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Archives of Rheumatology Jun 2022Biological medications have been used with an increasing frequency to treat rheumatological diseases. Autoimmune events can be induced by these drugs, such as... (Review)
Review
OBJECTIVES
Biological medications have been used with an increasing frequency to treat rheumatological diseases. Autoimmune events can be induced by these drugs, such as psoriasiform lesions, alopecia, lupus and, vasculitis, which more often affects the skin (small-sized vessels) and eventually other organs. In this review, we describe the clinical profile of patients with vasculitis induced by the main biological agents used in rheumatology.
PATIENTS AND METHODS
We performed a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. The PubMed database was used for searching eligible articles. We included case reports, case series, and letter to the editor of patients on anti-tumor necrosis factor-alpha (anti-TNF-a) molecules, as well as tocilizumab, ustekinumab, secukinumab, rituximab, and abatacept, who had vasculitis induced by these agents.
RESULTS
Eighty-one articles were included for final analysis (n=89). Twenty-seven patients were using infliximab, 20 adalimumab, 18 etanercept, seven secukinumab, four certolizumab, four rituximab, three golimumab, three ustekinumab, two abatacept, and one tocilizumab. Unspecific leukocytoclastic vasculitis (LCV) was the most common type of vasculitis (n=37), followed by anti-neutrophil cytoplasmic antibody (ANCA)- associated vasculitis (n=16). The medication was replaced with another biological molecule in 23 cases, with only four relapses. In six cases, the biological was maintained, but vasculitis worsened/persisted in one case, being necessary drug removal.
CONCLUSION
Infections, infusion reaction, cancer, and autoimmune events are well-known side effects of biological therapy. This review demonstrates that vasculitis is another adverse effect of this type of therapy, particularly the anti-TNF-a molecules, and LCV the most reported type of vasculitis.
PubMed: 36017201
DOI: 10.46497/ArchRheumatol.2022.9049 -
Journal For Immunotherapy of Cancer Jan 2024Immune checkpoint inhibitor (ICI) treatment has become an important therapeutic option for various cancer types. Although the treatment is effective, ICI can...
Immune checkpoint inhibitor (ICI) treatment has become an important therapeutic option for various cancer types. Although the treatment is effective, ICI can overstimulate the patient's immune system, leading to potentially severe immune-related adverse events (irAEs), including hepatitis, colitis, pneumonitis and myocarditis. The initial mainstay of treatments includes the administration of corticosteroids. There is little evidence how to treat steroid-resistant (sr) irAEs. It is mainly based on small case series or single case reports. This systematic review summarizes available evidence about sr-irAEs. We conducted a systematic literature search in PubMed. Additionally, we included European Society for Medical Oncology, Society for Immunotherapy of Cancer, National Comprehensive Cancer Network and American Society of Clinical Oncology Guidelines for irAEs in our assessment. The study population of all selected publications had to include patients with cancer who developed hepatitis, colitis, pneumonitis or myocarditis during or after an immunotherapy treatment and for whom corticosteroid therapy was not sufficient. Our literature search was not restricted to any specific cancer diagnosis. Case reports were also included. There is limited data regarding life-threatening sr-irAEs of colon/liver/lung/heart and the majority of publications are single case reports. Most publications investigated sr colitis (n=26), followed by hepatitis (n=21), pneumonitis (n=17) and myocarditis (n=15). There is most data for mycophenolate mofetil (MMF) to treat sr hepatitis and for infliximab, followed by vedolizumab, to treat sr colitis. Regarding sr pneumonitis there is most data for MMF and intravenous immunoglobulins (IVIG) while data regarding infliximab are conflicting. In sr myocarditis, most evidence is available for the use of abatacept or anti-thymocyte globulin (ATG) (both with or without MMF) or ruxolitinib with abatacept. This review highlights the need for prompt recognition and treatment of sr hepatitis, colitis, pneumonitis and myocarditis. Guideline recommendations for sr situations are not defined precisely. Based on our search, we recommend-as first line treatment-(1) MMF for sr hepatitis, (2) infliximab for sr colitis, followed by vedolizumab, (3) MMF and IVIG for sr pneumonitis and (4) abatacept or ATG (both with or without MMF) or ruxolitinib with abatacept for sr myocarditis. These additional immunosuppressive agents should be initiated promptly if there is no sufficient response to corticosteroids within 3 days.
