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Zhonghua Yi Xue Za Zhi Jul 2024The interleukin-6 (IL-6) pathway plays a crucial role in various rheumatic diseases. Tocilizumab, a biologic targeting IL-6 receptor, has been widely used in clinical...
The interleukin-6 (IL-6) pathway plays a crucial role in various rheumatic diseases. Tocilizumab, a biologic targeting IL-6 receptor, has been widely used in clinical practice, though it's officially approved in China for only three indications. To address clinical challenges associated with the off-label use of tocilizumab in treating rheumatic diseases, the Committee of Chinese Primary Health Care Foundation for Rheumatologists and Immunologists engaged multidisciplinary experts and highlight 12 related clinical issues. We aggregated the drug specifications, the guidelines for clinical management of rheumatic diseases and the evidence from clinical research. Recommendations were formed through voting with the consensus conference method incorporating the Oxford evidence-based medicine criteria to evaluate the strength of evidence and recommendations. We have formulated 10 recommendations for off-label use of tocilizumab related to giant cell arteritis, polymyalgia rheumatica, Takayasu arteritis, systemic sclerosis, adult-onset Still's disease, rheumatoid arthritis, and juvenile idiopathic arthritis. This consensus aims to provide references for the rational use of tocilizumab in clinical practice and enhance pharmacovigilance monitoring.
Topics: Humans; Antibodies, Monoclonal, Humanized; Rheumatic Diseases; Off-Label Use; China; Consensus; Interleukin-6; East Asian People
PubMed: 38951103
DOI: 10.3760/cma.j.cn112137-20240207-00294 -
Best Practice & Research. Clinical... Jun 2024The explosion in Mendelian randomization (MR) publications is hard to ignore and shows no signs of slowing. Clinician readers, who may not be familiar with jargon-ridden... (Review)
Review
The explosion in Mendelian randomization (MR) publications is hard to ignore and shows no signs of slowing. Clinician readers, who may not be familiar with jargon-ridden methods, are expected to discern the good from the many low-quality studies that make overconfident claims of causality or stretch the plausibility of what MR can investigate. We aim to equip readers with foundational concepts, contextualized using examples in rheumatology, to appraise the many MR papers that are or will appear in their journals. We highlight the importance of assessing whether exposures are under plausibly specific genetic influence, whether the hypothesized causal pathways make biological sense, and whether results stand up to replication and use of control outcomes. Quality of research can vary substantially using MR as with any design, and all methods have inherent limitations. MR studies have provided and can still contribute valuable insights in the context of evidence triangulation.
PubMed: 38951047
DOI: 10.1016/j.berh.2024.101967 -
Cleveland Clinic Journal of Medicine Jul 2024
Topics: Humans; Sodium-Glucose Transporter 2 Inhibitors; Diabetes Mellitus, Type 2; Renal Insufficiency, Chronic; Gout; Heart Failure; Hypoglycemic Agents
PubMed: 38950980
DOI: 10.3949/ccjm.91b.07024 -
Journal of Peptide Science : An... Jul 2024Cell-penetrating peptides (CPPs) with better biomolecule delivery properties will expand their clinical applications. Using the MLCPP2.0 machine algorithm, we screened...
Cell-penetrating peptides (CPPs) with better biomolecule delivery properties will expand their clinical applications. Using the MLCPP2.0 machine algorithm, we screened multiple candidate sequences with potential cellular uptake ability from the nuclear localization signal/nuclear export signal database and verified them through cell-penetrating fluorescent tracing experiments. A peptide (NCR) derived from the Rev protein of the caprine arthritis-encephalitis virus exhibited efficient cell-penetrating activity, delivering over four times more EGFP than the classical CPP TAT, allowing it to accumulate in lysosomes. Structural and property analysis revealed that a high hydrophobic moment and an appropriate hydrophobic region contribute to the high delivery activity of NCR. Trastuzumab emtansine (T-DM1), a HER2-targeted antibody-drug conjugate, could improve its anti-tumor activity by enhancing targeted delivery efficiency and increasing lysosomal drug delivery. This study designed a new NCR vector to non-covalently bind T-DM1 by fusing domain Z, which can specifically bind to the Fc region of immunoglobulin G and effectively deliver T-DM1 to lysosomes. MTT results showed that the domain Z-NCR vector significantly enhanced the cytotoxicity of T-DM1 against HER2-positive tumor cells while maintaining drug specificity. Our results make a useful attempt to explore the potential application of CPP as a lysosome-targeted delivery tool.
