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The New England Journal of Medicine Sep 2023Pegozafermin is a long-acting glycopegylated (pegylated with the use of site-specific glycosyltransferases) fibroblast growth factor 21 (FGF21) analogue in development... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Pegozafermin is a long-acting glycopegylated (pegylated with the use of site-specific glycosyltransferases) fibroblast growth factor 21 (FGF21) analogue in development for the treatment of nonalcoholic steatohepatitis (NASH) and severe hypertriglyceridemia. The efficacy and safety of pegozafermin in patients with biopsy-proven noncirrhotic NASH are not well established.
METHODS
In this phase 2b, multicenter, double-blind, 24-week, randomized, placebo-controlled trial, we randomly assigned patients with biopsy-confirmed NASH and stage F2 or F3 (moderate or severe) fibrosis to receive subcutaneous pegozafermin at a dose of 15 mg or 30 mg weekly or 44 mg once every 2 weeks or placebo weekly or every 2 weeks. The two primary end points were an improvement in fibrosis (defined as reduction by ≥1 stage, on a scale from 0 to 4, with higher stages indicating greater severity), with no worsening of NASH, at 24 weeks and NASH resolution without worsening of fibrosis at 24 weeks. Safety was also assessed.
RESULTS
Among the 222 patients who underwent randomization, 219 received pegozafermin or placebo. The percentage of patients who met the criteria for fibrosis improvement was 7% in the pooled placebo group, 22% in the 15-mg pegozafermin group (difference vs. placebo, 14 percentage points; 95% confidence interval [CI], -9 to 38), 26% in the 30-mg pegozafermin group (difference, 19 percentage points; 95% CI, 5 to 32; P = 0.009), and 27% in the 44-mg pegozafermin group (difference, 20 percentage points; 95% CI, 5 to 35; P = 0.008). The percentage of patients who met the criteria for NASH resolution was 2% in the placebo group, 37% in the 15-mg pegozafermin group (difference vs. placebo, 35 percentage points; 95% CI, 10 to 59), 23% in the 30-mg pegozafermin group (difference, 21 percentage points; 95% CI, 9 to 33), and 26% in the 44-mg pegozafermin group (difference, 24 percentage points; 95% CI, 10 to 37). The most common adverse events associated with pegozafermin therapy were nausea and diarrhea.
CONCLUSIONS
In this phase 2b trial, treatment with pegozafermin led to improvements in fibrosis. These results support the advancement of pegozafermin into phase 3 development. (Funded by 89bio; ENLIVEN ClinicalTrials.gov number, NCT04929483.).
Topics: Humans; Biopsy; Double-Blind Method; Fibroblast Growth Factors; Fibrosis; Gastrointestinal Agents; Injections, Subcutaneous; Non-alcoholic Fatty Liver Disease; Treatment Outcome
PubMed: 37356033
DOI: 10.1056/NEJMoa2304286 -
American Journal of Hematology Oct 2023Marginal zone lymphomas (MZL) are collectively the second most common type of indolent lymphoma.
DISEASE OVERVIEW
Marginal zone lymphomas (MZL) are collectively the second most common type of indolent lymphoma.
DIAGNOSIS
Three subtypes of MZL are recognized: splenic, extranodal, and nodal. The diagnosis is secured following biopsy of an involved nodal or extranodal site demonstrating a clonal B-cell infiltrate with CD5 and CD10 negative immunophenotype most common. Some cases will features IgM paraprotein, but MYD88 L256P mutations are less frequent than in Waldenstrom macroglobulinemia. Prognostication Several prognostic models have been developed, including the MALT-IPI and the MZL-IPI. The latter is broadly applicable across MZL subtypes and incorporates elevated serum LDH, anemia, lymphopenia, thrombocytopenia and nodal or disseminated subtypes as independent predictors of outcome.
TREATMENT
We discuss suggested approach to therapy for both early and advanced-stage disease, with reference to chemo-immunotherapy, radiotherapy, and emerging treatments in relapsed/refractory disease such as BTK inhibitors.
Topics: Humans; Lymphoma, B-Cell, Marginal Zone; B-Lymphocytes; Adaptor Proteins, Signal Transducing; Biopsy; Immunophenotyping
PubMed: 37605344
DOI: 10.1002/ajh.27058 -
JAMA Apr 2024Finding a reliable diagnostic biomarker for the disorders collectively known as synucleinopathies (Parkinson disease [PD], dementia with Lewy bodies [DLB], multiple...
IMPORTANCE
Finding a reliable diagnostic biomarker for the disorders collectively known as synucleinopathies (Parkinson disease [PD], dementia with Lewy bodies [DLB], multiple system atrophy [MSA], and pure autonomic failure [PAF]) is an urgent unmet need. Immunohistochemical detection of cutaneous phosphorylated α-synuclein may be a sensitive and specific clinical test for the diagnosis of synucleinopathies.
