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BACKGROUND: Preclinical rheumatoid arthritis (Pre-RA) is defined as the early stage before the development of clinical RA. While cachexia is a well-known and potentially modifiable complication of RA, it is not known if such an association exists also in the Pre-RA stage. To investigate such issue, we aimed to compare the longitudinal alterations in the muscle composition and adiposity of participants with Pre-RA with the matched controls. METHODS: In this observational cohort study, the Osteoarthritis Initiative (OAI) participants were categorized into Pre-RA and propensity score (PS)-matched control groups. Pre-RA was retrospectively defined as the absence of RA from baseline to year-2, with progression to physician-diagnosed clinical RA between years 3-8 of the follow-up period. Using a validated deep learning algorithm, we measured MRI biomarkers of thigh muscles and adiposity at baseline and year-2 follow-ups of the cohort. The outcomes were the differences between Pre-RA and control groups in the 2-year rate of change for thigh muscle composition [cross-sectional area (CSA) and intramuscular adipose tissue (Intra-MAT)] and adiposity [intermuscular adipose tissue (Inter-MAT) and subcutaneous adipose tissue (SAT)]. Linear mixed-effect regression models were used for comparison. RESULTS: After 1:3 PS-matching of the groups for confounding variables (demographics, risk factors, co-morbidities, and knee osteoarthritis status), 408 thighs (102 Pre-RA and 306 control) of 322 participants were included (age mean ± SD: 61.7 ± 8.9 years; female/male: 1.8). Over a 2-year period, Pre-RA was associated with a larger decrease in total thigh muscle CSA [estimate, 95% confidence interval (CI): -180.13 mm2/2-year, -252.80 to -107.47, P-value < 0.001]. Further examination of thigh muscle composition showed that the association of the presence of Pre-RA with a larger decrease in muscle CSA over 2 years was noticeable in the quadriceps, flexors, and sartorius muscle groups (P-values < 0.05). Comparison of changes in total adipose tissue showed no difference between Pre-RA and control participants (estimate, 95% CI: 48.48 mm2/2-year, -213.51 to 310.47, P-value = 0.691). However, in the detailed analysis of thigh adiposity, Pre-RA presence was associated with a larger increase in Inter-MAT (estimate, 95% CI: 150.55 mm2/2-year, 95.58 to 205.51, P-value < 0.001). CONCLUSIONS: Preclinical rheumatoid arthritis is associated with a decrease in muscle cross-sectional area and an increase in intermuscular adipose tissue, similar to rheumatoid cachexia in clinical rheumatoid arthritis. These findings suggest the presence of cachexia in the preclinical phase of rheumatoid arthritis. Given that cachexia, which can exacerbate health outcomes, is potentially modifiable, this study emphasizes the importance of early identification of patients in their preclinical phase.
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OBJECTIVE: Immune checkpoint inhibitor (ICI) therapies have dramatically improved outcomes in multiple cancers. ICI's mechanism of action involves immune system activation to augment anti-tumor immunity. Patients with pre-existing autoimmune diseases, such as systemic sclerosis (SSc), were excluded from initial ICI clinical trials due to concern that such immune system activation could precipitate an autoimmune disease flare or new, severe immune related adverse events (irAE). In the present study, we report our experience with ICIs in patients with pre-existing SSc. METHODS: Patients with SSc who received ICI therapy for cancer were identified from the Johns Hopkins Scleroderma Center Research Registry. Through chart review and prespecified definitions, we identified whether patients experienced worsening SSc activity or new irAEs. SSc disease activity worsening was pre-defined as an increase in modified Rodnan skin score (mRSS), new scleroderma renal crisis, progression of interstitial lung disease (ILD) on CT scan, increased Raynaud's phenomenon frequency or severity, new pulmonary hypertension, or myositis flare. IrAEs also included active inflammatory arthritis and dermatitis. RESULTS: Eight patients with SSc who received ICI therapy for cancer were included. Overall, SSc symptoms remained stable during and after ICI therapy. None of the patients with long-standing sine or limited cutaneous SSc (lcSSc) had progressive skin thickening after ICI therapy. One patient, who was early in his diffuse cutaneous SSc (dcSSc) disease course, experienced worsening skin thickening and renal crisis. Three patients (38 %) experienced a total of five irAEs (grade 2: diarrhea, mucositis and dermatitis; grade 3: pneumonitis, and grade 4: nephritis). The patient with grade 4 nephritis developed scleroderma renal crisis and immune checkpoint related nephritis simultaneously. There were no deaths due to irAEs. CONCLUSION: In this study, ICI therapy was well tolerated in patients with longstanding, sine or lcSSc. IrAE were common but generally manageable. Patients with early, active SSc may be at greater risk from ICI therapy, but more research is needed.
