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ACR Open Rheumatology Feb 2021Eosinophilic granulomatosis with polyangiitis (EGPA) is part of a group of vasculitides commonly referred to as antineutrophil cytoplasmic antibody (ANCA)-associated...
OBJECTIVE
Eosinophilic granulomatosis with polyangiitis (EGPA) is part of a group of vasculitides commonly referred to as antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), in addition to granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and renal-limited vasculitis. Patients with EGPA characteristically have asthma and marked peripheral eosinophilia with only approximately 30% to 35% of patients being myeloperoxidase (MPO)-ANCA positive, distinguishing it from other forms of AAV (1,2). The aim of this systematic review is to support the development of the American College of Rheumatology/Vasculitis Foundation guideline for the management of EGPA.
METHODS
A systematic review was conducted of the literature for seven forms of primary systemic vasculitis (GPA, MPA, EGPA, polyarteritis nodosa, Kawasaki disease, giant cell arteritis, and Takayasu arteritis). The search was done for articles in English using Ovid Medline, PubMed, Embase, and the Cochrane Library. Articles were screened for suitability in addressing population/patients, intervention, comparator, and outcomes (PICO) questions, with studies presenting the highest level of evidence given preference. Two independent reviewers conducted a title/abstract screen and full-text review for each eligible study.
RESULTS
The initial search, conducted in August 2019, included 13 800 articles, of which 2596 full-text articles were reviewed. There were 190 articles (addressing 34 PICO questions) reporting on the diagnosis and management of EGPA.
CONCLUSION
This comprehensive systematic review synthesizes and evaluates the accuracy of commonly used tests for EGPA as well as benefits and toxicities of different treatment options.
PubMed: 33512787
DOI: 10.1002/acr2.11194 -
Arthritis Research & Therapy Jan 2021To assess through systematic review and meta-analysis whether plasma exchange (PE) is associated with prognosis in antineutrophil cytoplasmic antibody (ANCA)-associated... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To assess through systematic review and meta-analysis whether plasma exchange (PE) is associated with prognosis in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) patients.
METHODS
A systematic search of PubMed, MEDLINE, Embase, and CENTRAL databases from inception to 17 June 2020 was conducted. Ongoing or unpublished trials were also searched in ClinicalTrials.gov and the World Health Organization trials portal. Randomised controlled trials (RCTs) comparing PE vs. non-PE in AAV patients (microscopic polyangiitis [MPA], granulomatosis with polyangiitis [GPA], or eosinophilic granulomatosis with polyangiitis [EGPA]) were included. The combined risk ratio (RR) was calculated by the random-effects model using the Mantel-Haenszel method. Heterogeneity was measured using the I statistic. Primary outcomes were mortality, clinical remission (CR), and adverse events (AEs).
RESULTS
Four RCTs comparing PE vs. no PE (N = 827) and 1 RCT comparing PE vs. pulse steroid treatment (N = 137) were included. All participants were MPA or GPA patients (no EGPA patients). PE was not associated with main primary outcomes compared with no PE (mortality RR 0.93 [95% confidence interval {CI} 0.70-1.24], I = 0%; CR RR 1.02 [95% CI 0.91-1.15], I = 0%; and AE RR 1.10 [95% CI 0.73-1.68], I = 37%) or pulse steroid (mortality RR 0.99 [95% CI 0.71-1.37]; CR [the Birmingham Vasculitis Activity score] mean difference - 0.53 [95% CI - 1.40-0.34]; and AE RR 1.05 [95% CI 0.74-1.48]). Focusing on the early treatment phases, PE was associated with a reduction in end-stage renal disease incidence compared with both no PE (PE 1/43 vs. no PE 10/41; RR 0.14 [0.03-0.77] at 3 months) and pulse steroid (PE 11/70 vs. pulse steroid 23/67; RR 0.46 [0.24-0.86] at 3 months).
