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ACR Open Rheumatology Dec 2023We estimated the association between immunosuppressive and immunomodulatory agent (IIA) exposure and severe COVID-19 outcomes in a population-based cohort study.
OBJECTIVE
We estimated the association between immunosuppressive and immunomodulatory agent (IIA) exposure and severe COVID-19 outcomes in a population-based cohort study.
METHODS
Participants were 18 years or older, tested positive for SARS-CoV-2 between February 6, 2020, and August 15, 2021, and were from administrative health data for the entire province of British Columbia, Canada. IIA use within 3 months prior to positive SARS-CoV-2 test included conventional disease-modifying antirheumatic drugs (antimalarials, methotrexate, leflunomide, sulfasalazine, individually), immunosuppressants (azathioprine, mycophenolate mofetil/mycophenolate sodium [MMF], cyclophosphamide, cyclosporine, individually and collectively), tumor necrosis factor inhibitor (TNFi) biologics (adalimumab, certolizumab, etanercept, golimumab, infliximab, collectively), non-TNFi biologics or targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) (rituximab separately from abatacept, anakinra, secukinumab, tocilizumab, tofacitinib and ustekinumab collectively), and glucocorticoids. Severe COVID-19 outcomes were hospitalizations for COVID-19, ICU admissions, and deaths within 60 days of a positive test. Exposure score-overlap weighting was used to balance baseline characteristics of participants with IIA use compared with nonuse of that IIA. Logistic regression measured the association between IIA use and severe COVID-19 outcomes.
RESULTS
From 147,301 participants, we identified 515 antimalarial, 573 methotrexate, 72 leflunomide, 180 sulfasalazine, 468 immunosuppressant, 378 TNFi biologic, 49 rituximab, 144 other non-TNFi biologic or tsDMARD, and 1348 glucocorticoid prescriptions. Risk of hospitalizations for COVID-19 was significantly greater for MMF (odds ratio [95% CI]): 2.82 [1.81-4.40], all immunosuppressants: 2.08 [1.51-2.87], and glucocorticoids: 1.63 [1.36-1.96], relative to nonuse. Similar outcomes were seen for ICU admission and MMF: 2.52 [1.34-4.74], immunosuppressants: 2.88 [1.73-4.78], and glucocorticoids: 1.86 [1.37-2.54]. Only glucocorticoids use was associated with a significant increase in 60-day mortality: 1.58 [1.21-2.06]. No other IIAs displayed statistically significant associations with severe COVID-19 outcomes.
CONCLUSION
Current use of MMF and glucocorticoids were associated with an increased risk of severe COVID-19 outcomes compared with nonuse. These results emphasize the variety of circumstances of patients taking IIAs.
PubMed: 37818772
DOI: 10.1002/acr2.11620 -
Frontiers in Immunology 2023Psoriasis is a chronic inflammatory skin disease characterized by hyperplasia of keratinocytes and immune cell infiltration. The IL-17-producing T cells play a key role...
Psoriasis is a chronic inflammatory skin disease characterized by hyperplasia of keratinocytes and immune cell infiltration. The IL-17-producing T cells play a key role in psoriasis pathogenesis, while regulatory T (Treg) cells are diminished during psoriatic inflammation. Current psoriasis treatments largely focus on IL-17 and IL-23, however, few studies have explored therapeutic drugs targeting an increase of Treg cells to control immune homeostasis. In this study, we investigated the effects of a cytotoxic T lymphocyte antigen-4 (CTLA-4) signaling peptide (dNP2-ctCTLA-4) in Th17, Tc17, γδ T cells, Treg cells and a mouse model of psoriasis. Treatment with dNP2-ctCTLA-4 peptide showed a significant reduction of psoriatic skin inflammation with increased Treg cell proportion and reduced IL-17 production by T cells, indicating a potential role in modulating psoriatic skin disease. We compared dNP2-ctCTLA-4 with CTLA-4-Ig and found that only dNP2-ctCTLA-4 ameliorated the psoriasis progression, with increased Treg cells and inhibited IL-17 production from γδ T cells. experiments using a T cell-antigen presenting cell co-culture system demonstrated the distinct mechanisms of dNP2-ctCTLA-4 compared to CTLA-4-Ig in the induction of Treg cells. These findings highlight the therapeutic potential of dNP2-ctCTLA-4 peptide in psoriasis by augmenting Treg/Teff ratio, offering a new approach to modulating the disease.