Topics: Humans; Abatacept; Adrenal Cortex Hormones; Colitis; Hepatitis; Immunoglobulins, Intravenous; Infliximab; Mycophenolic Acid; Myocarditis; Neoplasms; Nitriles; Pneumonia; Pyrazoles; Pyrimidines
PubMed: 38233099
DOI: 10.1136/jitc-2023-007409 -
Clinical and Experimental Immunology Jul 2021Cytotoxic T lymphocyte antigen 4 (CTLA-4) haploinsufficiency (CHAI) and lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency (LATAIE) are newly identified... (Review)
Review
Cytotoxic T lymphocyte antigen 4 (CTLA-4) haploinsufficiency (CHAI) and lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency (LATAIE) are newly identified inborn errors of immunity with shared molecular pathomechanisms and clinical manifestations. In this review, we aimed to provide differential comparisons regarding demographic, clinical, immunological and molecular characteristics between these two similar conditions. A literature search was conducted in PubMed, Web of Science and Scopus databases and included studies were systematically evaluated. Overall, 434 (222 CHAI and 212 LATAIE) patients were found in 101 eligible studies. The CHAI patients were mainly reported from North America and western Europe, while LATAIE patients were predominantly from Asian countries. In CHAI, positive familial history (P < 0·001) and in LATAIE, consanguineous parents (P < 0·001) were more common. In CHAI patients the rates of granulomas (P < 0·001), malignancies (P = 0·001), atopy (P = 0·001), cutaneous disorders (P < 0·001) and neurological (P = 0·002) disorders were higher, while LATAIE patients were more commonly complicated with life-threatening infections (P = 0·002), pneumonia (P = 0·006), ear, nose and throat disorders (P < 0·001), organomegaly (P = 0·023), autoimmune enteropathy (P = 0·038) and growth failure (P < 0·001). Normal lymphocyte subsets and immunoglobulins except low serum levels of CD9 B cells (14·0 versus 38·4%, P < 0·001), natural killer (NK) cells (21 versus 41·1%, P < 0·001), immunoglobulin (Ig)G (46·9 versus 41·1%, P = 0·291) and IgA (54·5 versus 44·7%, P = 0·076) were found in the majority of CHAI and LATAIE patients, respectively. The most frequent biological immunosuppressive agents prescribed for CHAI and LATAIE patients were rituximab and abatacept, respectively. Further investigations into the best conditioning and treatment regimens pre- and post-transplantation are required to improve the survival rate of transplanted CHAI and LATAIE patients.
Topics: Adaptor Proteins, Signal Transducing; CTLA-4 Antigen; Haploinsufficiency; Humans; Immunoglobulins; Immunosuppressive Agents; Lymphocytes
PubMed: 33788257
DOI: 10.1111/cei.13600 -
Immunity, Inflammation and Disease Feb 2023The risk of hepatitis B virus (HBV) reactivation after biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) therapy in patients with... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The risk of hepatitis B virus (HBV) reactivation after biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) therapy in patients with rheumatoid arthritis (RA) combined with HBsAg-/HBcAb+ is still inconsistent.
METHODS
We conducted a systematic review of existing databases from 1977 to August 22, 2021. Studies of RA patients combined with HBsAg-/HBcAb +, treated with b/tsDMARDs and the reported number of HBV reactivation were included.