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Inhibidores de Puntos de Control Inmunológico , Neoplasias , Esclerodermia Sistémica , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Esclerodermia Sistémica/tratamiento farmacológico , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/inmunología , Femenino , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Neoplasias/complicaciones , Anciano , Adulto , Resultado del Tratamiento , Progresión de la EnfermedadRESUMEN
Although anti-citrullinated protein autoantibodies (ACPAs) are a hallmark serological feature of rheumatoid arthritis (RA), the mechanisms and cellular sources behind the generation of the RA citrullinome remain incompletely defined. Peptidylarginine deiminase IV (PAD4), one of the key enzymatic drivers of citrullination in the RA joint, is expressed by granulocytes and monocytes; however, the subcellular localization and contribution of monocyte-derived PAD4 to the generation of citrullinated autoantigens remain underexplored. In this study, we demonstrate that PAD4 displays a widespread cellular distribution in monocytes, including expression on the cell surface. Surface PAD4 was enzymatically active and capable of citrullinating extracellular fibrinogen and endogenous surface proteins in a calcium dose-dependent manner. Fibrinogen citrullinated by monocyte-surface PAD4 could be specifically recognized over native fibrinogen by a panel of eight human monoclonal ACPAs. Several unique PAD4 substrates were identified on the monocyte surface via mass spectrometry, with citrullination of the CD11b and CD18 components of the Mac-1 integrin complex being the most abundant. Citrullinated Mac-1 was found to be a target of ACPAs in 25% of RA patients, and Mac-1 ACPAs were significantly associated with HLA-DRB1 shared epitope alleles, higher C-reactive protein and IL-6 levels, and more erosive joint damage. Our findings implicate the monocyte cell surface as a unique and consequential site of extracellular and cell surface autoantigen generation in RA.
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Ácidos Aminosalicílicos , Artritis Reumatoide , Monocitos , Humanos , Desiminasas de la Arginina Proteica , Monocitos/metabolismo , Autoantígenos , Autoanticuerpos , Fibrinógeno/metabolismo , Citrulina/metabolismoRESUMEN
OBJECTIVE: To develop a set of detailed definitions for foundational domains commonly used in OMERACT (Outcome Measures in Rheumatology) core domain sets. METHODS: We identified candidate domain definitions from prior OMERACT publications and websites and publications of major organizations involved in outcomes research for six domains commonly used in OMERACT Core Domain Sets: pain intensity, pain interference, physical function, fatigue, patient global assessment, and health-related quality of life. We conducted a two-round survey of OMERACT working groups, patient research partners, and then the OMERACT Technical Advisory Group to establish their preferred domain definitions. Results were presented at the OMERACT 2023 Methodology Workshop, where participants discussed their relevant lived experience and identified potential sources of variability giving the needed detail in our domain definitions. RESULTS: One-hundred four people responded to both rounds of the survey, and a preferred definition was established for each of the domains except for patient global assessment for which no agreement was reached. Seventy-five participants at the OMERACT 2023 Methodology Workshop provided lived experience examples, which were used to contextualise domain definition reports for each of the five domains. CONCLUSION: Using a consensus-based approach, we have created a detailed definition for five of the foundational domains in OMERACT core domain sets; patient global assessment requires further research. These definitions, although not mandatory for working groups to use, may facilitate the initial domain-match assessment step of instrument selection, and reduce the time and resources required by future OMERACT groups when developing core outcome sets.
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Consenso , Evaluación de Resultado en la Atención de Salud , Calidad de Vida , Reumatología , Humanos , Reumatología/normas , Enfermedades ReumáticasRESUMEN
OBJECTIVE: This real-world analysis assessed baseline demographics/characteristics and treatment patterns/effectiveness in patients with rheumatoid arthritis (RA) initiating tofacitinib (TOF) in the US CorEvitas RA Registry. METHODS: The primary analysis of this study included patients with RA initiating TOF with a 12-month follow-up visit from November 2012 to January 2021. Outcomes included baseline demographics/characteristics and TOF initiation/discontinuation reasons, treatment patterns, and effectiveness (disease activity and patient-reported outcomes [PROs] at 12 months); the primary effectiveness outcome was Clinical Disease Activity Index low disease activity (CDAI LDA). All data, analyzed descriptively, were stratified by TOF regimen (monotherapy vs combination therapy), line of therapy (second- to fourth-line), time of initiation (2012-2014, 2015-2017, or 2018-2020), and dose (5 mg twice daily vs 11 mg once daily). RESULTS: Of 2874 patients with RA who initiated TOF, 1298 had a qualifying 12-month follow-up visit; of these, 43.1% were monotherapy and 66.5% were fourth-line therapy. Overall, tumor necrosis factor inhibitors (40.8%) were the most common treatment immediately prior to TOF initiation. The most common reason for TOF initiation (among those with a reason) was lack/loss of efficacy of prior treatment (67.7%). Overall, at 12 months, 31.9% and 10.1% had achieved CDAI LDA and remission, respectively; 22.4%, 10.4%, and 5% had achieved ≥ 20%, ≥ 50%, and ≥ 70% improvement in modified American College of Rheumatology core set measures, respectively; and improvements in PROs were observed. Effectiveness was generally similar across TOF stratifications. CONCLUSION: TOF effectiveness (CDAI LDA) was observed in a US real-world setting of patients with RA regardless of TOF regimen, line of therapy, time of initiation, and dose. (ClinicalTrials.gov: NCT04721808).