Topics: Mice; Animals; T-Lymphocytes, Regulatory; Interleukin-17; CTLA-4 Antigen; Abatacept; Psoriasis; Dermatitis; Inflammation
PubMed: 37818377
DOI: 10.3389/fimmu.2023.1233514 -
Nature Communications Oct 2023Psoriasis is a chronic, systemic inflammatory condition primarily affecting skin. While the role of the immune compartment (e.g., T cells) is well established, the...
Psoriasis is a chronic, systemic inflammatory condition primarily affecting skin. While the role of the immune compartment (e.g., T cells) is well established, the changes in the skin compartment are more poorly understood. Using longitudinal skin biopsies (n = 375) from the "Psoriasis Treatment with Abatacept and Ustekinumab: A Study of Efficacy"(PAUSE) clinical trial (n = 101), we report 953 expression quantitative trait loci (eQTLs). Of those, 116 eQTLs have effect sizes that were modulated by local skin inflammation (eQTL interactions). By examining these eQTL genes (eGenes), we find that most are expressed in the skin tissue compartment, and a subset overlap with the NRF2 pathway. Indeed, the strongest eQTL interaction signal - rs1491377616-LCE3C - links a psoriasis risk locus with a gene specifically expressed in the epidermis. This eQTL study highlights the potential to use biospecimens from clinical trials to discover in vivo eQTL interactions with therapeutically relevant environmental variables.
Topics: Humans; Quantitative Trait Loci; Skin; Psoriasis; Immunosuppression Therapy; Biopsy; Genome-Wide Association Study; Polymorphism, Single Nucleotide
PubMed: 37805522
DOI: 10.1038/s41467-023-41984-2 -
The Journal of Allergy and Clinical... Feb 2023We report on the successful treatment of a severe, recalcitrant dermatitis caused by CTLA-4 insufficiency with dupilumab, raising the possibility of a role of type 2...
We report on the successful treatment of a severe, recalcitrant dermatitis caused by CTLA-4 insufficiency with dupilumab, raising the possibility of a role of type 2 immunity in clinical conditions associated with CTLA-4 insufficiency.
PubMed: 37780100
DOI: 10.1016/j.jacig.2022.08.004 -
Current Opinion in Allergy and Clinical... Dec 2023Common variable immunodeficiency (CVID) is the most common symptomatic inborn error of immunity. The disorder is characterized by variable clinical and immunological... (Review)
Review
PURPOSE OF REVIEW
Common variable immunodeficiency (CVID) is the most common symptomatic inborn error of immunity. The disorder is characterized by variable clinical and immunological manifestations, and, in a small minority of patients, a monogenic cause may be identified. In this review, we focalized on three different monogenic forms of CVID-like disease.
RECENT FINDINGS
Activated phosphoinositide 3-kinase delta syndrome (APDS) is a rare disorder characterized by hyperactivated class I phosphatidylinositol-3 kinase (PI3K) pathway. Affected patients present with respiratory infectious episodes, impaired viral clearance and lymphoproliferation. Recently, a direct PI3K inhibitor has been approved and it showed encouraging results both in controlling clinical and immunological manifestations of the disease. On the other hand, patients with defects in CTLA-4 or LRBA gene present with life-threatening immune dysregulation, autoimmunity and lymphocytic infiltration of multiple organs. Abatacept, a soluble cytotoxic T lymphocyte antigen 4 (CTLA-4) fusion protein that acts as a costimulation modulator, has been widely implemented for affected patients with good results as bridge treatment.
SUMMARY
Understanding the biological basis of CVID is important not only for enriching our knowledge of the human immune system, but also for setting the basis for potential targeted treatments in this disorder.
Topics: Humans; CTLA-4 Antigen; Phosphatidylinositol 3-Kinases; Common Variable Immunodeficiency; Autoimmunity; Adaptor Proteins, Signal Transducing
PubMed: 37767915
DOI: 10.1097/ACI.0000000000000947 -
Medicina (Kaunas, Lithuania) Sep 2023An increase in skin-related autoimmune disorders has been reported as an adverse effect of coronavirus disease 2019 (COVID-19) vaccines. We present the case of a...
An increase in skin-related autoimmune disorders has been reported as an adverse effect of coronavirus disease 2019 (COVID-19) vaccines. We present the case of a 90-year-old Taiwanese female who was newly diagnosed with anti-transcription intermediary factor 1-gamma (anti-TIF1-γ)-positive dermatomyositis (DM) after receiving a second dose of the AstraZeneca COVID-19 vaccine. Under treatment with prednisolone and monoclonal antibody therapy of abatacept, her skin lesions improved, and her muscle power increased. The serum creatinine phosphokinase level decreased from 4858 to 220 U/L, and the anti-TIF1-γ antibody titer decreased from 202 to 99. Flow cytometry data showed an increase in T cells, while NK cells, B cells (CD19), and plasma blasts all decreased. These findings suggest that standard DM treatment might be beneficial to patients with COVID-19 vaccine-induced DM.
