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Clinical and Experimental Rheumatology May 2022Due to the rarity of relapsing polychondritis (RP), no randomised clinical trial has been conducted to date and treatment remains empirical. We performed a systematic... (Review)
Review
OBJECTIVES
Due to the rarity of relapsing polychondritis (RP), no randomised clinical trial has been conducted to date and treatment remains empirical. We performed a systematic literature review to assess the efficacy of the main conventional immunosuppressants and biotherapies used in RP.
METHODS
We searched MEDLINE for original articles without language restriction. Abstracts from American College of Rheumatology (ACR) and European Alliance of Associations for Rheumatology (EULAR) were also considered for inclusion. Observational studies and clinical trials reporting on the efficacy of conventional immunosuppressants and biotherapies in adult patients with RP were selected and pooled response rates for each treatment were computed.
RESULTS
Of 304 articles and abstracts identified, 31 underwent full-text review, and 11 were included. The studies involved a total of 177 patients, exposed to a total of 247 lines of treatments. The main treatments studied (by number of lines) were: TNF inhibitors (TNFi), n=92; methotrexate (MTX), n=38; tocilizumab (TCZ), n=26; anakinra (ANA), n=21; rituximab (RTX), n=16; abatacept (ABT), n=14; cyclophosphamide (CYC), n=14; azathioprine (AZA), n=13. The pooled response rates across studies were: 72% [95% CI: 42-95] for ABT, 66% [95% CI: 49-82] for TCZ, 64% [95% CI: 53-74] for TNFi, 56% [95% CI: 37-73] for MTX, 47% [95% CI: 26-68] for ANA, 43% [95% CI: 20-68] for RTX. Based on more limited data, response rates for AZA and CYC ranged from 38 to 100% and from 25 to 100%, respectively.
CONCLUSIONS
In this systematic review of available evidence regarding the treatment of relapsing polychondritis, ABT, TCZ and TNFi were the drugs associated with the best outcomes. ABT efficacy must be interpreted in light of the small number of patients treated. While MTX had slightly less efficacy, it is one of the drugs for which data are the most robust.
Topics: Abatacept; Adult; Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Immunosuppressive Agents; Methotrexate; Polychondritis, Relapsing; Rituximab; Tumor Necrosis Factor Inhibitors
PubMed: 35238756
DOI: 10.55563/clinexprheumatol/h9gq1o -
Clinical Journal of the American... Aug 2021The long-term management of maintenance immunosuppression in kidney transplant recipients remains complex. The vast majority of patients are treated with the calcineurin... (Review)
Review
The long-term management of maintenance immunosuppression in kidney transplant recipients remains complex. The vast majority of patients are treated with the calcineurin inhibitor tacrolimus as the primary agent in combination with mycophenolate, with or without corticosteroids. A tacrolimus trough target 5-8 ng/ml seems to be optimal for rejection prophylaxis, but long-term tacrolimus-related side effects and nephrotoxicity support the ongoing evaluation of noncalcineurin inhibitor-based regimens. Current alternatives include belatacept or mammalian target of rapamycin inhibitors. For the former, superior kidney function at 7 years post-transplant compared with cyclosporin generated initial enthusiasm, but utilization has been hampered by high initial rejection rates. Mammalian target of rapamycin inhibitors have yielded mixed results as well, with improved kidney function tempered by higher risk of rejection, proteinuria, and adverse effects leading to higher discontinuation rates. Mammalian target of rapamycin inhibitors may play a role in the secondary prevention of squamous cell skin cancer as conversion from a calcineurin inhibitor to an mammalian target of rapamycin inhibitor resulted in a reduction of new lesion development. Early withdrawal of corticosteroids remains an attractive strategy but also is associated with a higher risk of rejection despite no difference in 5-year patient or graft survival. A major barrier to long-term graft survival is chronic alloimmunity, and regardless of agent used, managing the toxicities of immunosuppression against the risk of chronic antibody-mediated rejection remains a fragile balance.