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Antirreumáticos , Artritis Reumatoide , Piperidinas , Pirimidinas , Sistema de Registros , Humanos , Artritis Reumatoide/tratamiento farmacológico , Pirimidinas/uso terapéutico , Piperidinas/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Antirreumáticos/uso terapéutico , Resultado del Tratamiento , Anciano , Adulto , Inhibidores de Proteínas Quinasas/uso terapéutico , Medición de Resultados Informados por el Paciente , Índice de Severidad de la Enfermedad , Quimioterapia CombinadaRESUMEN
Positive emotions are a promising target for intervention in chronic pain, but mixed findings across trials to date suggest that existing interventions may not be optimized to efficiently engage the target. The aim of the current pilot mechanistic randomized controlled trial was to test the effects of a positive emotion-enhancing intervention called Savoring Meditation on pain-related neural and behavioral targets in patients with rheumatoid arthritis. Participants included 44 patients with a physician-confirmed diagnosis of rheumatoid arthritis (n = 29 included in functional magnetic resonance imaging (fMRI) analyses), who were randomized to either Savoring Meditation or a Slow Breathing control. Both meditation interventions were brief (four 20-minute sessions). Self-report measures were collected pre-and post-intervention. An fMRI task was conducted at post-intervention, during which participants practiced the meditation technique on which they had been trained while exposed to non-painful and painful thermal stimuli. Savoring significantly reduced experimental pain intensity ratings relative to rest (P < .001). Savoring also increased cerebral blood flow in the ventromedial prefrontal cortex and increased connectivity between the ventromedial prefrontal cortex and caudate during noxious thermal stimulation relative to Slow Breathing (z = 2.3 voxelwise, false discovery rate cluster corrected P = .05). Participants in the Savoring condition also reported significantly increased positive emotions (ps < .05) and reduced anhedonic symptoms (P < .01) from pre- to post-intervention. These findings suggest that Savoring recruits reward-enhancing corticostriatal circuits in the face of pain, and future work should extend these findings to evaluate if these mechanisms of Savoring are associated with improved clinical pain outcomes in diverse patient populations. PERSPECTIVE: Savoring Meditation is a novel positive emotion-enhancing intervention designed for patients with chronic pain. The present findings provide preliminary evidence that Savoring Meditation is acutely analgesic, and engages neural and subjective emotional targets that are relevant to pain self-management. Future work should evaluate the clinical translation of these findings.
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Artritis Reumatoide , Emociones , Imagen por Resonancia Magnética , Meditación , Humanos , Femenino , Masculino , Persona de Mediana Edad , Artritis Reumatoide/fisiopatología , Artritis Reumatoide/terapia , Artritis Reumatoide/psicología , Emociones/fisiología , Adulto , Anciano , Dolor Crónico/terapia , Dolor Crónico/fisiopatología , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Proyectos PilotoRESUMEN
BACKGROUND: Given that autoantibodies to peptidylarginine deiminase 4 (PAD4) are associated with erosive disease in established rheumatoid arthritis (RA), this study was conducted to compare the clinical and prognostic use of anti-PAD4 antibodies in patients with early and established RA. METHODS: Sera from patients with early (duration <2 years; n = 422) or established (duration ≥2 years; n = 359) RA from two randomized clinical trials of tofacitinib ± methotrexate compared with adalimumab + MTX or MTX alone were evaluated for the presence of anti-PAD4 and anti-PAD3/4 antibodies at baseline and posttreatment time points. Summary statistics were calculated for demographic, clinical, and serological characteristics, and generalized estimating equations were used to model clinical outcomes by disease duration according to anti-PAD4 status. RESULTS: Anti-PAD4 antibodies were present in 22% and 40% of patients with early and established RA, respectively, stable following treatment, and associated with baseline joint damage only in established RA. In early RA, baseline anti-PAD4 antibodies were associated with a greater improvement in disease activity score 28-joint count using C-reactive protein levels after treatment compared with individuals with negative anti-PAD4 (P = 0.049). Tofacitinib ± MTX was more broadly efficacious than MTX alone at improving clinical outcomes in early and established RA, irrespective of anti-PAD4 status (P < 0.05 for all), whereas adalimumab + MTX exhibited differential benefits in achieving disease activity score remission in early RA (P = 0.036) and American College of Rheumatology 20 responses in established RA (P = 0.002). CONCLUSION: Differences in prevalence, clinical associations, and treatment-response outcomes according to anti-PAD4 antibody status in early and established RA suggests the existence of a therapeutic window to prevent the accumulation of irreversible joint damage in early patients with RA with anti-PAD4 antibodies.