PubMed: 37763807
DOI: 10.3390/medicina59091688 -
Arthritis Research & Therapy Sep 2023To compare a treat-to-target (T2T) approach and routine care (RC) in adults with active to severely active rheumatoid arthritis (RA) initiating subcutaneous abatacept. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
To compare a treat-to-target (T2T) approach and routine care (RC) in adults with active to severely active rheumatoid arthritis (RA) initiating subcutaneous abatacept.
METHODS
A 12-month cluster-randomized trial in active RA patients treated with abatacept was conducted. Physicians were randomized to RC or T2T with a primary endpoint of achieving sustained Clinical Disease Activity Index (CDAI) low disease activity (LDA) at two consecutive assessments approximately 3 months apart. Additional outcomes included Simple Disease Activity Index (SDAI), Disease Activity Score 28-CRP (DAS28-CRP), Routine Assessment of Patient Index Data 3 (RAPID3), and the Health Assessment Questionnaire-Disability Index (HAQ-DI). Time to achieve therapeutic endpoints was assessed with survival analysis.
RESULTS
Among the 284 enrolled patients, 130 were in the T2T group and 154 in RC. Primary endpoint was achieved by 36.9% and 40.3% of patients in T2T and RC groups, respectively. No significant between-group differences were observed in the odds of achieving secondary outcomes, except for a higher likelihood of CDAI LDA in the T2T group vs. RC (odds ratio [95% confidence interval]: 1.33 [1.03-1.71], p = 0.0263). Compared with RC, patients in the T2T group achieved SDAI remission significantly faster (Kaplan-Meier-estimated mean [standard error]: 14.0 [0.6] vs. 19.3 [0.8] months, p = 0.0428) with a trend toward faster achievement of CDAI LDA/remission, DAS28-CRP remission, and HAQ-DI minimum clinically important difference.
CONCLUSIONS
Patients managed per T2T and those under RC experienced significant improvements in RA disease activity at 12 months of abatacept treatment. T2T was associated with higher odds of CDAI LDA and a shorter time to achieving therapeutic endpoints.
TRIAL REGISTRATION
Name of the registry: ClinicalTrials.gov.
TRIAL REGISTRATIONS
NCT03274141 . Date of registration: September 6, 2017.
Topics: Adult; Humans; Abatacept; Arthritis, Rheumatoid; Kaplan-Meier Estimate; Minimal Clinically Important Difference; Odds Ratio
PubMed: 37759330
DOI: 10.1186/s13075-023-03151-2 -
Rheumatology (Oxford, England) Jul 2024This study aimed to evaluate if and how the incidence of serious infection (SI) and active tuberculosis (TB) differ among seven biologic DMARDs (bDMARDs) in patients...
Evaluation of serious infections, including Mycobacterium tuberculosis, during treatment with biologic disease-modifying anti-rheumatic drugs: does line of therapy matter?
OBJECTIVES
This study aimed to evaluate if and how the incidence of serious infection (SI) and active tuberculosis (TB) differ among seven biologic DMARDs (bDMARDs) in patients with RA considering the line of therapy.
METHODS
Patients with RA from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR-RA) cohort who initiated etanercept, certolizumab, infliximab, adalimumab, abatacept, rituximab or tocilizumab from the first to fifth line of therapy were included. Follow-up extended up to 3 years. The primary outcome was SI and the secondary outcome was TB. Event rates were calculated and compared using Cox proportional hazards models, controlling for confounding with inverse probability of treatment weights. Comparisons were made overall and stratified by line of therapy. Sensitivity analysis was restricted to all treatment courses from 2009 (tocilizumab availability) until the end of the study (2018).
RESULTS
Among 33 897 treatment courses (62 513 patient-years) the incidence of SI was 4.4/100 patient-years (95% CI 4.2, 4.5). After adjustment, hazards ratios (HRs) of SI were slightly higher with adalimumab and infliximab compared with etanercept. However, no clear pattern was observed when stratifying by line of therapy in terms of incidence rate or HR. Sensitivity analyses showed similar HRs among these treatments. Regarding TB, all 49 cases occurred during the first three lines of treatment and rarely since 2009.
CONCLUSION
The risk of serious infections does not appear to be influenced by the line of therapy in patients with RA. However, the risk of TB seems to be more frequent during the initial lines of treatment or prior to 2009.