Topics: Abatacept; Adrenal Cortex Hormones; Calcineurin Inhibitors; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; MTOR Inhibitors; Maintenance Chemotherapy; Mycophenolic Acid; Tacrolimus; Time Factors
PubMed: 33853841
DOI: 10.2215/CJN.15040920 -
Autoimmunity Reviews Jun 2021The primary vasculitides constitute a heterogeneous group of immune mediated diseases of incompletely understood pathogenesis currently classified by the size of blood... (Review)
Review
The primary vasculitides constitute a heterogeneous group of immune mediated diseases of incompletely understood pathogenesis currently classified by the size of blood vessels affected (Chapel Hill classification). In recent years, several drugs with well-characterized immunological targets have been tested in clinical trials in large vessel vasculitis and small vessel vasculitis. Such trials provide "reverse translational" or bedside to bench information about underlying pathogenic mechanisms. Therefore, the aim of this systematic literature review was to examine the evidence base for a more refined mechanistic immunological classification of vasculitis. A total of 40 studies (20 randomized controlled trials (RCTs), 16 prospective studies, 1 retrospective cohort study and 3 case series) were included for full qualitative assessment. RCTs concerning biologic therapy for large vessel vasculitis mainly supports interleukin 6 receptor inhibition (tocilizumab). RCTs concerning biologic therapy for granulomatosis with polyangiitis and microscopic polyangiitis mainly support anti-CD20 treatment (rituximab) and complement inhibition with a small molecule C5a receptor antagonist (avacopan) is an emerging treatment option. The biologic treatment of eosinophilic granulomatosis with polyangiitis is centered around interleukin 5 inhibition (mepolizumab). Studies on tumor necrosis factor alpha inhibition (adalimumab, infliximab, and etanercept) showed negative results in giant cell arteritis but some effect in Takayasu arteritis. Taken together, clinical studies with cytokine and cell specific drugs are dissecting the heterogeneous immunopathogenic mechanisms of vasculitis and support a mechanistic immunological classification. Especially, cytokine antagonism is pointing towards immunological distinctions between eosinophilic granulomatosis with polyangiitis and granulomatosis with polyangiitis/microscopic polyangiitis and differences between giant cell arteritis and Takayasu arteritis.
Topics: Churg-Strauss Syndrome; Etanercept; Giant Cell Arteritis; Granulomatosis with Polyangiitis; Humans; Microscopic Polyangiitis; Randomized Controlled Trials as Topic; Rituximab; Takayasu Arteritis
PubMed: 33872767
DOI: 10.1016/j.autrev.2021.102829 -
Journal of Clinical Oncology : Official... Jun 2021Severe (grade 3-4) acute graft-versus-host disease (AGVHD) is a major cause of death after unrelated-donor (URD) hematopoietic cell transplant (HCT), resulting in... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Severe (grade 3-4) acute graft-versus-host disease (AGVHD) is a major cause of death after unrelated-donor (URD) hematopoietic cell transplant (HCT), resulting in particularly high mortality after HLA-mismatched transplantation. There are no approved agents for AGVHD prevention, underscoring the critical unmet need for novel therapeutics. ABA2 was a phase II trial to rigorously assess safety, efficacy, and immunologic effects of adding T-cell costimulation blockade with abatacept to calcineurin inhibitor (CNI)/methotrexate (MTX)-based GVHD prophylaxis, to test whether abatacept could decrease AGVHD.
METHODS
ABA2 enrolled adults and children with hematologic malignancies under two strata: a randomized, double-blind, placebo-controlled stratum (8/8-HLA-matched URD), comparing CNI/MTX plus abatacept with CNI/MTX plus placebo, and a single-arm stratum (7/8-HLA-mismatched URD) comparing CNI/MTX plus abatacept versus CNI/MTX CIBMTR controls. The primary end point was day +100 grade 3-4 AGVHD, with day +180 severe-AGVHD-free-survival (SGFS) a key secondary end point. Sample sizes were calculated using a higher type-1 error (0.2) as recommended for phase II trials, and were based on predicting that abatacept would reduce grade 3-4 AGVHD from 20% to 10% (8/8s) and 30% to 10% (7/8s). ABA2 enrolled 142 recipients (8/8s, median follow-up = 716 days) and 43 recipients (7/8s, median follow-up = 708 days).