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Patients with inflammatory arthritis (IA) are at increased risk of severe COVID-19 due to medication-induced immunosuppression that impairs host defenses. The aim of this study was to assess antibody and B cell responses to COVID-19 mRNA vaccination in IA patients receiving immunomodulatory therapies. Adults with IA were enrolled through the Johns Hopkins Arthritis Center and compared with healthy controls (HC). Paired plasma and peripheral blood mononuclear cell (PBMC) samples were collected prior to and 30 days or 6 months following the first two doses of mRNA vaccines (D2; HC=77 and IA=31 patients), or 30 days following a third dose of mRNA vaccines (D3; HC=11 and IA=96 patients). Neutralizing antibody titers, total binding antibody titers, and B cell responses to vaccine and Omicron variants were analyzed. Anti-Spike (S) IgG and S-specific B cells developed appropriately in most IA patients following D3, with reduced responses to Omicron variants, and negligible effects of medication type or drug withholding. Neutralizing antibody responses were lower compared to healthy controls after both D2 and D3, with a small number of individuals demonstrating persistently undetectable neutralizing antibody levels. Most IA patients respond as well to mRNA COVID-19 vaccines as immunocompetent individuals by the third dose, with no evidence of improved responses following medication withholding. These data suggest that IA-associated immune impairment may not hinder immunity to COVID-19 mRNA vaccines in most individuals.
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Formación de Anticuerpos , Artritis , Vacunas contra la COVID-19 , COVID-19 , Adulto , Humanos , Anticuerpos Neutralizantes , Artritis/tratamiento farmacológico , COVID-19/prevención & control , Vacunas contra la COVID-19/inmunología , Inmunomodulación , Leucocitos Mononucleares , Cambio de Clase de Inmunoglobulina , Vacunas de ARNm/inmunología , Linfocitos B/inmunología , Anticuerpos AntiviralesRESUMEN
Positive emotions are a promising target for intervention in chronic pain, but mixed findings across trials to date suggest that existing interventions may not be optimized to efficiently engage the target. The aim of the current mechanistic randomized controlled trial was to test the effects of a single skill positive emotion-enhancing intervention called Savoring Meditation on pain-related neural and behavioral targets in patients with rheumatoid arthritis (RA). Participants included 44 patients with a physician-confirmed diagnosis of RA (n=29 included in fMRI analyses), who were randomized to either Savoring Meditation or a Slow Breathing control. Both meditation interventions were brief (four 20-minute sessions). Self-report measures were collected pre- and post-intervention. An fMRI task was conducted at post-intervention, during which participants practiced the meditation technique on which they had been trained while exposed to non-painful and painful thermal stimuli. Relative to Slow Breathing, Savoring significantly reduced experimental pain intensity ratings relative to rest (p<.001), increased cerebral blood flow in the ventromedial prefrontal cortex (vmPFC) and increased connectivity between the vmPFC and caudate during noxious thermal stimulation (z=2.3 voxelwise, FDR cluster corrected p=0.05). Participants in the Savoring condition also reported significantly increased positive emotions (ps<.05) and reduced anhedonic symptoms (p<.01) from pre- to post-intervention. These findings suggest that that Savoring recruits reward-enhancing corticostriatal circuits in the face of pain, and future work should extend these findings to evaluate if these mechanisms of Savoring are associated with improved clinical pain outcomes in diverse patient populations.
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Patients with pre-existing autoimmune disorders and cancer considering immune checkpoint inhibitors (ICIs) need to receive balanced information about the benefits and risk of developing immune-related adverse events (irAEs) and flare-ups of their autoimmune disease. To assess the learning needs of patients with cancer and pre-existing autoimmune disease regarding ICI treatment, we interviewed 29 patients with autoimmune disease and cancer from a comprehensive cancer center, of whom 20 had received ICI and 9 were candidates to receive ICI at a US Cancer Center. In-depth semi-structured interviews were conducted from August 2021 and January 2022. Interviewee's opinions and preferences about content and information delivery methods were collected. We recorded and transcribed interviews and analyzed them using thematic analysis. Half of the participants were female, and their median (SD) age was 62.9 (±10.9) years. The identified health information needs included the following: (1) information on irAEs and autoimmune disease flare-ups; (2) benefits of ICI; (3) ICI mechanism in the context of autoimmune disease; (4) management of flare-ups; (5) reasons for stopping or modifying cancer or autoimmune disease treatment; (6) likelihood of autoimmune disease progression or organ damage; and (7) lifestyle changes that could help avoid irAEs. Patients who had received ICI and those who had not yet received treatment reported similar needs, although patients who had received ICI had more questions about cancer treatment modifications. Patients also expressed the need to better understand when to contact their provider and how to share information with multiple providers. Most patients wanted to receive information in visual formats for review at home and at their own pace. Patients expressed interest in having educational tools to facilitate shared decision-making with their physicians, and they identified several areas of health information concerning therapy with ICI. They also highlighted the importance of communication among their various providers.