Topics: Humans; Antirheumatic Agents; Female; Male; Arthritis, Rheumatoid; Middle Aged; Tuberculosis; Etanercept; Biological Products; Incidence; Infliximab; Abatacept; Adalimumab; Mycobacterium tuberculosis; Aged; Adult; Proportional Hazards Models; Antibodies, Monoclonal, Humanized; Rituximab; Certolizumab Pegol; Infections
PubMed: 37758229
DOI: 10.1093/rheumatology/kead515 -
Journal of Rheumatic Diseases Oct 2023To assess the effects of biological and targeted synthetic disease-modifying antirheumatic drugs (DMARDs) on lipid profiles in patients with moderate-to-severe...
OBJECTIVE
To assess the effects of biological and targeted synthetic disease-modifying antirheumatic drugs (DMARDs) on lipid profiles in patients with moderate-to-severe rheumatoid arthritis (RA).
METHODS
This retrospective single-center observational study included patients with RA taking a tumor necrosis factor-α inhibitor (TNFi), abatacept, tocilizumab, or a Janus kinase inhibitor (JAKi) for at least 6 months. Changes in lipid profile were assessed at 6 months after the start of treatment, and associations between changes in lipid profiles and clinical efficacy, concomitant medications, and comorbidities were evaluated.
RESULTS
This study included 114 patients treated with TNFi, 81 with abatacept, 103 with tocilizumab, and 89 with JAKi. The mean percentage change (from baseline to 6 months) in total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and non-HDL-C levels was higher in those taking tocilizumab and JAKi than in those taking TNFi and abatacept. A significant change in non-HDL-C was associated with JAKi (versus TNFi odds ratio [OR], 3.228; 95% confidence interval [CI], 1.536~6.785), tocilizumab (versus TNFi OR, 2.203; 95% CI, 1.035~4.689), and statins (OR, 0.487; 95% CI, 0.231~1.024). However, changes in disease activity in 28 joints were not associated with a significant change in non-HDL-C.
CONCLUSION
Tocilizumab- and JAKi-associated increases in serum non-HDL-C levels were observed regardless of changes in disease activity. Statins are recommended for RA patients showing a significant increase in cholesterol levels after initiating biological and targeted synthetic DMARDs.
PubMed: 37736594
DOI: 10.4078/jrd.2023.0030 -
World Journal of Clinical Cases Sep 2023Cytotoxic T Lymphocyte Antigen-4 (CTLA4) deficiency is a genetic defect that causes a common variable immunodeficiency (CVID) clinical phenotype. Several studies have...
BACKGROUND
Cytotoxic T Lymphocyte Antigen-4 (CTLA4) deficiency is a genetic defect that causes a common variable immunodeficiency (CVID) clinical phenotype. Several studies have reported an association between CTLA mutations or variants and various autoimmune diseases. Targeted therapy models, which have become increasingly popular in recent years, have been successful in treating CTLA4 deficiency. In this article, we discuss the clinical outcomes of abatacept treatment in a patient with CTLA4 and lipopolysaccharide-responsive beige-like anchor (LRBA) variants that was previously diagnosed with CVID.
CASE SUMMARY
A 25-year-old female patient, who was visibly cachectic, visited our clinic over the course of five years, complaining of diarrhea. The patient was diagnosed with ulcerative colitis in the centers she had visited previously, and various treatments were administered; however, clinical improvement could not be achieved. Severe hypokalemia was detected during an examination. Her serum immunoglobulin levels, CD19 B-cell percentage, and CD4/CD8 ratio were low. An endoscopic examination revealed erosive gastritis, nodular duodenitis, and pancolitis. Histopathological findings supported the presence of immune mediated enteropathy. When the patient was examined carefully, she was diagnosed with CVID, and intravenous immunoglobulin treatment was initiated. Peroral and rectal therapeutic drugs including steroid therapy episodes were administered to treat the immune mediated enteropathy. Strict follow-ups and treatment were performed due to the hypokalemia. After conducting genetic analyses, the CTLA4 and LRBA variants were identified and abatacept treatment was initiated. With targeted therapy, the patient's clinical and laboratory findings rapidly regressed, and there was an increase in weight.
CONCLUSION
The heterozygous CTLA4 variant identified in the patient has been previously shown to be associated with various autoimmune diseases. The successful clinical outcome of abatacept treatment in this patient supports the idea that this variant plays a role in the immunopathogenesis of the disease. In the presence of severe disease, abatacept therapy should be considered until further testing can be conducted.
PubMed: 37731560
DOI: 10.12998/wjcc.v11.i26.6176