CONCLUSION
We carried out a systematic review and meta-analysis targeting all AAV patients, including MPA, GPA, and EGPA. In AAV patients, performing PE was not associated with the risk of mortality, CR, and AE. No RCT exists evaluating the efficacy of PE for EGPA; hence, this is required in the future. The results may affect the development of guidelines for AAV and may indicate the direction of future clinical research on AAV.
TRIAL REGISTRATION
UMIN R000045239 , PROSPERO CRD42020182566 .
Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Churg-Strauss Syndrome; Granulomatosis with Polyangiitis; Humans; Microscopic Polyangiitis; Plasma Exchange
PubMed: 33446268
DOI: 10.1186/s13075-021-02415-z -
Rheumatology (Oxford, England) Dec 2020Pleuroparenchymal fibroelastosis (PPFE) is characterized by predominantly upper lobe pleural and subjacent parenchymal fibrosis; PPFE features were described in patients...
OBJECTIVES
Pleuroparenchymal fibroelastosis (PPFE) is characterized by predominantly upper lobe pleural and subjacent parenchymal fibrosis; PPFE features were described in patients with rheumatic autoimmune diseases (RAID). A systematic literature review was performed to investigate the prevalence, prognosis and potential association of PPFE with previous immunosuppression in RAID.
METHODS
EMBASE, Web of Science and PubMed databases were questioned from inception to 1 September 2019. Articles published in English and addressing PPFE in patients with RAID were selected.
RESULTS
Twenty out of 794 papers were selected with a total of 76 cases of RAID-PPFE patients (20 SSc, 9 RA, 6 IIM6 primary SS, 5 overlap syndromes, 3 ANCA-associated vasculitides, 2 granulomatosis with polyangiitis, 1 microscopic polyangiitis, 1 UCTD, 1 SLE, 1 GCA and 21 patients with non-specified RAID). Dyspnoea was the most frequently reported symptom (37/48 patients, 77%). Patients frequently presented with a restrictive pattern and decline in diffusing lung capacity for carbon monoxide. During the follow-up, 7/12 patients had progression at imaging, 22/39 presented a generic clinical worsening, 19/38 had a functional deterioration and 15/43 remained stable.
CONCLUSION
The present systematic literature review confirms that PPFE features are present in RAID. Rheumatologists should be aware of this new radiological pattern that holds a bad prognosis.
Topics: Autoimmune Diseases; Humans; Pleural Diseases; Pulmonary Fibrosis; Rheumatic Diseases
PubMed: 33313932
DOI: 10.1093/rheumatology/keaa451 -
Artificial Organs Jun 2021Modern extracorporeal life-support (ECLS) technology has been successfully utilized to treat patients with diffuse alveolar damage (DAD) and diffuse alveolar hemorrhage...
Modern extracorporeal life-support (ECLS) technology has been successfully utilized to treat patients with diffuse alveolar damage (DAD) and diffuse alveolar hemorrhage (DAH); however, reports in the literature remain scarce. We sought to pool existing evidence to better characterize ECLS use in these patients. An electronic search was conducted to identify all studies in the English literature reporting the use of ECLS for DAD/DAH. Thirty-two articles consisting of 38 patients were selected, and patient-level data were extracted and pooled for analysis. Median patient age was 36 [IQR: 27, 48] years, and the majority (63.2%) were female. Most common etiological factors included granulomatosis with polyangiitis (8/38, 21.1%), systemic lupus erythematosus (8/38, 21.1%), Goodpasture's syndrome (4/38, 10.5%), and microscopic polyangiitis (4/38, 10.5%). Immunologic markers included anti-neutrophil cytoplasmic antibody (ANCA) in 15/38 (39.5%), anti-nuclear antibody (ANA) in 6/38 (15.8%), and anti-glomerular basement membrane (anti-GBM) antibodies in 4/38 (10.5%). DAH was present in 32/38 (84.2%) of cases and DAD without evidence of DAH was present in 6/38 (15.8%) of cases. ECLS strategies included extracorporeal membrane oxygenation of veno-venous type (VV-ECMO) in 28/38 (73.7%), veno-arterial type (VA-ECMO) in 5/38 (13.2%), and one case of right ventricular assist device with oxygenator (RVAD-ECMO). Heparin was utilized in 18/38 (47.4%) of cases with no difference in use between DAH versus no DAH (P = .46) or VA- versus VV-ECLS (P = 1). Median duration of ECLS was 10 [5, 14] days. Pre- versus post-ECLS comparison of blood gases showed improvement in median PaO (49 [45, 59] mm Hg vs. 80 [70, 99] mm Hg, P < .001), PaO2:FiO ratio (48.2 [41.4, 54.8] vs. 182.0 [149.4, 212.2], P < .01), and pulse oximetry values (76% [72, 80] vs. 96% [94, 97], P = .086). Overall, 94.7% (36/38) of patients survived to decannulation while 30-day mortality was 10.5% (4/38) with no differences between VA- and VV-ECMO (P = 1 and P = .94, respectively). DAD/DAH occurs in a younger, predominantly female population, and tends to be associated with systemic autoimmune processes. ECLS, independent of its type, appears to result in favorable short-term survival.