OBJECTIVE
To evaluate the positivity rate of cutaneous α-synuclein deposition in patients with PD, DLB, MSA, and PAF.
DESIGN, SETTING, AND PARTICIPANTS
This blinded, 30-site, cross-sectional study of academic and community-based neurology practices conducted from February 2021 through March 2023 included patients aged 40 to 99 years with a clinical diagnosis of PD, DLB, MSA, or PAF based on clinical consensus criteria and confirmed by an expert review panel and control participants aged 40 to 99 years with no history of examination findings or symptoms suggestive of a synucleinopathy or neurodegenerative disease. All participants completed detailed neurologic examinations and disease-specific questionnaires and underwent skin biopsy for detection of phosphorylated α-synuclein. An expert review panel blinded to pathologic data determined the final participant diagnosis.
EXPOSURE
Skin biopsy for detection of phosphorylated α-synuclein.
MAIN OUTCOMES
Rates of detection of cutaneous α-synuclein in patients with PD, MSA, DLB, and PAF and controls without synucleinopathy.
RESULTS
Of 428 enrolled participants, 343 were included in the primary analysis (mean [SD] age, 69.5 [9.1] years; 175 [51.0%] male); 223 met the consensus criteria for a synucleinopathy and 120 met criteria as controls after expert panel review. The proportions of individuals with cutaneous phosphorylated α-synuclein detected by skin biopsy were 92.7% (89 of 96) with PD, 98.2% (54 of 55) with MSA, 96.0% (48 of 50) with DLB, and 100% (22 of 22) with PAF; 3.3% (4 of 120) of controls had cutaneous phosphorylated α-synuclein detected.
CONCLUSIONS AND RELEVANCE
In this cross-sectional study, a high proportion of individuals meeting clinical consensus criteria for PD, DLB, MSA, and PAF had phosphorylated α-synuclein detected by skin biopsy. Further research is needed in unselected clinical populations to externally validate the findings and fully characterize the potential role of skin biopsy detection of phosphorylated α-synuclein in clinical care.
Topics: Aged; Female; Humans; Male; alpha-Synuclein; Biopsy; Cross-Sectional Studies; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Synucleinopathies; Phosphorylation; Skin; Pure Autonomic Failure; Reproducibility of Results; Adult; Middle Aged; Aged, 80 and over; Single-Blind Method; Prospective Studies
PubMed: 38506839
DOI: 10.1001/jama.2024.0792 -
Hepatology (Baltimore, Md.) Nov 2023HBV infection is restricted to the liver, where it drives exhaustion of virus-specific T and B cells and pathogenesis through dysregulation of intrahepatic immunity. Our...
BACKGROUND AND AIMS
HBV infection is restricted to the liver, where it drives exhaustion of virus-specific T and B cells and pathogenesis through dysregulation of intrahepatic immunity. Our understanding of liver-specific events related to viral control and liver damage has relied almost solely on animal models, and we lack useable peripheral biomarkers to quantify intrahepatic immune activation beyond cytokine measurement. Our objective was to overcome the practical obstacles of liver sampling using fine-needle aspiration and develop an optimized workflow to comprehensively compare the blood and liver compartments within patients with chronic hepatitis B using single-cell RNA sequencing.
APPROACH AND RESULTS
We developed a workflow that enabled multi-site international studies and centralized single-cell RNA sequencing. Blood and liver fine-needle aspirations were collected, and cellular and molecular captures were compared between the Seq-Well S 3 picowell-based and the 10× Chromium reverse-emulsion droplet-based single-cell RNA sequencing technologies. Both technologies captured the cellular diversity of the liver, but Seq-Well S 3 effectively captured neutrophils, which were absent in the 10× dataset. CD8 T cells and neutrophils displayed distinct transcriptional profiles between blood and liver. In addition, liver fine-needle aspirations captured a heterogeneous liver macrophage population. Comparison between untreated patients with chronic hepatitis B and patients treated with nucleoside analogs showed that myeloid cells were highly sensitive to environmental changes while lymphocytes displayed minimal differences.
CONCLUSIONS
The ability to electively sample and intensively profile the immune landscape of the liver, and generate high-resolution data, will enable multi-site clinical studies to identify biomarkers for intrahepatic immune activity in HBV and beyond.