RESULTS
We included 26 studies of 2252 HBsAg-/HBcAb+ RA patients treated with b/tsDMARDs. The pooled HBV reactivation rate was 2.0% (95% confidence interval [CI]: 0.01-0.04; I = 66%, p < .01). In the subgroup analysis, the HBV reactivation rate of rituximab (RTX), abatacept, and inhibitors of Janus kinase (JAK), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were 9.0% (95% CI: 0.04-0.15; I = 61%, p = .03), 6.0% (95% CI: 0.01-0.13; I = 40%, p = .19), 1.0% (95% CI: 0.00-0.03; I = 41%, p = .19), 0.0% (95% CI: 0.00-0.02; I = 0%, p = .43), 0.0% (95% CI: 0.00-0.01; I = 0%, p = .87), respectively. While HBsAb- patients have a significant risk of reactivation (odds ratio [OR] = 4.56, 95% CI = 2.45-8.48; I = 7%, p = .37), low HBsAb+ group also display a significant risk of reactivation (OR = 5.45, 95% CI: 1.35-21.94; I = 0%, p = .46).
CONCLUSIONS
This meta-analysis demonstrates the highest potential risk of HBV reactivation in HBsAg-/HBcAb+ RA patients receiving RTX treatment, especially HBsAb- patients. Our study furthers the understanding of the prophylactic use of anti-HBV drugs in such patients. However, it is relative safety to use the inhibitors of IL-6, TNF-α, and JAK in these patients.
Topics: Humans; Arthritis, Rheumatoid; Biological Products; Hepatitis B; Hepatitis B Antibodies; Hepatitis B Surface Antigens; Hepatitis B virus; Interleukin-6; Janus Kinase Inhibitors; Rituximab; Tumor Necrosis Factor-alpha
PubMed: 36840482
DOI: 10.1002/iid3.780 -
RMD Open Oct 2023We conducted a systematic review and meta-analysis to determine the efficacy of non-conventional synthetic disease-modifying antirheumatic drug (ncs-DMARD) strategies on... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
We conducted a systematic review and meta-analysis to determine the efficacy of non-conventional synthetic disease-modifying antirheumatic drug (ncs-DMARD) strategies on patients with rheumatoid arthritis (RA)-associated interstitial lung disease (ILD).
METHODS
PubMed, EMBASE, the Cochrane Library and Web of Science were searched for relevant articles from inception to 1 June 2022. The results obtained from the analysis were expressed as mean difference (MD), effect size and 95% CI.
RESULTS
A total of 17 studies, including 1315 patients with RA-ILD, were eligible. The ncs-DMARDs included abatacept, rituximab, tocilizumab, tumour necrosis factor and Janus kinase inhibitors. Compared with the baseline, there were no significant changes in forced vital capacity (FVC), forced expiratory volume in the first second (FEV) and diffusion lung capacity for carbon monoxide (DLCO) values in the pooled data after ncs-DMARD treatment (alone or combined with conventional therapy) (p=0.36 for FVC; p=0.96 for FEV and p=0.46 for DLCO). Of note, FVC was obviously increased in rituximab subgroup (MD=-4.62, 95% CI -8.90 to -0.33, p=0.03). Also, high-resolution CT non-progression rate and fatality rate due to ILD progression in patients with RA-ILD were 0.792 (95% CI 0.746 to 0.834, p=0.015) and 0.049 (95% CI 0.035 to 0.065, p=0.000), respectively.
CONCLUSION
ncs-DMARDs alone or combined with conventional therapy might be an optimal and promising treatment for stabilising or improving ILD in patients with RA-ILD.
PROSPERO REGISTRATION NUMBER
CRD42022356816.
Topics: Humans; Rituximab; Antirheumatic Agents; Arthritis, Rheumatoid; Lung Diseases, Interstitial; Abatacept
PubMed: 37899093
DOI: 10.1136/rmdopen-2023-003487 -
Clinical and Experimental Rheumatology Sep 2023Abatacept (Orencia) is a drug used to treat patients with rheumatoid arthritis. The agent improves patients' pain and joint inflammation through modulation of a... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
Abatacept (Orencia) is a drug used to treat patients with rheumatoid arthritis. The agent improves patients' pain and joint inflammation through modulation of a co-stimulatory signal necessary for T cell activation. We aimed to analyse the efficacy and safety of abatacept in the management of rheumatoid arthritis using the Cochrane systematic review.
