Allergy Clin Immunol Research Articles

Bowman's layer transplantation—A new hope for regaining of correct ocular surface

Aims/Purpose: To present a novel surgical technique of selective Bowman's layer transplantation as well as results of the surgery in patients with neurotrophic corneal ulcers.Methods: 3 eyes from 3 patients with neurotrophic corneal ulcers who underwent corneal grafting with Bowman's layer. Pre‐ and postoperative analyses of the anterior segment of the eye were based on optical coherence tomography and slit lamp assessment.Results: Postoperatively a gradual corneal stroma restoration and fast corneal epithelialisation were noticed.Conclusions: Based on our observations, stiff and firm structure of Bowman's layer is supposed to strengthen corneal surface and maintain its shape. It acts also as an anti‐pathogen and anti‐toxin corneal barrier. Application of this acellular corneal layer transplantation to cover trophic corneal ulcers is an interesting, modern and crucial method of neurotrophic keratitis treatment.Reference1. Hsu HY, Modi D. Etiologies, quantitative hypoesthesia, and clinical outcomes of neurotrophic keratopathy. Eye Contact Lens 2015;41(5):314–7.2. Sacchetti M, Lambiase A. Diagnosis and management of neurotrophic keratitis. Clin Ophthalmol 2014;8:571–9.3. Mantelli F, Mauris J, Argüeso P. The ocular surface epithelial barrier and other mechanisms of mucosal protection: from allergy to infectious diseases. Curr Opin Allergy Clin Immunol. 2013 Oct;13(5): 563–8.4. Wilson SE. Bowman's layer in the cornea‐ structure and function and regeneration. Exp Eye Res 2020 Jun;195:108033.5. Lagali N, Germundsson J, Fagerholm P. The Role of Bowman's Layer in Corneal Regeneration after Phototherapeutic Keratectomy: A Prospective Study Using In Vivo Confocal Microscopy. Invest Ophthalmol Vis Sc. 2009 Sep;50(9):4192–8.

The Phase 3 Natron Study Evaluating Benralizumab in Patients with Hypereosinophilic Syndrome: Study Design and Patient Characteristics

Background and Significance: Hypereosinophilic syndrome (HES) is a rare, heterogeneous disorder defined by blood eosinophilia (absolute eosinophil count [AEC] >1500 cells/μL) on 2 examinations ≥1 month apart and eosinophil-mediated end-organ involvement, including dermatologic, pulmonary, gastrointestinal, and/or cardiovascular manifestations. Symptoms and health-related quality of life vary depending on the organ systems involved. HES is often treated with corticosteroids and other immunosuppressants. However, long-term use of these agents is associated with decreased efficacy and significant toxicity. Whereas anti-IL-5 antibody mepolizumab was recently approved for the treatment of HES (Roufosse, et al. J Allergy Clin Immunol. 2020;146(6):1397-1405), response is not universal and additional targeted agents are clearly warranted. Benralizumab is a humanized, afucosylated, anti-interleukin-5 receptor α monoclonal antibody that induces rapid, near-complete depletion of eosinophils through antibody-dependent, cell-mediated cytotoxicity. It is currently approved for use in patients with severe eosinophilic asthma and has demonstrated AEC-reducing effects in patients with HES (Kuang, et al. N Engl J Med. 2019;380(14):1336-46). Study Design and Methods:This phase 3, multicenter, randomized, double-blind (DB), placebo-controlled study (NATRON; NCT04191304) evaluating the efficacy of benralizumab versus placebo will enroll ~120 patients with documented HES (Figure 1A). Recruitment will stop after approximately 38 patients have had their first HES worsening/flare during the DB period, at which point the data cutoff for the primary analysis will occur. Eligible patients are ≥12 years of age with an AEC ≥1000 cells/mL at screening, have active signs/symptoms of an HES worsening/flare or a history of ≥2 HES worsening/flares within 12 months before enrollment, and have a stable treatment regimen (≥4 weeks). Patients must be FIP1L1-PDGFRA-negative and corticosteroid-responsive, defined as an AEC of <1000 cells/μL after 2 days of corticosteroid treatment. The primary endpoint is time to first HES worsening/flare during the DB period. Key secondary endpoints during the DB period include the proportion of patients who experience HES worsening/flare events, the number of HES worsening/flare events (annualized rate/year), time to first hematologic relapse, and change from baseline in fatigue at week 24 as assessed by the Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form 7a. Patients who complete the 24-week DB treatment period will continue with active treatment in a ≥52-week open-label extension. We present the study design and interim baseline characteristics of patients recruited to date. Results:As of the June 6, 2023, cutoff date, 87 patients were enrolled in the full analysis set (Figure 1B). Among these patients, the mean (SD) age was 48.4 (17.79) years, 64.4% were female, and 84.3% were White. The mean (SD) time since the first appearance of HES symptoms and since HES diagnosis was 8.14 (8.12) and 4.87 (6.54) years, respectively. The proportion of patients with the lymphocytic variant HES was 14.9%. The most common primary organs involved were the lungs (35.6%), followed by the skin (25.3%) and the gastrointestinal tract (21.8%). Thirty-four (39.1%) and 32 (36.8%) patients experienced 2 and ≥3 HES worsening/flare events in the previous 12 months, respectively. The mean (SD) PROMIS Fatigue T-score was 55.0 (9.42). Mean (SD) baseline eosinophil levels were 1960 (2610) cells/µL, with median (interquartile range) levels of 1120 (60, 20910) cells/µL. Conclusions: Results from the NATRON study will provide insight into whether benralizumab is beneficial in addition to background therapy in patients with FIP1L1-PDGFRA-negative steroid-responsive HES. Funding: This study is funded by AstraZeneca (Gothenburg, Sweden). This work is funded in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. Acknowledgments:Vivian H. Shih, Dianne Griffis, Himanshu Parikh, Ron A. Chen, Ying Fan, Gaëll Mayer, Rohit Katial, and Ioannis Psallidas.