Topics: Animals; Humans; Hepatitis B, Chronic; Biopsy, Fine-Needle; Hepatitis B virus; Liver; CD8-Positive T-Lymphocytes; Biomarkers; Sequence Analysis, RNA
PubMed: 37158243
DOI: 10.1097/HEP.0000000000000438 -
The Lancet. Gastroenterology &... Dec 2023Fibroblast growth factor 21 (FGF21) regulates metabolism and protects cells against stress. Efruxifermin is a bivalent Fc-FGF21 analogue that replicates FGF21 agonism of... (Randomized Controlled Trial)
Randomized Controlled Trial
Safety and efficacy of once-weekly efruxifermin versus placebo in non-alcoholic steatohepatitis (HARMONY): a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial.
BACKGROUND
Fibroblast growth factor 21 (FGF21) regulates metabolism and protects cells against stress. Efruxifermin is a bivalent Fc-FGF21 analogue that replicates FGF21 agonism of fibroblast growth factor receptor 1c, 2c, or 3c. The aim of this phase 2b study was to assess its efficacy and safety in patients with non-alcoholic steatohepatitis (NASH) and moderate (F2) or severe (F3) fibrosis.
METHODS
HARMONY is a multicentre, randomised, double-blind, placebo-controlled, 96-week, phase 2b trial that was initiated at 41 clinics in the USA. Adults with biopsy-confirmed NASH, defined by a non-alcoholic fatty liver disease activity score (NAS) of 4 or higher and scores of 1 or higher in each of steatosis, ballooning, and lobular inflammation, with histological stage F2 or F3 fibrosis, were randomly assigned (1:1:1), via an interactive response system, to receive placebo or efruxifermin (28 mg or 50 mg), subcutaneously once weekly. Patients, investigators, pathologists, site staff, and the sponsor were masked to group assignments during the study. The primary endpoint was the proportion of patients with improvement in fibrosis of at least 1 stage and no worsening of NASH, based on analyses of baseline and week 24 biopsies (liver biopsy analysis set [LBAS]). A sensitivity analysis evaluated the endpoint in the full analysis set (FAS), for which patients with missing biopsies were considered non-responders. This trial is registered with ClinicalTrials.gov, NCT04767529, and is ongoing.
FINDINGS
Between March 22, 2021, and Feb 7, 2022, 747 patients were assessed for eligibility and 128 patients (mean age 54·7 years [SD 10·4]; 79 [62%] female and 49 male [38%]; 118 [92%] white; and 56 [41%] Hispanic or Latino) were enrolled and randomly assigned to receive placebo (n=43), efruxifermin 28 mg (n=42; two randomised patients were not dosed because of an administrative error), or efruxifermin 50 mg (n=43). In the LBAS (n=113), eight (20%) of 41 patients in the placebo group had an improvement in fibrosis of at least 1 stage and no worsening of NASH by week 24 versus 15 (39%) of 38 patients in the efruxifermin 28 mg group (risk ratio [RR] 2·3 [95% CI 1·1-4·8]; p=0·025) and 14 (41%) of 34 patients in the efruxifermin 50 mg group (2·2 [1·0-5·0]; p=0·036). Based on the FAS (n=128), eight (19%) of 43 patients in the placebo group met this endpoint versus 15 (36%) of 42 in the efruxifermin 28 mg group (RR 2·2 [95% CI 1·0-4·8]; p=0·033) and 14 (33%) of 43 in the efruxifermin 50 mg group (1·9 [0·8-4·3]; p=0·123). The most frequent efruxifermin-related adverse events were diarrhoea (16 [40%] of 40 patients in the efruxifermin 28 mg group and 17 [40%] of 43 patients in efruxifermin 50 mg group vs eight [19%] of 43 patients in the placebo group; all events except one were grade 1-2) and nausea (11 [28%] patients in the efruxifermin 28 mg group and 18 [42%] patients in the efruxifermin 50 mg group vs ten [23%] patients in the placebo group; all grade 1-2). Five patients (two in the 28 mg group and three in the 50 mg group) discontinued due to adverse events. Serious adverse events occurred in four patients in the 50 mg group; one was defined as drug related (ulcerative esophagitis in a participant with a history of gastro-oesophageal reflux disease). No deaths occurred.
INTERPRETATION
Efruxifermin improved liver fibrosis and resolved NASH over 24 weeks in patients with F2 or F3 fibrosis, with acceptable tolerability, supporting further assessment in phase 3 trials.
FUNDING
Akero Therapeutics.
Topics: Adult; Female; Humans; Male; Middle Aged; Double-Blind Method; Inflammation; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease; Treatment Outcome
PubMed: 37802088
DOI: 10.1016/S2468-1253(23)00272-8 -
Nature Medicine Oct 2023There are no approved diagnostic biomarkers for at-risk non-alcoholic steatohepatitis (NASH), defined by the presence of NASH, high histological activity and fibrosis...