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Chikungunya fever is a global vector-borne viral disease. Patients with acute chikungunya are usually treated symptomatically. The arthritic phase may be self-limiting. However, many patients develop extremely disabling arthritis that does not improve after months. The aim of this study was to describe the treatment of chikungunya arthritis (CHIKA) patients. A medical records review was conducted in 133 CHIKA patients seen at a rheumatology practice. Patients were diagnosed by clinical criteria and confirmed by the presence of anti-chikungunya IgM. Patients were treated with methotrexate (20 mg/week) and/or leflunomide (20 mg/day) and dexamethasone (0-4 mg/day) for 4 weeks. At baseline visit and 4 weeks after treatment, Disease Activity Score 28 (DAS28) and pain (using a visual analog scale) were ascertained. Five months after the end of treatment, patients were contacted to assess pain, tender joint count, and swollen joint count. The mean age of patients was 58.6 ± 13.7 years, and 119 (85%) were female. After 4 weeks of treatment, mean (SD) DAS28-erythrocyte sedimentation rate (6.0 [1.2] versus 2.7 [1.0], P < 0.001) and pain (81.8 [19.2] to 13.3 [22.9], P < 0.001) scores significantly decreased. A total of 123 patients were contacted 5 months after the end of treatment. Pain score, tender joint count, and swollen joint count significantly declined after 4 weeks of treatment, and the response was sustained for 5 months. In this group of patients with CHIKA, 4-week treatment induced a rapid clinical improvement that was maintained 5 months after the end of therapy; however, the contribution of treatment to these outcomes is uncertain.
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Antirreumáticos , Artritis Reumatoide , Fiebre Chikungunya , Humanos , Femenino , Adulto , Persona de Mediana Edad , Anciano , Masculino , Antirreumáticos/uso terapéutico , Brasil/epidemiología , Fiebre Chikungunya/diagnóstico , Fiebre Chikungunya/tratamiento farmacológico , Resultado del Tratamiento , Quimioterapia Combinada , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVES: To determine baseline risk factors for requiring immunosuppression and having persistent arthritis in patients with immune checkpoint inhibitor-induced inflammatory arthritis (ICI-IA). METHODS: Participants were adults with rheumatologist diagnosed ICI-IA. The primary outcome was requirement of conventional synthetic (cs) or biologic (b) DMARDs; other outcomes were persistence of IA > 6 months after ICI cessation and requirement of corticosteroids. Logistic regression models evaluated associations between clinical features and primary and secondary outcomes, with adjustment for potential confounders, as appropriate. RESULTS: 126 patients with ICI-IA were included; 53 patients (42%) required a csDMARD/bDMARD. In univariate logistic regressions, higher CDAI, tenosynovitis, longer symptom duration before first rheumatology visit, and longer ICI duration were significantly associated with a higher likelihood of requiring DMARDs; there was a trend toward those treated with prior chemotherapy being less likely to need DMARDs. After adjustment, tenosynovitis, longer symptom duration, and higher CDAI remained associated with requiring DMARDs, while those with prior chemotherapy were significantly less likely to require DMARDs. Combination anti-CTLA-4/PD-1 therapy and steroid use at baseline were associated with a higher risk of persistent IA. CONCLUSION: Higher levels of disease activity, tenosynovitis, and longer symptom duration prior to rheumatology referral were associated with requiring DMARDs for ICI-IA, while those treated previously with chemotherapy were less likely to require additional immunosuppression. The presence of risk factors for severe disease at baseline may indicate a role for higher initial steroid dose, earlier rheumatology referral, and adoption of immunosuppression beyond steroids to improve outcomes.
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OBJECTIVE: Women with rheumatoid arthritis (RA) have higher pain and worse functional outcomes compared to men, even when treated with similar medications. The objective of this study was to identify sex differences in pain intensity, pain interference, and quantitative sensory tests (QST), which are independent of inflammation, in patients with RA. METHODS: This study is a post hoc analysis of participants in the Central Pain in Rheumatoid Arthritis cohort. Pain intensity was assessed using a 0-10 numeric rating scale. Pain interference was measured using a Patient-Reported Outcomes Measurement Information System computerized adaptive test. QST included pressure pain detection thresholds, temporal summation, and conditioned pain modulation. Women and men were compared using multiple linear regression, adjusted for age, education, race, research site, depression, obesity, RA disease duration, swollen joint count, and C-reactive protein. RESULTS: Mean ± SD pain intensity was 5.32 ± 2.29 among women with RA, compared to 4.60 ± 2.23 among men with RA (adjusted difference 0.83 [95% confidence interval (95% CI) 0.14, 1.53]). Women with RA had lower pressure pain detection thresholds at the trapezius (adjusted difference -1.22 [95% CI -1.73, -0.72]), wrist (adjusted difference -0.57 [95% CI -1.07, -0.06]), and knee (adjusted difference -1.10 [95% CI -2.00, -0.21]). No statistically significant differences in pain interference, temporal summation, and conditioned pain modulation were observed. CONCLUSION: Women reported higher pain intensity and lower pressure pain detection thresholds (higher pain sensitivity) than men. However, pain interference, temporal summation, and conditioned pain modulation did not differ between men and women.