PubMed: 38950972
DOI: 10.1002/psc.3628 -
The Journal of Rheumatology Jul 2024Rheumatoid arthritis (RA) is prevalent in many Indigenous North American First Nations (FN) and tends to be seropositive, familial, and disabling, as well as associated... (Review)
Review
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 , 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.
Topics: Humans; Anti-Citrullinated Protein Antibodies; Arthritis, Rheumatoid; Biomarkers; Gene-Environment Interaction; HLA-DRB1 Chains; Indians, North American
PubMed: 38950968
DOI: 10.3899/jrheum.2024-0369_dunlop-dottridge -
The Journal of Rheumatology Jul 2024The sudden and unanticipated emergence of SARS-Cov-2 at the beginning of the present decade, associated with high morbidity and mortality among people infected, prompted...
The sudden and unanticipated emergence of SARS-Cov-2 at the beginning of the present decade, associated with high morbidity and mortality among people infected, prompted the rapid emergence of telemedicine approaches for the management of patients with rheumatoid arthritis (RA). The rationale was to limit the likelihood for viral contagion in a hospital outpatient setting for people rendered potentially more vulnerable by the immunosuppressive nature of many of the pharmacological interventions in the treatment armamentarium.
PubMed: 38950956
DOI: 10.3899/jrheum.2024-0579 -
The Journal of Rheumatology Jul 2024Incidence and manifestations of post-acute sequelae of COVID-19 (PASC) are poorly defined among immunosuppressed populations. We reported, phenotyped, and assessed risk...
OBJECTIVE
Incidence and manifestations of post-acute sequelae of COVID-19 (PASC) are poorly defined among immunosuppressed populations. We reported, phenotyped, and assessed risk factors for PASC in adults with systemic autoimmune diseases.
METHODS
Persons ≥18 years with systemic autoimmune diseases were recruited into a national, prospective cohort of SARS-CoV-2 vaccination between 12/2020-4/2021. Serial surveys assessed vaccination status, SARS-CoV-2 infection incidence, and disease flares. Participants reporting SARS-CoV-2 infection received a questionnaire assessing symptom duration, severity, and quality of life (QoL) impact; PASC was defined as ≥1 symptom persisting for >12 weeks. PASC syndromes were mapped via overlapping symptom domains. Characteristics were compared between participants who did versus did not report PASC.
RESULTS
Among 1615 participants, 590 (36.5%) reported SARS-CoV-2 infection and were sent PASC surveys, 299 (50.7%) of whom responded >12 weeks following reported infection. Respondents were 1.62% female, 90.2% white, median (IQR) age 48(40-60) years with median (IQR) 3 (2-3) vaccine doses at time of first infection. Common diagnoses included inflammatory arthritis (38.5%) and inflammatory bowel disease (14.4%). 89/299 (29.8%) reported PASC, with the most reported symptom domain being neurological/psychological (83.1%); 84% reported an impact on QoL. Participants with PASC reported lower number of preceding vaccines (median [IQR] 2[2-3] versus 3[2-3]; p<0.001) and more reinfections (16.9% versus 5.7%; p=0.004).
CONCLUSION
29.8% of persons with systemic autoimmune disease in a large real-world cohort reported PASC, often affecting QoL. Preceding vaccination may reduce PASC, whereas multiple infections may increase risk, supporting ongoing booster vaccine campaigns and efforts to limit breakthrough infections.
PubMed: 38950954
DOI: 10.3899/jrheum.2023-1212 -
The Journal of Rheumatology Jul 2024Rheumatoid arthritis (RA) has been associated with an elevated dementia risk. The study aimed to examine how different diagnostic dementia definitions perform in those...
OBJECTIVE
Rheumatoid arthritis (RA) has been associated with an elevated dementia risk. The study aimed to examine how different diagnostic dementia definitions perform in those with RA compared to individuals without RA.