METHODS
We conducted a systematic search among PubMed, Cochrane central register of controlled trials, Web of Science, and Embase databases from the establishment of these databases to April 2022. The effectiveness and safety of abatacept in treating rheumatoid arthritis were assessed in terms of American College of Rheumatology (ACR) 20/50/70/90 responses, Disease Activity Score-28 for Rheumatoid Arthritis with C-reactive protein (DAS-28-CRP), and adverse events. The Relative Risks (RRs) of relative safety and efficacy and their corresponding 95 confidence intervals (CIs) were used to compute the pooled assessments of the outcomes. We used the review manager software version 5.4 to analyse our data, and the PRISMA checklist 2020 was used to ensure that our work conforms with the specification of meta-analysis.
RESULTS
Our study included 13 randomised control trials with a total of 5978 adult patients from different geographic regions and races. Following the combined analysis of these enrolled studies, the RRs for ACR 20/50/70/90 responses were 1.57 [95%CI 1.27, 1.93], 1.84 [95%CI 1.38, 2.44], 2.36 [95%CI 1.60, 3.47], and 2.95 [95%CI 1.88, 4.63], respectively. Such findings suggest that abatacept-treated patients were 1.57, 1.84, 2.36, and 2.95 times more likely to achieve ACR 20/50/70/90 responses, respectively, than those treated with placebo, conventional synthetic disease-modifying antirheumatic drugs, and or other biologic disease-modifying anti-rheumatic drugs. An exclusive comparison of abatacept and other biologic/targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) indicated that participants who were treated with abatacept could achieve better ACR responses than those treated with other b/tsDMARDs. Adverse events were less seen in abatacept-treated patients than in those who were given other b/tsDMARDs.
CONCLUSIONS
This meta-analysis concludes that in adult with rheumatoid arthritis, abatacept can achieve better health outcomes than other biologic drugs.
Topics: Adult; Humans; Abatacept; Methotrexate; Arthritis, Rheumatoid; Antirheumatic Agents; Biological Products; Randomized Controlled Trials as Topic
PubMed: 36912326
DOI: 10.55563/clinexprheumatol/2xjg0d -
Vaccines Nov 2023Pneumococcal pneumonia is an important cause of morbidity and mortality amongst patients with inflammatory arthritis. Vaccination is recommended by the National... (Review)
Review
BACKGROUND
Pneumococcal pneumonia is an important cause of morbidity and mortality amongst patients with inflammatory arthritis. Vaccination is recommended by the National Institute for Health and Care Excellence (NICE) but it remains unclear how vaccine efficacy is impacted by different immunosuppressive agents. Our objective was to compare the chance of a seroconversion following vaccination against pneumococcus in patients with inflammatory arthritis to that in the general population, as well as to compare the chance of seroconversion across different targeted therapies.
METHODS
We searched MEDLINE, Embase and the Cochrane Library databases from inception until 20 June 2023. We included randomized controlled trials and observational studies. Aggregate data were used to undertake a pairwise meta-analysis. Our primary outcome of interest was vaccine seroconversion. We accepted the definition of serological response reported by the authors of each study.
RESULTS
Twenty studies were identified in the systematic review (2807 patients) with ten reporting sufficient data to be included in the meta-analysis (1443 patients). The chance of seroconversion in patients receiving targeted therapies, relative to the general population, was 0.61 (95% CI 0.35 to 1.08). The reduced odds of response were skewed strongly by the effects of abatacept and rituximab with no difference between patients on TNF inhibitors (TNFis) or IL-6 inhibition and healthy controls. Within different inflammatory arthritis populations the findings remained consistent, with rituximab having the strongest negative impact on vaccine response. TNF inhibition monotherapy was associated with a greater chance of vaccine response compared with methotrexate (2.25 (95% CI 1.28 to 3.96)). JAK inhibitor (JAKi) studies were few in number and did not present comparable vaccine response endpoints to include in the meta-analysis. The information available does not suggest any significant detrimental effects of JAKi on vaccine response.