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Artritis Reumatoide , Caracteres Sexuales , Humanos , Femenino , Masculino , Dolor , Artritis Reumatoide/complicaciones , Artritis Reumatoide/diagnóstico , Umbral del Dolor , Dimensión del DolorRESUMEN
Immune checkpoint inhibitors (ICIs) have improved cancer outcomes but can cause severe immune-related adverse events (irAEs) and flares of autoimmune conditions in cancer patients with pre-existing autoimmune disease. The objective of this study was to identify the information physicians perceived as most useful for these patients when discussing treatment initiation with ICIs. Twenty physicians at a cancer institution with experience in the treatment of irAEs were interviewed. Qualitative thematic analysis was performed to organize and interpret data. The physicians were 11 medical oncologists and 9 non-oncology specialists. The following themes were identified: (1) current methods used by physicians to provide information to patients and delivery options; (2) factors to make decisions about whether or not to start ICIs in patients who have cancer and pre-existing autoimmune conditions; (3) learning points for patients to understand; (4) preferences for the delivery of ICI information; and (5) barriers to the implementation of ICI information in clinics. Regarding points to discuss with patients, physicians agreed that the benefits of ICIs, the probability of irAEs, and risks of underlying autoimmune condition flares with the use of ICIs were most important. Non-oncologists were additionally concerned about how ICIs affect the autoimmune disease (e.g., impact on disease activity, need for changes in medications for the autoimmune disease, and monitoring of autoimmune conditions).
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OBJECTIVES: To compare the safety and effectiveness of biologic and conventional disease-modifying antirheumatic drugs (DMARDs) for immune checkpoint inhibitor-associated inflammatory arthritis (ICI-IA). METHODS: The retrospective multicentre observational study included patients with a diagnosis of ICI-IA treated with a tumour necrosis factor inhibitor (TNFi), interleukin-6 receptor inhibitor (IL6Ri) and/or methotrexate (MTX); patients with pre-existing autoimmune disease were excluded. The primary outcome was time to cancer progression from ICI initiation; the secondary outcome was time to arthritis control from DMARD initiation. Cox proportional hazard models were used to compare medication groups, adjusting for confounders. RESULTS: 147 patients were included (mean age 60.3 (SD 11.9) years, 66 (45%) women). ICI-IA treatment was TNFi in 33 (22%), IL6Ri 42 (29%) and MTX 72 (49%). After adjustment for time from ICI initiation to DMARD initiation, time to cancer progression was significantly shorter for TNFi compared with MTX (HR 3.27 (95% CI 1.21 to 8.84, p=0.019)) while the result for IL6Ri was HR 2.37 (95% CI 0.94 to 5.98, p=0.055). Time to arthritis control was faster for TNFi compared with MTX (HR 1.91 (95% CI 1.06 to 3.45, p=0.032)) while the result for IL6Ri was HR 1.66 (95% CI 0.93 to 2.97, p=0.089). A subset analysis in patients with melanoma gave similar results for both cancer progression and arthritis control. CONCLUSION: The treatment of ICI-IA with a biologic DMARD is associated with more rapid arthritis control than with MTX, but may be associated with a shorter time to cancer progression.
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Antirreumáticos , Artritis Reumatoide , Productos Biológicos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Productos Biológicos/uso terapéutico , Quimioterapia Combinada , Inhibidores de Puntos de Control Inmunológico , Inhibidores de la Interleucina-6 , Metotrexato/uso terapéutico , Resultado del Tratamiento , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Factor de Necrosis Tumoral alfaRESUMEN
OBJECTIVE: Randomized controlled trials (RCTs) in biologic-naïve rheumatoid arthritis (RA) patients with high disease activity and inadequate response/intolerance to methotrexate have shown interleukin-6 (IL-6) receptor inhibitors (IL-6Ri) to be superior to tumor necrosis factor inhibitors (TNFi) as monotherapy. This observational study aimed to compare the effectiveness of TNFi vs IL-6Ri as mono- or combination therapy in biologic/targeted synthetic (b/ts) -experienced RA patients with moderate/high disease activity. METHODS: Eligible b/ts-experienced patients from the CorEvitas RA registry were categorized as TNFi and IL-6Ri initiators, with subgroups initiating as mono- or combination therapy. Mixed-effects regression models evaluated the impact of treatment on Clinical Disease Activity Index (CDAI), patient-reported outcomes, and disproportionate pain (DP). Unadjusted and covariate-adjusted effects were reported. RESULTS: Patients initiating IL-6Ri (n = 286) vs TNFi monotherapy (n = 737) were older, had a longer RA history and higher baseline CDAI, and were more likely to initiate as third-line therapy; IL-6Ri (n = 401) vs TNFi (n = 1315) combination therapy initiators had higher baseline CDAI and were more likely to initiate as third-line therapy. No significant differences were noted in the outcomes between TNFi and IL-6Ri initiators (as mono- or combination therapy). CONCLUSION: This observational study showed no significant differences in outcomes among b/ts-experienced TNFi vs IL-6Ri initiators, as either mono- or combination therapy. These findings were in contrast with the previous RCTs in biologic-naïve patients and could be explained by the differences in the patient characteristics included in this study. Further studies are needed to help understand the reasons for this discrepancy in the real-world b/ts-experienced population.