There are no approved diagnostic biomarkers for at-risk non-alcoholic steatohepatitis (NASH), defined by the presence of NASH, high histological activity and fibrosis stage ≥2, which is associated with higher incidence of liver-related events and mortality. FNIH-NIMBLE is a multi-stakeholder project to support regulatory approval of NASH-related biomarkers. The diagnostic performance of five blood-based panels was evaluated in an observational (NASH CRN DB2) cohort (n = 1,073) with full spectrum of non-alcoholic fatty liver disease (NAFLD). The panels were intended to diagnose at-risk NASH (NIS4), presence of NASH (OWLiver) or fibrosis stages >2, >3 or 4 (enhanced liver fibrosis (ELF) test, PROC3 and FibroMeter VCTE). The prespecified performance metric was an area under the receiver operating characteristic curve (AUROC) ≥0.7 and superiority over alanine aminotransferase for disease activity and the FIB-4 test for fibrosis severity. Multiple biomarkers met these metrics. NIS4 had an AUROC of 0.81 (95% confidence interval: 0.78-0.84) for at-risk NASH. The AUROCs of the ELF test, PROC3 and FibroMeterVCTE for clinically significant fibrosis (≥stage 2), advanced fibrosis (≥stage 3) or cirrhosis (stage 4), respectively, were all ≥0.8. ELF and FibroMeter VCTE outperformed FIB-4 for all fibrosis endpoints. These data represent a milestone toward qualification of several biomarker panels for at-risk NASH and also fibrosis severity in individuals with NAFLD.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Liver; Liver Cirrhosis; Fibrosis; Biomarkers; Biopsy
PubMed: 37679433
DOI: 10.1038/s41591-023-02539-6 -
American Journal of Clinical Dermatology Jan 2024The diagnosis of cutaneous lymphomas is challenging and requires skin tissue for histology and immunophenotyping using immunohistochemistry and molecular studies. In... (Review)
Review
The diagnosis of cutaneous lymphomas is challenging and requires skin tissue for histology and immunophenotyping using immunohistochemistry and molecular studies. In recent years, the role of non-invasive imaging techniques has been described as part of the clinical assessment of cutaneous lymphoma lesions. Imaging modalities such as dermoscopy, reflectance confocal microscopy (RCM), and high frequency ultrasound (HFUS) have been shown to be very valuable in raising the clinical suspicion for lymphomas of the skin, and in distinguishing cutaneous lymphomas from inflammatory dermatoses such as lupus, psoriasis, or eczema. These non-invasive methods can be used to direct the clinician to the optimal biopsy site to maximize the histopathological results and minimize false negatives. These methods also have a potential place in monitoring treatment response. In this review we present a concise summary of the dermoscopic imaging, RCM, and HFUS features seen in cutaneous T-cell lymphomas (CTCL) and B-cell lymphomas (CBCL).
Topics: Humans; Dermoscopy; Skin Neoplasms; Skin; Lymphoma, T-Cell, Cutaneous; Ultrasonography
PubMed: 37964050
DOI: 10.1007/s40257-023-00824-1 -
International Journal of Oral and... Nov 2023The aim of this study was to critically evaluate the diagnostic yields of direct immunofluorescence (DIF) analysis on perilesional and normal-appearing mucosa biopsy... (Review)
Review
The aim of this study was to critically evaluate the diagnostic yields of direct immunofluorescence (DIF) analysis on perilesional and normal-appearing mucosa biopsy samples, to determine the optimal biopsy site for patients presenting with oral pemphigus vulgaris (PV) or mucous membrane pemphigoid (MMP). Electronic databases and article bibliographies were searched in December 2022. The primary outcome was the rate of DIF positivity. Of 374 records identified after the elimination of duplicates, 21 studies with 1027 samples were ultimately included. Meta-analysis revealed a pooled DIF positivity rate of 99.6% (95% confidence interval (CI) 97.4-100.0%, I = 0%) for PV and 92.6% (95% CI 87.9-96.5%, I = 44%) for MMP for biopsies from perilesional sites, and of 95.4% (95% CI 88.6-99.5%, I = 0%) for PV and 94.1% (95% CI 86.5-99.2%, I = 42%) for MMP for biopsies from normal-appearing sites. For MMP, there was no significant difference in the rate of DIF positivity between the two biopsy sites (odds ratio 1.91, 95% CI 0.91-4.01, I = 0%). The results suggest that the perilesional mucosa remains the optimal biopsy site for DIF diagnosis of oral PV, while the normal-appearing mucosa biopsy is optimal for oral MMP.
PubMed: 37268547
DOI: 10.1016/j.ijom.2023.05.005