Publications by authors named "J E Krueger"

1,190 Publications

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Comparison of the Inflammatory Circuits in Psoriasis Vulgaris, Non-Pustular Palmoplantar Psoriasis, and Palmoplantar Pustular Psoriasis.

J Invest Dermatol 2022 Aug 4. Epub 2022 Aug 4.

Laboratory for Investigative Dermatology, Rockefeller University, New York, NY, USA. Electronic address:

Palmoplantar pustular psoriasis (PPPP) and non-pustular palmoplantar psoriasis (NPPP) are localized, debilitating forms of psoriasis. The inflammatory circuits involved in PPPP and NPPP are not well understood. To compare the cellular and immunological features that differentiate PPPP and NPPP, skin biopsies were collected from a total of 30 participants with PPPP, NPPP, and psoriasis vulgaris (PV) and from 10 healthy participants. A subset consented to a second biopsy after 3 weeks off medication. Histologic staining of lesional and non-lesional skin showed higher neutrophil counts in PPPP compared with NPPP and PV, and higher CD8 T-cell counts in NPPP. RNA sequencing and transcriptional analysis of skin biopsies showed enhanced IFN-γ pathway activation in NPPP lesions, but stronger signatures of IL-17 pathway and neutrophil-related genes (e.g. IL36A) in PPPP lesional skin. Serum analysis on the Olink platform detected higher concentrations of T helper (Th) type 1, IFN-γ inducible chemokines in NPPP and higher neutrophil-associated cytokines in PPPP. Taken together, this evidence suggests more pronounced Th1-mediated inflammation in NPPP compared to PV and PPPP, and stronger neutrophil-associated activity in PPPP compared to NPPP and PV. These data support targeting inflammatory pathways associated with neutrophilic inflammation (e.g. IL-36 signaling) for therapeutic development in PPPP.
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http://dx.doi.org/10.1016/j.jid.2022.05.1094DOI Listing
August 2022

A Biodegradable Polymeric Matrix for the Repair of Annulus Fibrosus Defects in Intervertebral Discs.

Tissue Eng Regen Med 2022 Jul 11. Epub 2022 Jul 11.

TransTissue Technologies GmbH, Charitéplatz 1/Virchowweg 11, 10117, Berlin, Germany.

Background: Tissue defects in the annulus fibrosus (AF) due to intervertebral disc (IVD) degeneration or after nucleodiscectomy have little self-healing capacity. To prevent progressive degeneration of the IVD, the AF must be repaired. Biological closure has not yet been achieved and is a challenge for the research community. In this study, a scaffold made of absorbable poly (glycolic acid) (PGA) and hyaluronan (HA) that exhibit excellent biocompatibility and cell colonization properties was used to repair AF defects in an ovine model.

Methods: A partial resection was performed in AF in L3/4 or L4/5 of 10 sheep and PGA-HA scaffolds were implanted on the defects (n = 5), while defects in the control group were left untreated (n = 5). Three months post-operation, the lumbar discs were sectioned and stained with hematoxylin and eosin and safranin-O/fast-green. Histological features including proteoglycan content, annular structure, cellular morphology, blood vessel ingrowth and tear/cleft formation were scored using a modified scoring scheme by 3 investigators and evaluated by a pathologist independently.

Results: The treated AF exhibited significantly enhanced repair tissue structure with signs of proteoglycan formation compared to the untreated group. The median scores were 4.3 for the treated and 9.8 for the untreated group. Cystic degeneration, perivascular infiltration, inflammation and necrosis were only present in the untreated group. Blood vessel ingrowth and tear/cleft formation were increased, though not significant, in the untreated group while cell morphology was comparable in both groups.

Conclusion: PGA-HA scaffolds used for AF closure support repair tissue formation in an ovine lumbar disc defect model.
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http://dx.doi.org/10.1007/s13770-022-00466-0DOI Listing
July 2022

Onasemnogene abeparvovec for presymptomatic infants with three copies of SMN2 at risk for spinal muscular atrophy: the Phase III SPR1NT trial.

Nat Med 2022 07 17;28(7):1390-1397. Epub 2022 Jun 17.

Novartis Gene Therapies, Inc., Bannockburn, IL, USA.