Topics: Extracorporeal Membrane Oxygenation; Hemorrhage; Humans; Lung Diseases; Pulmonary Alveoli
PubMed: 33190331
DOI: 10.1111/aor.13861 -
Seminars in Arthritis and Rheumatism Dec 2020A comprehensive review of outcome measures used in randomized controlled trials (RCTs) of ANCA-associated vasculitis (AAV) could advance trial conductance for this... (Review)
Review
BACKGROUND
A comprehensive review of outcome measures used in randomized controlled trials (RCTs) of ANCA-associated vasculitis (AAV) could advance trial conductance for this disease.
METHODS
A systematic literature review of outcome measures (as specified in methods section as primary and/or secondary outcomes) in RCTs of AAV was conducted. Medline, Cochrane CENTRAL, and ClinicalTrials.gov were searched from inception until April 30, 2019 for RCTs enrolling patients with granulomatosis with polyangiitis and/or microscopic polyangiitis. Outcome measures were organized according to domains (e.g. disease activity) and instruments [e.g. Birmingham Vasculitis Activity Score (BVAS)].
RESULTS
Out of 1101 identified records, 68 RCTs were eligible. Disease activity was an outcome domain collected in 67 (98%) of the RCTs. The BVAS was the most widely used instrument for disease assessment but definitions for remissions and relapse varied for the purpose of primary endpoint definitions. Damage, most often assessed by the Vasculitis Damage Index, was an outcome in 30 (44%) of the RCTs. Mortality was specified as an outcome in 26 (38%) studies. The following outcome domains were assessed: patient-reported outcomes (PROs) in 28 (41%), drug exposure/safety in 58 (85%), and biomarkers [acute phase reactants, ANCA levels] in 24 (35%). Timing for outcome assessment differed substantially, with 3, 6, or 12 months being the most frequent time points.
CONCLUSION
Outcome measures used in trials in AAV commonly included vasculitis-specific tools for disease assessment, but with heterogeneity in endpoint-definitions and timing of assessments. Other core outcomes in AAV, including PROs, and damage measures, are often omitted in AAV trials.
Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Humans; Microscopic Polyangiitis; Outcome Assessment, Health Care; Randomized Controlled Trials as Topic
PubMed: 33130459
DOI: 10.1016/j.semarthrit.2020.09.010 -
The Cochrane Database of Systematic... Sep 2020Anti-neutrophilic cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) are a group of rare auto-inflammatory diseases that affects mainly small vessels. AAV... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Anti-neutrophilic cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) are a group of rare auto-inflammatory diseases that affects mainly small vessels. AAV includes: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). Anti-cytokine targeted therapy uses biological agents capable of specifically targeting and neutralising cytokine mediators of the inflammatory response.
OBJECTIVES
To assess the benefits and harms of anti-cytokine targeted therapy for adults with AAV.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (2019, Issue 7), MEDLINE and Embase up to 16 August 2019. We also examined reference lists of articles, clinical trial registries, websites of regulatory agencies and contacted manufacturers.
