for developing RA.
Asunto(s)
Artritis Reumatoide/genética , Autoinmunidad/genética , Citocinas/genética , Predisposición Genética a la Enfermedad , Indígenas Norteamericanos/genética , Adulto , Artritis Reumatoide/sangre , Artritis Reumatoide/inmunología , Autoanticuerpos/sangre , Autoanticuerpos/genética , Autoanticuerpos/inmunología , Autoinmunidad/inmunología , Proteína C-Reactiva/genética , Proteína C-Reactiva/inmunología , Citocinas/sangre , Citocinas/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Péptidos Cíclicos/sangre , Péptidos Cíclicos/inmunología , Factor Reumatoide/sangre , Factor Reumatoide/genética , Factor Reumatoide/inmunologíaRESUMEN
Cytokines IL-32 and IL-17 are emerging as critical players in the pathophysiology of immune-mediated chronic inflammatory diseases. It has been speculated that the molecular mechanisms governing IL-32- and IL-17-mediated cellular responses are differentially dependent on the TNF pathway. In this study, kinome analysis demonstrated that following stimulation with cytokine IL-32, but not IL-17, there was increased phosphorylation of a peptide target corresponding to TNF-R1. Consistent with this observation, blocking TNF-R1 resulted in a suppression of IL-32-induced downstream responses, indicating that IL-32-mediated activity may be dependent on TNF-R1. In contrast, blocking TNF-R1 did not affect IL-17-induced downstream responses. Kinome analysis also implicated p300 (transcriptional coactivator) and death-associated protein kinase-1 (DAPK-1) as signaling intermediates for both IL-32 and IL-17. Phosphorylation of p300 and DAPK-1 upon stimulation with either IL-32 or IL-17 was confirmed by immunoblots. The presence of common targets was supported by results demonstrating similar downstream responses induced in the presence of IL-32 and IL-17, such as transcriptional responses and the direct activation of NF-κB. Furthermore, knockdown of p300 and DAPK-1 altered downstream responses induced by IL-32 and IL-17, and impacted certain cellular responses induced by TNF-α and IL-1ß. We hypothesize that p300 and DAPK-1 represent nodes where the inflammatory networks of IL-32 and IL-17 overlap, and that these proteins would affect both TNF-R1-dependent and -independent pathways. Therefore, p300 and DAPK-1 are viable potential therapeutic targets for chronic inflammatory diseases.
Asunto(s)
Citocinas/metabolismo , Mediadores de Inflamación/metabolismo , Interleucina-17/metabolismo , Interleucinas/metabolismo , Receptores del Factor de Necrosis Tumoral/inmunología , Proteínas Reguladoras de la Apoptosis , Proteínas Quinasas Dependientes de Calcio-Calmodulina , Proteínas Quinasas Asociadas a Muerte Celular , Humanos , Transducción de Señal , Factores de Transcripción p300-CBPRESUMEN
Curcumin, a component of the South-Asian spice turmeric, elicits anti-inflammatory functions. We have previously demonstrated that a highly bioavailable formulation of cucurmin, Cureit/Acumin™ (CUR), can suppress disease onset and severity, in a collagen-induced arthritis (CIA) mouse model. In a previous study, we have also shown that the abundance of antimicrobial host defence peptides, specifically cathelicidin (CRAMP) and calprotectin (S100A8 and S100A9), is significantly increased in the joint tissues of CIA mice. Elevated levels of cathelicidin and calprotectin have been associated with the pathogenesis of rheumatoid arthritis. Therefore, in this study, we examined the effect CUR administration on the abundance of cathelicidin and calprotectin in the joints, in a CIA mouse model. Here, we demonstrate that daily oral administration of CUR significantly reduces the elevated levels of CRAMP and calprotectin to baseline in the joints of CIA mice. We also show a linear correlation between the abundance of these peptides in the joints with serum inflammatory cytokines TNFα, IFNγ, and MCP-1. Overall, our results suggest that oral administration of a bioavailable CUR can suppress cathelicidin and calprotectin in the joints and regulate both local (joints) and systemic (serum) inflammation, in inflammatory arthritis.
Asunto(s)
Artritis Experimental , Curcumina , Animales , Ratones , Péptidos Catiónicos Antimicrobianos , Catelicidinas , Complejo de Antígeno L1 de Leucocito , Artritis Experimental/tratamiento farmacológico , Modelos Animales de EnfermedadRESUMEN
Rheumatoid Arthritis (RA) is a common autoimmune disease that targets the synovial joints leading to arthritis. Although the etiology of RA remains largely unknown, it is clear that numerous modifiable risk factors confer increased risk to developing RA. Of these risk factors, cigarette smoking, nutrition, obesity, occupational exposures and periodontal disease all incrementally increase RA risk. However, the precise immunological mechanisms by which these risk factors lead to RA are not well understood. Basic and translational studies have provided key insights into the relationship between inflammation, antibody production and the influence in other key cellular events such as T cell polarization in RA risk. Improving our general understanding of the mechanisms which lead to RA will help identify targets for prevention trials, which are underway in at-risk populations. Herein, we review the modifiable risk factors that are linked to RA development and describe immune mechanisms that may be involved. We highlight the few studies that have sought to understand if modification of these risk factors reduces RA risk. Finally, we speculate that modification of risk factors may be an appealing avenue for prevention for some at-risk individuals, specifically those who prefer lifestyle interventions due to safety and economic reasons.