RESULTS
In 8/8s, grade 3-4 AGVHD was 6.8% (abatacept) versus 14.8% (placebo) ( = .13, hazard ratio = 0.45). SGFS was 93.2% (CNI/MTX plus abatacept) versus 82% (CNI/MTX plus placebo, = .05). In the smaller 7/8 cohort, grade 3-4 AGVHD was 2.3% (CNI/MTX plus abatacept, intention-to-treat population), which compared favorably with a nonrandomized matched cohort of CNI/MTX (30.2%, < .001), and the SGFS was better (97.7% 58.7%, < .001). Immunologic analysis revealed control of T-cell activation in abatacept-treated patients.
CONCLUSION
Adding abatacept to URD HCT was safe, reduced AGVHD, and improved SGFS. These results suggest that abatacept may substantially improve AGVHD-related transplant outcomes, with a particularly beneficial impact on HLA-mismatched HCT.
Topics: Abatacept; Adolescent; Adult; Aged; Child; Cyclosporine; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Methotrexate; Middle Aged; Tacrolimus; Young Adult
PubMed: 33449816
DOI: 10.1200/JCO.20.01086 -
Cureus Jan 2023Rheumatoid arthritis (RA) is a chronic inflammatory joint disease that can cause cartilage and bone damage as well as a disability. Various cytokines play an essential... (Review)
Review
Rheumatoid arthritis (RA) is a chronic inflammatory joint disease that can cause cartilage and bone damage as well as a disability. Various cytokines play an essential role in disease formation such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6, IL-17, and macrophages; osteoclast is also activated by the cytokines, which cause bone degradation. Early diagnosis is key to optimal therapeutic success, particularly in patients with well-characterized risk factors for poor outcomes such as high disease activity, presence of autoantibodies, and early joint damage. Treatment algorithms involve measuring disease activity with composite indices, applying a treatment-to-target strategy, and using conventional, biological, and new non-biological disease-modifying antirheumatic drugs. After the treatment target of stringent remission (or at least low disease activity) is maintained, dose reduction should be attempted. Although the prospects for most patients are now favorable, many still do not respond to current therapies. The biologics have changed the disease progression over the past few decades, such as TNF-alpha inhibitors (infliximab, etanercept, adalimumab, golimumab, certolizumab), IL-1 inhibitors (anakinra), IL-6 inhibitors (tocilizumab), CD20 inhibitors (rituximab), and cytotoxic T-lymphocyte associated antigen (CTLA)-4 inhibitors (abatacept). In treatment with biologics, only little is known if "biologic-free" remission is possible in patients with sustained remission following intensive biological therapy. Infliximab and etanercept, in the long run, develop the drug antibody. This article has reviewed the action of the cytokine on joints and biological drug's action in blocking the cytokine degradation effect, benefits of biologics, and adverse effects in the long and short term. They are also effective alone or in combination with other drugs.
PubMed: 36606106
DOI: 10.7759/cureus.33293 -
Pharmacology 2023To date, no studies have described randomized controlled trials (RCTs) evaluating the effectiveness and safety of various biological agents used in induction therapy for... (Meta-Analysis)
Meta-Analysis
BACKGROUND
To date, no studies have described randomized controlled trials (RCTs) evaluating the effectiveness and safety of various biological agents used in induction therapy for lupus nephritis.
OBJECTIVES
We designed this study to assess the relative efficacy and safety of some of these biological agents in patients with lupus nephritis.
METHOD
We collected data from RCTs that examined the efficacy and safety of any biological agents for lupus nephritis and then used these data to complete a Bayesian network meta-analysis to combine the direct and indirect evidence from these studies.