SELECTION CRITERIA
Randomised controlled trials (RCTs) or controlled clinical trials of targeted anti-cytokine therapy in adults (18 years or older) with AAV compared with placebo, standard therapy or another modality and anti-cytokine therapy of different type or dose.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane.
MAIN RESULTS
We included four RCTs with a total of 440 participants (mean age 48 to 56 years). We analysed the studies in three groups: 1) mepolizumab (300 mg; three separate injections every four weeks for 52 weeks) versus placebo in participants with relapsing or refractory EGPA; 2) belimumab (10 mg/kg on days 0, 14, 28 and every 28 days thereafter until 12 months after the last participant was randomised) or etanercept (25 mg twice a week) with standard therapy (median 25 months) versus placebo with standard therapy (median 19 months) in participants with GPA/MPA; and 3) infliximab (3 mg/kg on days 1 and 14, before the response assessment on day 42) versus rituximab (0.375g/m on days 1, 8, 15 and 22) in participants with refractory GPA for up to 12 months. None of the studies were assessed as low risk of bias in all domains: one study did not report randomisation or blinding methods clearly. Three studies were at high risk and one study was at unclear risk of bias for selective outcome reporting. One trial with 136 participants with relapsing or refractory EGPA compared mepolizumab with placebo during 52 weeks of follow-up and observed one death in the mepolizumab group (1/68, 1.5%) and none in the placebo group (0/68, 0%) (Peto odds ratio (OR) 7.39, 95% confidence interval (CI) 0.15 to 372.38; low-certainty evidence). Low-certainty evidence suggests that more participants in the mepolizumab group had ≥ 24 weeks of accrued remission over 52 weeks compared to placebo (27.9% versus 2.9%; risk ratio (RR) 9.5, 95% CI 2.30 to 39.21), and durable remission within the first 24 weeks sustained until week 52 (19.1% mepolizumab versus 1.5% placebo; RR 13.0, 95% CI 1.75 to 96.63; number needed to treat for an additional beneficial outcome (NNTB) 6, 95% Cl 4 to 13). Mepolizumab probably decreases risk of relapse (55.8% versus 82.4%; RR 0.68, 95% CI 0.53 to 0.86; NNTB 4, 95% CI 3 to 9; moderate-certainty evidence). There was low-certainty evidence regarding similar frequency of adverse events (AEs): total AEs (96.9% versus 94.1%; RR 1.03, 95% CI 0.96 to 1.11), serious AEs (17.7% versus 26.5%; RR 0.67, 95% CI 0.35 to 1.28) and withdrawals due to AEs (2.9% versus 1.5%; RR 2.00, 95% CI 0.19 to 21.54). Disease flares were not measured. Based on two trials with different follow-up periods (mean of 27 months for etanercept study; up to four years for belimumab study) including people with GPA (n = 263) and a small group of participants with MPA (n = 22) analysed together, we found low-certainty evidence suggesting that adding an active drug (etanercept or belimumab) to standard therapy does not increase or reduce mortality (3.4% versus 1.4%; Peto OR 2.45, 95% CI 0.55 to 10.97). Etanercept may have little or no effect on remission (92.3% versus 89.5%; RR 0.97, 95% CI 0.89 to 1.07), durable remission (70% versus 75.3%; RR 0.93, 95% CI 0.77 to 1.11; low-certainty evidence) and disease flares (56% versus 57.1%; RR 0.98, 95% CI 0.76 to 1.27; moderate-certainty evidence). Low-certainty evidence suggests that belimumab does not increase or reduce major relapse (1.9% versus 0%; RR 2.94, 95% CI 0.12 to 70.67) or any AE (92.5% versus 82.7%; RR 1.12, 95% CI 0.97 to 1.29). Low-certainty evidence suggests a similar frequency of serious or severe AEs (47.6% versus 47.6%; RR 1.00, 95% CI 0.80 to 1.27), but more frequent withdrawals due to AEs in the active drug group (11.2%) compared to the placebo group (4.2%), RR 2.66, 95% CI 1.07 to 6.59). One trial involving 17 participants with refractory GPA compared infliximab versus rituximab added to steroids and cytotoxic agents for 12 months. One participant died in each group (Peto OR 0.88, 95% CI, 0.05 to 15.51; 11% versus 12.5%). We have very low-certainty evidence for remission (22% versus 50%, RR 0.44, 95% Cl 0.11 to 1.81) and durable remission (11% versus 50%, RR 0.22, 95% CI 0.03 to 1.60), any severe AE (22.3% versus 12.5%; RR 1.78, 95% CI 0.2 to 16.1) and withdrawals due to AEs (0% versus 0%; RR 2.70, 95% CI 0.13 to 58.24). Disease flare/relapse and the frequency of any AE were not reported.