Asunto(s)
Artritis Reumatoide , Enfermedades Autoinmunes , Humanos , Artritis Reumatoide/etiología , Artritis Reumatoide/prevención & control , Factores de Riesgo , Inflamación , ObesidadRESUMEN
Advances in rheumatoid arthritis (RA) management have significantly improved clinical outcomes of this disease; however, some Indigenous North Americans (INA) with RA have not achieved the high rates of treatment success observed in other populations. We review factors contributing to poor long-term outcomes for INA with RA. We conducted a narrative review of studies evaluating RA in INA supplemented with regional administrative health and clinical cohort data on clinical outcomes and health care utilisation. We discuss factors related to conducting research in INA populations including studies of RA prevention. NA with RA have a high burden of genetic and environmental predisposing risk factors that may impact disease phenotype, delayed or limited access to rheumatology care and advanced therapy. These factors may contribute to the observed increased rates of persistent synovitis, premature end-stage joint damage and mortality. Novel models of care delivery that are culturally sensitive and address challenges associated with providing speciality care to patients residing in remote communities with limited accessibility are needed. Progress in establishing respectful research partnerships with INA communities has created a foundation for ongoing initiatives to address care gaps including those aimed at RA prevention. This review highlights some of the challenges of diagnosing, treating, and ultimately perhaps preventing, RA in INA populations.
Asunto(s)
Artritis Reumatoide , Humanos , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/tratamiento farmacológico , Estudios Longitudinales , Grupos de Población , Pueblos Indígenas , América del NorteRESUMEN
BACKGROUND: Rheumatoid arthritis (RA) occurs across the globe in different ethnic populations. Most RA patients harbor anti-modified protein antibodies (AMPA); however, it is unclear whether differences exist in autoantibody responses at different geographic locations and between different ethnic groups, which could provide new clues regarding factors underlying autoantibody development. We therefore investigated AMPA prevalence and association with HLA DRB1 alleles and smoking in four ethnically diverse populations on four different continents. METHODS: Anti-carbamylated (anti-CarP), anti-malondialdehyde acetaldehyde (anti-MAA), and anti-acetylated protein antibodies (anti-AcVim) IgG were determined in anti-citrullinated protein antibody-positive Dutch (NL, n = 103), Japanese (JP, n = 174), First Nations Peoples in Canada (FN, n = 100), and black South African (SA, n = 67) RA patients. Ethnicity-matched local healthy controls were used to calculate cut-offs. Risk factors associated with AMPA seropositivity in each cohort were identified using logistic regression. RESULTS: Median AMPA levels were higher in First Nations Peoples in Canada and especially South African patients, as reflected by percentage seropositivity: NL, JP, FN, and SA: anti-CarP: 47%, 43%, 58%, and 76% (p < 0.001); anti-MAA: 29%, 22%, 29%, and 53% (p < 0.001); and anti-AcVim: 20%, 17%, 38%, and 28% (p < 0.001). Total IgG levels also differed markedly, and when autoantibody levels were normalized to total IgG, differences between cohorts became less pronounced. Although there were some associations with AMPA and HLA risk alleles and smoking, none was consistent across all four cohorts. CONCLUSIONS: AMPA against various post-translational modifications could consistently be detected on different continents across ethnically diverse RA populations. Differences in AMPA levels corresponded to differences in total serum IgG levels. This suggests that, despite differences in risk factors, a common pathway may be involved in AMPA development across geographic locations and ethnicities.
Asunto(s)
Artritis Reumatoide , Autoanticuerpos , Humanos , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico , Factores de Riesgo , Inmunoglobulina G , Péptidos CíclicosRESUMEN
BACKGROUND: Inflammatory bowel disease is the result of both genes and environment. Canadian First Nations people, despite living in a region with a high prevalence of inflammatory bowel disease, are relatively protected from this disease. We aimed to compare the carriage of genetic variants associated with inflammatory bowel disease in healthy First Nations and white people. METHODS: DNA was extracted from the venous blood of healthy First Nations (n = 340) and white (n = 285) participants from Manitoba. Genotyping was performed for 69 single nucleotide polymorphisms (SNPs) with known or suspected associations with inflammatory bowel disease. We compared the genotypes between groups by logistic regression, adjusting for multiple testing. We calculated a risk score for the NOD2 gene by adding the number of risk alleles at three important NOD2 SNPs (G908R, R702W and 3020insC). RESULTS: We found genetic variation between white and First Nations participants at 45 of 69 SNPs. Notably, carriage of the ATG16L1 T300A mutation was lower in First Nations participants (p = 4.1 × 10(-30)). Cumulative carriage of important NOD2 variants was significantly lower among First Nations participants (3.9% v. 15.2%; p < 0.0001 for risk score) than among white participants. Risk variants in IL23R (p = 0.014) and IL12B (p = 1.2 × 10(-16)), among others, were more prevalent among First Nations participants than among white participants. INTERPRETATION: The low prevalence of variants associated with bacterial processing and handling in First Nations people may explain their relative protection from inflammatory bowel disease. Increased carriage of a number of risk variants, for example in the interleukin-23/Th17 pathway, is especially intriguing given their importance in other inflammatory diseases of high incidence in First Nations populations.