CONCLUSION
This updated meta-analysis confirms that, for most patients with inflammatory arthritis, pneumococcal vaccine can be administered with confidence and that it will achieve comparable seroconversion rates to the healthy population. Patients on rituximab were the group least likely to achieve a response and further research is needed to explore the value of multiple-course pneumococcal vaccination schedules in this population.
PubMed: 38006012
DOI: 10.3390/vaccines11111680 -
Arthritis Research & Therapy Dec 2015Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Tofacitinib modulates the signaling of cytokines that are integral to... (Meta-Analysis)
Meta-Analysis Review
Systematic review and meta-analysis of serious infections with tofacitinib and biologic disease-modifying antirheumatic drug treatment in rheumatoid arthritis clinical trials.
BACKGROUND
Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Tofacitinib modulates the signaling of cytokines that are integral to lymphocyte activation, proliferation, and function. Thus, tofacitinib therapy may result in suppression of multiple elements of the immune response. Serious infections have been reported in tofacitinib RA trials. However, limited head-to-head comparator data were available within the tofacitinib RA development program to directly compare rates of serious infections with tofacitinib relative to biologic agents, and specifically adalimumab (employed as an active control agent in two randomized controlled trials of tofacitinib).
METHODS
A systematic literature search of data from interventional randomized controlled trials and long-term extension studies with biologics in RA was carried out. Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) consensus was followed for reporting results of the review and meta-analysis. Incidence rates (unique patients with events/100 patient-years) for each therapy were estimated based on data from randomized controlled trials and long-term extension studies using a random-effects model. Relative and absolute risk comparisons versus placebo used Mantel-Haenszel methods.
RESULTS
The search produced 657 hits. In total, 66 randomized controlled trials and 22 long-term extension studies met the selection criteria. Estimated incidence rates (95% confidence intervals [CIs]) for abatacept, rituximab, tocilizumab, and tumor necrosis factor inhibitors were 3.04 (2.49, 3.72), 3.72 (2.99, 4.62), 5.45 (4.26, 6.96), and 4.90 (4.41, 5.44), respectively. Incidence rates (95% CIs) for tofacitinib 5 and 10 mg twice daily (BID) in phase 3 trials were 3.02 (2.25, 4.05) and 3.00 (2.24, 4.02), respectively. Corresponding incidence rates in long-term extension studies were 2.50 (2.05, 3.04) and 3.19 (2.74, 3.72). The risk ratios (95% CIs) versus placebo for tofacitinib 5 and 10 mg BID were 2.21 (0.60, 8.14) and 2.02 (0.56, 7.28), respectively. Risk differences (95% CIs) versus placebo for tofacitinib 5 and 10 mg BID were 0.38% (-0.24%, 0.99%) and 0.40% (-0.22%, 1.02%), respectively.
CONCLUSIONS
In interventional studies, the risk of serious infections with tofacitinib is comparable to published rates for biologic disease-modifying antirheumatic drugs in patients with moderate to severely active RA.
Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Biological Products; Communicable Diseases; Humans; Janus Kinase 3; Piperidines; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 26669566
DOI: 10.1186/s13075-015-0880-2 -
Vaccine Jun 2023Patients with autoimmune rheumatic diseases (ARD) are at a potentially higher risk for COVID-19 infection complications. Given their inherent altered immune system and... (Review)
Review
BACKGROUND
Patients with autoimmune rheumatic diseases (ARD) are at a potentially higher risk for COVID-19 infection complications. Given their inherent altered immune system and the use of immunomodulatory medications, vaccine immunogenicity could be unpredictable with a suboptimal or even an exaggerated immunological response. The aim of this study is to provide real-time data on the emerging evidence of COVID-19 vaccines' efficacy and safety in patients with ARDs.
METHODS
We performed a literature search of the PubMed, EMBASE, and OVID databases up to 11-13 April 2022 on the efficacy and safety of both types of the mRNA-vaccines and the AstraZeneca COVID-19 vaccines in patients with ARD. The risk of bias in the retrieved studies was evaluated using the Quality in Prognostic Studies tool. Also, current clinical practice guidelines from multiple international professional societies were reviewed.