AUTHORS' CONCLUSIONS
We found four studies but concerns about risk of bias and small sample sizes preclude firm conclusions. We found moderate-certainty evidence that in patients with relapsing or refractory EGPA, mepolizumab compared to placebo probably decreases disease relapse and low-certainty evidence that mepolizumab may increase the probability of accruing at least 24 weeks of disease remission. There were similar frequencies of total and serious AEs in both groups, but the study was too small to reliably assess these outcomes. Mepolizumab may result in little to no difference in mortality. However, there were very few events. In participants with GPA (and a small subgroup of participants with MPA), etanercept or belimumab may increase the probability of withdrawal due to AEs and may have little to no impact on serious AEs. Etanercept may have little or no impact on durable remission and probably does not reduce disease flare.
Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Monoclonal, Humanized; Churg-Strauss Syndrome; Etanercept; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Infliximab; Microscopic Polyangiitis; Middle Aged; Numbers Needed To Treat; Placebos; Randomized Controlled Trials as Topic; Rituximab; Secondary Prevention; Steroids
PubMed: 32990324
DOI: 10.1002/14651858.CD008333.pub2 -
Clinical Immunology (Orlando, Fla.) Nov 2020We conducted a systematic review to identify cases of infection-induced anti-myeloperoxidase (MPO) antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).
BACKGROUND
We conducted a systematic review to identify cases of infection-induced anti-myeloperoxidase (MPO) antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).
METHODS
PubMed/Medline databases were searched from inception to July of 2020, according to PRISMA guidelines.
RESULTS
Among the 618 abstracts identified, 18 articles describing 23 patients (60.9% female, mean age 50.5 years) were included. Median time between infection and vasculitis development was 3 months. Five (21.7%) patients expired during follow-up. Vasculitis regressed after the resolution of infection in 12/23 (52.2%). ANCA titers decreased significantly on follow-up in 14/16 patients and in all survivors in which they were measured. Pathogens reported included Mycobacterium spp., Coccidioides spp., Rickettsia rickettsii, Staphylococcus spp., EBV, CMV and Dengue virus.
CONCLUSIONS
MPO-AAV can occur after infection and may regress after its resolution. Infection should be considered in cases of MPO-AAV, as immunosuppressive treatment can have catastrophic results if the infection is not adequately treated.
Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Humans; Immunosuppressive Agents; Infections; Peroxidase
PubMed: 32961330
DOI: 10.1016/j.clim.2020.108595 -
The Journal of Rheumatology Apr 2021In 2015, the Canadian Vasculitis Research Network (CanVasc) created recommendations for the management of antineutrophil cytoplasm antibody (ANCA)-associated...
OBJECTIVE
In 2015, the Canadian Vasculitis Research Network (CanVasc) created recommendations for the management of antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) in Canada. The current update aims to revise existing recommendations and create additional recommendations, as needed, based on a review of new available evidence.
METHODS
A needs assessment survey of CanVasc members informed questions for an updated systematic literature review (publications spanning May 2014 to September 2019) using Medline, Embase, and Cochrane. New and revised recommendations were developed and categorized according to the level of evidence and strength of each recommendation. The CanVasc working group used a 2-step modified Delphi procedure to reach > 80% consensus on the inclusion, wording, and grading of each new and revised recommendation.