METHODS
This study population included 2050 individuals (1025 with RA) from a retrospective population-based cohort in southern Minnesota and compared the performance of three code-based dementia diagnostic algorithms with medical record review diagnosis of dementia. For the overall comparison, no time frames were used, and each patient's complete medical history was used. Sensitivity analyses were performed using 1, 2, and 5-year windows around the date that dementia was identified in the medical record (reference standard).
RESULTS
Algorithms performed very similarly in persons with and without RA. The algorithms generally had high specificity, negative predictive values, and accuracy, regardless of the time window studied (>88%). Sensitivity and positive predictive values varied depending on the algorithm and the time window studied. Sensitivity values ranged from 56.5% to 95.9%, and positive predictive values ranged from 55.2% to 83.1%. Performance measures declined with more restrictive time windows.
CONCLUSION
Routinely collected electronic health record (EHR) data was used to define code-based dementia diagnosis algorithms with good performance (vs. diagnosis by medical record review). These results can inform future studies that use retrospective databases (especially in the same or similar EHR infrastructure) to identify dementia in individuals with RA.
PubMed: 38950951
DOI: 10.3899/jrheum.2024-0299 -
The Journal of Rheumatology Jul 2024To provide a set of living treatment recommendations that will provide contemporary guidance on the management of patients with axial spondyloarthritis (axSpA) in Canada.
OBJECTIVE
To provide a set of living treatment recommendations that will provide contemporary guidance on the management of patients with axial spondyloarthritis (axSpA) in Canada.
METHODS
The Spondyloarthritis Research Consortium of Canada (SPARCC), in conjunction with the Canadian Rheumatology Association, organized a treatment recommendations panel composed of rheumatologists, researchers, allied health professionals, and a patient advocate. A Grading of Recommendations Assessment, Development, and Evaluation (GRADE)-ADOLOPMENT approach was used in which existing guidelines were adopted or adapted to a Canadian context. Recommendations were also placed in a health equity framework.
RESULTS
56 recommendations were made for patients with active axSpA, stable axSpA, active or stable axSpA, comorbidities, and for assessment, screening, and imaging. Recommendations were also made for principles of management, disease monitoring, and ethical considerations.
CONCLUSION
These living treatment recommendations will provide up to date guidance for the management of axSpA for Canadian practice. As part of the living model, they will be updated regularly as changes occur in the treatment landscape.
PubMed: 38950949
DOI: 10.3899/jrheum.2023-1237 -
ACR Open Rheumatology Jul 2024Rheumatoid arthritis (RA) has a "pre-RA" period in which multiple autoantibodies, including antibodies to citrullinated (cit) proteins (ACPA), rheumatoid factor (RF),...
OBJECTIVE
Rheumatoid arthritis (RA) has a "pre-RA" period in which multiple autoantibodies, including antibodies to citrullinated (cit) proteins (ACPA), rheumatoid factor (RF), anti-peptidyl arginine deiminase (anti-PAD), among others, have been described; however, few studies have tested all autoantibodies in a single pre-RA cohort. This study aims to evaluate the prevalence of multiple autoantibodies in pre-RA and potentially identify an autoantibody profile in pre-RA that indicates imminent onset of clinical RA.
METHODS
We evaluated 148 individuals with two pre- and one post-RA diagnosis samples available from the Department of Defense Serum Repository and matched controls. Samples were tested for immuglobulin (Ig) G anti-cyclic cit peptide-3 (anti-CCP3), five ACPA fine specificities, five anti-PAD isoforms, as well as RF IgA and RF IgM using commercial platforms; cutoffs were determined using levels present in <1% of controls.
RESULTS
Positivity of anti-CCP3, RF IgA and RF IgM, anti-PAD1, anti-cit-vimentin 2, anti-cit-fibrinogen, and anti-cit-histone 1 increased over time in pre-RA, although anti-PAD and ACPA fine specificities were predominately present within anti-CCP3-positive individuals. Within anti-CCP3-positive samples from the pre-RA period, positivity for RFs as well as anti-PAD and ACPA fine specificities classified samples as being closer to the time of RA diagnosis.
CONCLUSION
Multiple autoantibodies are present in pre-RA and increase in positivity as the time of RA diagnosis approaches. These results confirm previous findings predicting imminent RA and provide a pathway using commercial-grade assays to assess the risk for and timing of development of clinical RA.
PubMed: 38950890
DOI: 10.1002/acr2.11704