RESULTS
We identified 60 prognostic studies, 69 case reports and case series, and eight international clinical practice guidelines. Our results demonstrated that most patients with ARDs were able to mount humoral and/or cellular responses after two doses of COVID-19 vaccine although this response was suboptimal in patients receiving certain disease-modifying medications including rituximab, methotrexate, mycophenolate mofetil, daily glucocorticoids >10 mg, abatacept, as well as in older individuals, and those with comorbid interstitial lung diseases. Safety reports on COVID-19 vaccines in patients with ARDs were largely reassuring with mostly self-limiting adverse events and very minimal post-vaccination disease flares.
CONCLUSION
Both types of the mRNA-vaccines and the AstraZeneca COVID-19 vaccines are highly effective and safe in patients with ARD. However, due to their suboptimal response in some patients, alternative mitigation strategies such as booster vaccines and shielding practices should also be followed. Management of immunomodulatory treatment regimens during the peri vaccination period should be individualized through shared decision making with patients and their attending rheumatologists.
Topics: Humans; Aged; COVID-19 Vaccines; RNA, Messenger; COVID-19; ChAdOx1 nCoV-19; Autoimmune Diseases; Rheumatic Diseases
PubMed: 37244811
DOI: 10.1016/j.vaccine.2023.05.048 -
Journal of Clinical Rheumatology :... Mar 2023The aim of this study was to examine the effect and safety of biological agents for lupus nephritis (LN). (Meta-Analysis)
Meta-Analysis
OBJECTIVES
The aim of this study was to examine the effect and safety of biological agents for lupus nephritis (LN).
METHODS
PubMed, EMBASE, and the Cochrane Library databases were searched from their inception up to November 2021. The outcomes were overall response, complete remission, proteinuria, renal activity index, and adverse events (AEs). Only randomized controlled trials (RCTs) were included.
RESULTS
Nine RCTs (1645 patients) were included. The RCTs evaluated abatacept (n = 2), belimumab (n = 1), obinutuzumab (n = 1), atacicept (n = 1), IL-2 (n = 1), ocrelizumab (n = 1), and rituximab (n = 2). The use of biological agents was associated with higher likelihoods of achieving an overall response (relative risk [RR], 1.26; 95% confidence interval [CI], 1.15-1.39; p < 0.001; I2 = 14.3%; pQ = 0.301) and a complete response (RR, 1.33; 95% CI, 1.16-1.54; p < 0.001; I2 = 41.8%; pQ = 0.056). The use of biological agents was not associated with improvements in the urinary protein-to-creatinine ratio (weighted mean difference, 3.83; 95% CI, -3.71 to 11.38; p = 0.319; I2 = 99.4%; pQ < 0.001). The use of biological agents in patients with LN was also not associated with an increased risk of any AEs (RR, 1.01; 95% CI, 0.98-1.04; p = 0.519; I2 = 0.0%; pQ = 0.533), serious AEs (RR, 0.95; 95% CI, 0.82-1.09; p = 0.457; I2 = 0.0%; pQ = 0.667), grade >3 AEs (RR, 0.91; 95% CI, 0.67-1.22; p = 0.522; I2 = 0.0%; pQ = 0.977), infections (RR, 1.09; 95% CI, 0.99-1.20; p = 0.084; I2 = 0.0%; pQ = 0.430), and deaths (RR, 0.67; 95% CI, 0.36-1.24; p = 0.200; I2 = 0.0%; pQ = 0.439). The meta-regression analysis showed that follow-up duration and the sample size did not influence the complete response rate, whereas publications in 2012 to 2014 influence the rate compared with 2015 to 2020.
CONCLUSIONS
Biological agents seem to be effective and safe for managing patients with LN.
Topics: Humans; Abatacept; Lupus Nephritis; Rituximab; Biological Products; Randomized Controlled Trials as Topic
PubMed: 35699520
DOI: 10.1097/RHU.0000000000001877