RESULTS
Eleven new and 16 revised recommendations were created and 12 original (2015) recommendations were retained. New and revised recommendations are discussed in detail within this document. Five original recommendations were removed, of which 4 were incorporated into the explanatory text. The supplementary material for practical use was revised to reflect the updated recommendations.
CONCLUSION
The 2020 updated recommendations provide rheumatologists, nephrologists, and other specialists caring for patients with AAV in Canada with new management guidance, based on current evidence and consensus from Canadian experts.
Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Canada; Consensus; Cytoplasm; Humans
PubMed: 32934123
DOI: 10.3899/jrheum.200721 -
Clinical and Experimental Immunology Dec 2020We compared the common pathway components C3a, C5a and membrane attack complex (MAC), also known as C5b-9, and the alternative pathway components factor B and properdin... (Meta-Analysis)
Meta-Analysis
We compared the common pathway components C3a, C5a and membrane attack complex (MAC), also known as C5b-9, and the alternative pathway components factor B and properdin in patients with ANCA-associated vasculitis (AAV) and healthy controls, and conducted a meta-analysis of the available clinical evidence for the role of complement activation in the pathogenesis of AAV. Complement components were evaluated in 59 patients with newly diagnosed or relapsing granulomatosis with polyangiitis or microscopic polyangiitis and 36 healthy volunteers. In 28 patients, testing was repeated in remission. Next, we performed a meta-analysis by searching databases to identify studies comparing complement levels in AAV patients and controls. A random-effects model was used for statistical analyses. The median concentrations of MAC, C5a, C3a and factor B were higher in active AAV patients (P < 0·001). Achievement of remission was associated with reductions in C3a (P = 0·005), C5a (P = 0·035) and factor B levels (P = 0·045), whereas MAC and properdin levels did not change. In active AAV, there were no effects of ANCA specificity, disease phenotype, previous immunosuppression or disease severity on complement levels. A total of 1122 articles were screened, and five studies, including this report, were entered into the meta-analysis. Plasma MAC, C5a and factor B in patients with active AAV were increased compared to patients in remission (excluding factor B) and controls. Changes in C3a were of borderline significance. Our findings and the results of the meta-analysis support activation of the complement system predominantly via the alternative pathway in AAV patients.
Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Complement Pathway, Alternative; Complement System Proteins; Humans
PubMed: 32691878
DOI: 10.1111/cei.13498 -
SAGE Open Medicine 2020The ear, nose and throat region has been reported to be one of the commonest sites involved in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis diseases... (Review)
Review
BACKGROUND
The ear, nose and throat region has been reported to be one of the commonest sites involved in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis diseases and often precedes the diagnosis of ANCA-associated vasculitis by many months. Although treatment for ANCA-associated vasculitis primarily requires systemic immunosuppressive therapy, there are specific indications for sinonasal surgery during the course of the disease process. The three major roles for surgery in sinonasal vasculitis are to aid diagnosis through biopsy, enable symptom relief and nasal reconstructive surgery consideration when in remission.
PURPOSE
The aim of this systematic review is to provide an overview of the surgical procedures which can be performed in patients with ANCA-associated vasculitis presenting with sinonasal involvement.
MATERIALS AND METHODS
A systematic literature search was performed for scientific articles on MEDLINE (PubMed Advanced MEDLINE Search) and EMBASE. The search included all articles up to April 2020.
CONCLUSION
Surgical intervention during the active phase of ANCA-associated vasculitis disease can improve the patient's symptoms and enable histological diagnosis. The surgical decision to manage the nose requires a multidisciplinary approach involving the vasculitis specialist and the ear, nose and throat surgeon. Nasal reconstruction can be performed to restore form and function but only when the disease is in remission so as to maximise success and minimise complications.
PubMed: 32676189
DOI: 10.1177/2050312120936731