RESULTS
We identified nine RCTs evaluating rituximab, abatacept, belimumab, anifrolumab, obinutuzumab, ocrelizumab, and low-dose interleukin-2 (IL-2) across 1,480 patients. Low-dose IL-2, obinutuzumab, rituximab, and belimumab achieved complete remission in a significant proportion of respondents when compared with that in the control. Ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that low-dose IL-2 had the highest probability of achieving complete remission, followed by obinutuzumab, rituximab, belimumab, anifrolumab, abatacept, ocrelizumab, and the control. The risk of serious adverse events (SAE) tended to be lower for low-dose IL-2, rituximab, belimumab, and obinutuzumab than for the control. SUCRA-based ranking indicated that IL-2 had the highest probability of being safe, followed by rituximab, belimumab, obinutuzumab, control, anifrolumab, abatacept, and ocrelizumab.
CONCLUSIONS
Low-dose IL-2 was the most effective induction treatment for patients with lupus nephritis and had the lowest potential for SAE. Higher complete remission rates and a more favorable safety profile suggest that low-dose IL-2, obinutuzumab, rituximab, and belimumab may be superior to the current control as treatments for lupus nephritis.
Topics: Humans; Immunosuppressive Agents; Lupus Nephritis; Rituximab; Abatacept; Interleukin-2; Biological Factors; Network Meta-Analysis; Treatment Outcome
PubMed: 36327917
DOI: 10.1159/000527223 -
Annals of the Rheumatic Diseases Oct 2022JAK-inhibitors (JAKi), recently approved in rheumatoid arthritis (RA), have changed the landscape of treatment choices. We aimed to compare the effectiveness of four... (Observational Study)
Observational Study
Effectiveness of TNF-inhibitors, abatacept, IL6-inhibitors and JAK-inhibitors in 31 846 patients with rheumatoid arthritis in 19 registers from the 'JAK-pot' collaboration.
BACKGROUND
JAK-inhibitors (JAKi), recently approved in rheumatoid arthritis (RA), have changed the landscape of treatment choices. We aimed to compare the effectiveness of four current second-line therapies of RA with different modes of action, since JAKi approval, in an international collaboration of 19 registers.
METHODS
In this observational cohort study, patients initiating tumour necrosis factor inhibitors (TNFi), interleukin-6 inhibitors (IL-6i), abatacept (ABA) or JAKi were included. We compared the effectiveness of these treatments in terms of drug discontinuation and Clinical Disease Activity Index (CDAI) response rates at 1 year. Analyses were adjusted for patient, disease and treatment characteristics, including lines of therapy and accounted for competing risk.
RESULTS
We included 31 846 treatment courses: 17 522 TNFi, 2775 ABA, 3863 IL-6i and 7686 JAKi. Adjusted analyses of overall discontinuation were similar across all treatments. The main single reason of stopping treatment was ineffectiveness. Compared with TNFi, JAKi were less often discontinued for ineffectiveness (adjusted HR (aHR) 0.75, 95% CI 0.67 to 0.83), as was IL-6i (aHR 0.76, 95% CI 0.67 to 0.85) and more often for adverse events (aHR 1.16, 95% CI 1.03 to 1.33). Adjusted CDAI response rates at 1 year were similar between TNFi, JAKi and IL-6i and slightly lower for ABA.
CONCLUSION
The adjusted overall drug discontinuation and 1 year response rates of JAKi and IL-6i were similar to those observed with TNFi. Compared with TNFi, JAKi were more often discontinued for adverse events and less for ineffectiveness, as were IL-6i.
Topics: Abatacept; Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Interleukin-6; Janus Kinase Inhibitors; Treatment Outcome; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha
PubMed: 35705376
DOI: 10.1136/annrheumdis-2022-222586 -
Autoimmunity Reviews Jan 2023Rheumatoid arthritis (RA) is an autoimmune disease characterized by symmetrical peripheral polyarthritis in the hands and/or feet, leading to long-term disability if not... (Review)
Review
BACKGROUND
Rheumatoid arthritis (RA) is an autoimmune disease characterized by symmetrical peripheral polyarthritis in the hands and/or feet, leading to long-term disability if not treated effectively. RA is preceded by a preclinical phase, in which genetically predisposed individuals accumulate environmental risk factors, and during which autoimmunity develops, followed by the emergence of non-specific signs and symptoms before arthritis becomes manifest. Early treatment in at-risk individuals - i.e. before the disease is fully established - has the theoretical potential to delay or prevent disease onset, with a positive impact on both patients' life and society.