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Antirreumáticos , Artritis Reumatoide , Productos Biológicos , Humanos , Metotrexato/uso terapéutico , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Antirreumáticos/efectos adversos , Resultado del Tratamiento , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/inducido químicamente , Sistema de Registros , Factor de Necrosis Tumoral alfa , Índice de Severidad de la Enfermedad , Productos Biológicos/uso terapéutico , Receptores de Interleucina-6/uso terapéuticoRESUMEN
BACKGROUND: AVERT-2 (a phase IIIb, two-stage study) evaluated abatacept + methotrexate versus methotrexate alone, in methotrexate-naive, anti-citrullinated protein antibody-positive patients with early (≤ 6 months), active RA. This subanalysis investigated whether individual patients who achieved the week 24 Simplified Disease Activity Index (SDAI) remission primary endpoint could sustain remission to 1 year and then maintain it following changes in therapy. METHODS: During the 56-week induction period (IP), patients were randomized to weekly subcutaneous abatacept 125 mg + methotrexate or abatacept placebo + methotrexate. Patients completing the IP who achieved SDAI remission (≤ 3.3) at weeks 40 and 52 entered a 48-week de-escalation (DE) period. Patients treated with abatacept + methotrexate were re-randomized to continue weekly abatacept + methotrexate, or de-escalate and then withdraw abatacept (after 24 weeks), or receive abatacept monotherapy. Proportions of patients achieving sustained SDAI and Boolean remission, and Disease Activity Score in 28 joints using C-reactive protein (DAS28 [CRP]) < 2.6, were assessed. For patients achieving early sustained SDAI remission at weeks 24/40/52, flow between disease activity categories and individual trajectories was evaluated; flow was also evaluated for later remitters (weeks 40/52 but not week 24). RESULTS: Among patients treated with abatacept + methotrexate (n/N = 451/752) at IP week 24, 22% achieved SDAI remission, 17% achieved Boolean remission, and 42% achieved DAS28 (CRP) < 2.6; of these, 56%, 58%, and 74%, respectively, sustained a response throughout IP weeks 40/52. Among patients with a sustained response at IP weeks 24/40/52, 82% (14/17) on weekly abatacept + methotrexate, 81% (13/16) on abatacept monotherapy, 63% (12/19) who de-escalated/withdrew abatacept, and 65% (11/17) on abatacept placebo + methotrexate were in SDAI remission at end of the DE period; rates were higher than for later remitters in all arms except abatacept placebo + methotrexate. CONCLUSIONS: A high proportion of individual patients achieving clinical endpoints at IP week 24 with abatacept + methotrexate sustained their responses through week 52. Of patients achieving early and sustained SDAI remission through 52 weeks, numerically more maintained remission during the DE period if weekly abatacept treatment continued. TRIAL REGISTRATION: NCT02504268 (ClinicalTrials.gov), registered July 21, 2015.
Asunto(s)
Antirreumáticos , Artritis Reumatoide , Humanos , Abatacept/uso terapéutico , Abatacept/efectos adversos , Metotrexato , Antirreumáticos/efectos adversos , Resultado del Tratamiento , Artritis Reumatoide/tratamiento farmacológico , Quimioterapia Combinada , Inducción de RemisiónRESUMEN
INTRODUCTION: One target of rheumatoid arthritis (RA) treatment is to achieve early sustained remission; over the long term, patients in sustained remission have less structural joint damage and physical disability. We evaluated Simplified Disease Activity Index (SDAI) remission with abatacept + methotrexate versus abatacept placebo + methotrexate and impact of de-escalation (DE) in anti-citrullinated protein antibody (ACPA)-positive patients with early RA. METHODS: The phase IIIb, randomized, AVERT-2 two-stage study (NCT02504268) evaluated weekly abatacept + methotrexate versus abatacept placebo + methotrexate. PRIMARY ENDPOINT: SDAI remission (≤ 3.3) at week 24. Pre-planned exploratory endpoint: maintenance of remission in patients with sustained remission (weeks 40 and 52) who, from week 56 for 48 weeks (DE period), (1) continued combination abatacept + methotrexate, (2) tapered abatacept to every other week (EOW) + methotrexate for 24 weeks with subsequent abatacept withdrawal (abatacept placebo + methotrexate), or (3) withdrew methotrexate (abatacept monotherapy). RESULTS: Primary study endpoint was not met: 21.3% (48/225) of patients in the combination and 16.0% (24/150) in the abatacept placebo + methotrexate arm achieved SDAI remission at week 24 (p = 0.2359). There were numerical differences favoring combination therapy in clinical assessments, patient-reported outcomes (PROs) and week 52 radiographic non-progression. After week 56, 147 patients in sustained remission with abatacept + methotrexate were randomized (combination, n = 50; DE/withdrawal, n = 50; abatacept monotherapy, n = 47) and entered DE. At DE week 48, SDAI remission (74%) and PRO improvements were mostly maintained with continued combination therapy; lower remission rates were observed with abatacept placebo + methotrexate (48.0%) and with abatacept monotherapy (57.4%). Before withdrawal, de-escalating to abatacept EOW + methotrexate preserved remission. CONCLUSIONS: The stringent primary endpoint was not met. However, in patients achieving sustained SDAI remission, numerically more maintained remission with continued abatacept + methotrexate versus abatacept monotherapy or withdrawal. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02504268. Video abstract (MP4 62241 KB).