Most children with biallelic SMN1 deletions and three SMN2 copies develop spinal muscular atrophy (SMA) type 2. SPR1NT ( NCT03505099 ), a Phase III, multicenter, single-arm trial, investigated the efficacy and safety of onasemnogene abeparvovec for presymptomatic children with biallelic SMN1 mutations treated within six postnatal weeks. Of 15 children with three SMN2 copies treated before symptom onset, all stood independently before 24 months (P < 0.0001; 14 within normal developmental window), and 14 walked independently (P < 0.0001; 11 within normal developmental window). All survived without permanent ventilation at 14 months; ten (67%) maintained body weight (≥3rd WHO percentile) without feeding support through 24 months; and none required nutritional or respiratory support. No serious adverse events were considered treatment-related by the investigator. Onasemnogene abeparvovec was effective and well-tolerated for presymptomatic infants at risk of SMA type 2, underscoring the urgency of early identification and intervention.
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http://dx.doi.org/10.1038/s41591-022-01867-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9205287PMC
July 2022

Onasemnogene abeparvovec for presymptomatic infants with two copies of SMN2 at risk for spinal muscular atrophy type 1: the Phase III SPR1NT trial.

Nat Med 2022 07 17;28(7):1381-1389. Epub 2022 Jun 17.

Novartis Gene Therapies, Inc., Bannockburn, IL, USA.

SPR1NT ( NCT03505099 ) was a Phase III, multicenter, single-arm study to investigate the efficacy and safety of onasemnogene abeparvovec for presymptomatic children with biallelic SMN1 mutations treated at ≤6 weeks of life. Here, we report final results for 14 children with two copies of SMN2, expected to develop spinal muscular atrophy (SMA) type 1. Efficacy was compared with a matched Pediatric Neuromuscular Clinical Research natural-history cohort (n = 23). All 14 enrolled infants sat independently for ≥30 seconds at any visit ≤18 months (Bayley-III item #26; P < 0.001; 11 within the normal developmental window). All survived without permanent ventilation at 14 months as per protocol; 13 maintained body weight (≥3rd WHO percentile) through 18 months. No child used nutritional or respiratory support. No serious adverse events were considered related to treatment by the investigator. Onasemnogene abeparvovec was effective and well-tolerated for children expected to develop SMA type 1, highlighting the urgency for universal newborn screening.
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http://dx.doi.org/10.1038/s41591-022-01866-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9205281PMC
July 2022

Analysis of alopecia areata surveys suggests a threshold for improved patient-reported outcomes.

Br J Dermatol 2022 Jun 3. Epub 2022 Jun 3.

Department of Dermatology, and Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Background: Although alopecia areata (AA) greatly impacts patients' quality of life (QoL), there is no adequate validation of AA-targeted QoL surveys in clinical trials, hindering sufficient representation of patient-reported outcomes.

Objectives: Better understanding of patient-reported outcomes may guide treatment goals and future clinical trials.

Methods: In a recent randomized controlled trial testing dupilumab in AA, patients were administered the Alopecia Areata Quality of Life Index (AA-QLI) and the Alopecia Areata Symptom Impact Scale (AASIS) surveys, specifically evaluating QoL in patients with AA. An in-depth analysis was performed to assess the utility of these questionnaires in this patient population, both at baseline and after treatment, and to determine a threshold for improved patient-reported outcomes.

Results: While AASIS correlated with baseline Severity of Alopecia Tool (SALT) scores and with therapeutic response, AA-QLI showed no correlation with AA severity before or after treatment. Itch strongly correlated with serum IgE levels across both surveys. Using various approaches to estimate a discriminative threshold for decreased impact of AA on QoL (by AASIS) following treatment, a SALT score of 20 points or less post-treatment was associated with improved patient-reported outcomes, including both AA-related symptoms and items within the daily activities/feelings domain such as 'feeling sad' and 'feeling anxious or worry'.

Conclusions: AASIS is better than AA-QLI to assess patient-reported outcomes. SALT ≤ 20 following treatment should be considered as a threshold for meaningful therapeutic outcome and as a clinical endpoint in future clinical trials for AA. What is already known about this topic? Alopecia areata greatly compromises quality of life, and affected patients have increased prevalences of depression, anxiety and social phobia. Despite the significant negative impact of the disease on patients' wellbeing, validation of targeted questionnaires in alopecia areata is lacking, and a therapeutic response threshold for improved patient-reported outcomes is unknown. What does this study add? This study investigated the utility of two different alopecia areata-targeted questionnaires - Alopecia Areata Quality of Life Index and Alopecia Areata Symptom Impact Scale (AASIS) - in a clinical trial setting. AASIS was found to correlate strongly with alopecia areata severity and clinical response. What are the clinical implications of this work? Patients with ≤ 20% scalp hair loss after treatment reported improvement in multiple quality-of-life items, suggesting this as a meaningful therapeutic outcome that may guide clinicians and improve the development of future clinical trials.
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http://dx.doi.org/10.1111/bjd.21696DOI Listing
June 2022
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