OBJECTIVES
We aimed to understand the feasibility of preventive treatment in at-risk individuals, taking into account recently performed studies and ongoing clinical trials, as well as patient perspectives.
METHODS
We performed a systematic literature review (SLR) on Medline and Embase, searching articles published between 2010 and 2021 with the following key-words: "Rheumatoid arthritis", "arthralgia", "pre-treatment" or "prevent".
RESULTS
Our SLR identified a total of 1821 articles. Articles were independently screened by two researchers. A total of 14 articles were included after screening, and an additional 8 reports were manually included. We identified ten relevant clinical trials performed in at-risk individuals, or in individuals with undifferentiated inflammatory arthritis. Although no treatment was shown to prevent RA onset, early treatment with rituximab and abatacept delayed onset of full-blown RA, and both conventional and biological disease-modifying anti-rheumatic drugs (DMARDs) decreased disease-related physical limitations and increased DAS28-defined remission, at least temporarily.
CONCLUSIONS
This SLR demonstrates that early treatment of at-risk individuals may be effective in delaying RA onset, thereby decreasing disease-related limitations in individuals in the pre-clinical phase of RA. Whether this may ultimately lead to prevention of RA remains to be determined.
Topics: Humans; Arthritis, Rheumatoid; Antirheumatic Agents; Abatacept; Rituximab; Autoimmunity
PubMed: 36280095
DOI: 10.1016/j.autrev.2022.103217 -
Diabetes Care May 2023Previous studies showed that inhibiting lymphocyte costimulation reduces declining β-cell function in individuals newly diagnosed with type 1 diabetes. We tested... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Previous studies showed that inhibiting lymphocyte costimulation reduces declining β-cell function in individuals newly diagnosed with type 1 diabetes. We tested whether abatacept would delay or prevent progression of type 1 diabetes from normal glucose tolerance (NGT) to abnormal glucose tolerance (AGT) or to diabetes and the effects of treatment on immune and metabolic responses.
RESEARCH DESIGN AND METHODS
We conducted a phase 2, randomized, placebo-controlled, double-masked trial of abatacept in antibody-positive participants with NGT who received monthly abatacept/placebo infusions for 12 months. The end point was AGT or diabetes, assessed by oral glucose tolerance tests.
RESULTS
A total of 101 participants received abatacept and 111 placebo. Of these, 81 (35 abatacept and 46 placebo) met the end point of AGT or type 1 diabetes diagnosis (hazard ratio 0.702; 95% CI 0.452, 1.09; P = 0.11) The C-peptide responses to oral glucose tolerance tests were higher in the abatacept arm (P < 0.03). Abatacept reduced the frequency of inducible T-cell costimulatory (ICOS)+ PD1+ T-follicular helper (Tfh) cells during treatment (P < 0.0001), increased naive CD4+ T cells, and also reduced the frequency of CD4+ regulatory T cells (Tregs) from the baseline (P = 0.0067). Twelve months after treatment, the frequency of ICOS+ Tfh, naive CD4+ T cells, and Tregs returned to baseline.
CONCLUSIONS
Although abatacept treatment for 1 year did not significantly delay progression to glucose intolerance in at-risk individuals, it impacted immune cell subsets and preserved insulin secretion, suggesting that costimulation blockade may modify progression of type 1 diabetes.
Topics: Humans; Abatacept; Diabetes Mellitus, Type 1; Immunosuppressive Agents; T-Lymphocytes, Regulatory; Glucose
PubMed: 36920087
DOI: 10.2337/dc22-2200