Patients with rheumatoid arthritis (RA) experience inflamed and damaged joints. RA is an autoimmune disease in which proteins called autoantibodies, particularly anti-citrullinated protein autoantibodies, target the patient's own joint tissue and organs by mistake, leading to symptomatic inflammation. Successful treatment can decrease the disease's activity to a state known as remission. Patients in remission may experience little or no symptoms and it may be possible for some to then be able to decrease their treatment. Here, we report the results of a large, international study that looked at two treatments, abatacept and methotrexate, in patients with RA and anti-citrullinated protein autoantibodies. The study had two parts. Firstly, to see how many patients had success (remission) with weekly abatacept and/or methotrexate treatment, and secondly, to see if remission was maintained when treatment was either continued or decreased and stopped. The study showed that the number of patients in remission 6 months after treatment started was not greatly different between patients treated with both abatacept and methotrexate and those treated with just methotrexate. Those taking abatacept and methotrexate together had better remission rates 1 year later. More patients also stayed in remission when they continued to receive both abatacept and methotrexate compared with those who were just treated with abatacept or when their abatacept treatment was decreased and stopped. More patients stayed in remission when abatacept was decreased than when it was stopped. The results from this study may help determine possible future treatment reduction and/or withdrawal plans for some patients with RA.
RESUMEN
Aim: We developed the Patient-Engaged Health Technology Assessment strategy for survey-based goal collection from patients to yield patient-important outcomes suitable for use in multi-criteria decision analysis. Methods: Rheumatoid arthritis patients were recruited from online patient networks for proof-of-concept testing of goal collection and prioritization using a survey. A Project Steering Committee and Expert Panel rated the feasibility of scaling to larger samples. Results: Survey respondents (n = 47) completed the goal collection exercise. Finding effective treatments was rated by respondents as the most important goal, and reducing stiffness was rated as the least important. Feedback from our steering committee and expert panel support the approach's feasibility for goal identification and ranking. Conclusion: Goals relevant for treatment evaluation can be identified and rated for importance by patients to permit wide input from patients with lived experience of disease.
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Artritis Reumatoide , Objetivos , Humanos , Participación del Paciente , Calidad de Vida , Resultado del Tratamiento , Artritis Reumatoide/terapiaRESUMEN
OBJECTIVE: Recently, there has been consensus on domains that constitute flares in rheumatoid arthritis (RA); however, variations in patients' flare descriptions continue to be observed. This study evaluates how demographic and clinical characteristics influence these differences. METHODS: Participants enrolled in a prospective RA registry completed a qualitative survey that included the open-ended question "What does a flare mean to you?" Responses were categorized into Outcome Measures in Rheumatology (OMERACT) core and research domains. Univariate analyses evaluated demographic and clinical characteristics. Regression analyses determined independent variables associated with flare description variations. RESULTS: Among 645 participants, the median Disease Activity Score in 28 joints (DAS28) with C-reactive protein was 2.1 (IQR 1.6-2.9); 58% of the participants reported at least 1 flare in the past 6 months. Participants reported a median of 3 (IQR 2-5) OMERACT domains when describing flares. Fatigue was more commonly noted among females (odds ratio [OR] 6.12; P < 0.001). Older participants were less likely to report emotional distress (OR 0.97; P = 0.03), swollen joints (OR 0.99; P = 0.04), physical function decrease (OR 0.98; P = 0.02), and a general increase in RA symptoms (OR 0.98; P = 0.005). Participants with a higher DAS28 score were less likely to report symptoms of stiffness (OR 0.70; P = 0.009), and those who experienced a flare within the last 6 months were more likely to describe flares as pain (OR 2.53; P < 0.001) and fatigue (OR 2.00; P = 0.007). CONCLUSION: Variations in patients' flare descriptions can be driven by a patient's disease activity, the experience of a recent flare, as well as different demographic characteristics, such as age and gender. Understanding the interplay of these characteristics can guide a physician's approach to the management of patients' RA flares.