A Phase 1 Study of Avapritinib in Combination with Decitabine in Patients with Systemic Mastocytosis with an Associated Hematologic Neoplasm

Background and Rationale: Systemic mastocytosis (SM) is a clonal hematologic neoplasm characterized by abnormal accumulation of mast cells which can lead to symptoms related to mast cell degranulation and/or, in the case of advanced systemic mastocytosis (AdvSM), organ dysfunction due to mast cell infiltration. AdvSM is a category of SM comprised of aggressive systemic mastocytosis (ASM), mast cell leukemia (MCL), and SM with an associated hematologic neoplasm (SM-AHN). Among these, SM-AHN is the most common subtype, accounting for approximately 70% of AdvSM. A KIT D816V mutation found in up to 95% of SM cases is the primary oncogenic driver, making it a key therapeutic target. Avapritinib, a highly potent and selective inhibitor of D816V mutant KIT, has demonstrated high rates of rapid, deep, and durable responses in all AdvSM subtypes, including SM-AHN. However, a recent analysis of the EXPLORER study showed that avapritinib-treated patients were still at risk for progression of the AHN component, despite continued control of mast cell disease burden, indicating that combination therapy is likely to be required for optimal control of SM-AHN due to its inherent molecular complexity. Hypomethylating agents (HMA) form the backbone of therapy for advanced myelodysplastic syndrome (MDS) and myelodysplastic/myeloproliferative neoplasm (MDS/MPN), hematologic neoplasms most likely to co-occur with SM in patients (pts) with SM-AHN. To date, the combination of HMA and KIT inhibitors has not been clinically evaluated. In this study, we aim to assess the safety and tolerability of the combination of avapritinib and decitabine in patients with SM-AHN. Study design: The primary objective of the study is to establish the recommended dose (RP2D) of avapritinib in combination with decitabine based on dose-limiting toxicity, overall safety, and clinical activity data. A dose evaluation steering committee (DESC) comprised of participating investigators will review the totality of safety and efficacy data to determine RP2D. Secondary endpoints include SM overall response rate by the end of 6 cycles by the m-IWG consensus criteria and proposed ECNM-AIM criteria ( Gotlib et al., J Allergy Clin Immunol Pract, 2022), as well as incidence and frequency of adverse events. Exploratory endpoints will consist of patient reported outcomes, progression free survival, overall survival, and correlative biomarkers linked to mast cell disease or AHN. Adult pts with a diagnosis of SM-AHN by the WHO 2022 classification criteria will be eligible for inclusion. Eligible pts must have any of the following myeloid AHN per WHO 2022 criteria: MDS, chronic myelomonocytic leukemia, MDS/MPN with neutrophilia, MDS/MPN with SF3B1 mutation and thrombocytosis, or MDS/MPN- not otherwise specified. Patients with MDS must have intermediate, high- or very-high risk by IPSS-R. Patients with very-low or low-risk MDS by IPSS-R must be intolerant/refractory to ESA or have serum EPO > 200 U/L. A baseline platelet count of ≥ 75 x 10 9/L and ≥ 25 x 10 9/L will be required for inclusion in the dose-finding and the dose-expansion phases, respectively (Figure). Key exclusion criteria include a diagnosis of acute myeloid leukemia, history of intracranial hemorrhage or risk of major hemorrhage, prior treatment with avapritinib or decitabine with documented progression in SM or AHN component, respectively, or history of treatment with alternative KIT inhibitor or azacitidine within 4 weeks of study treatment initiation. In the dose finding part of the study, a Bayesian adaptive design will be employed to assess different doses of avapritinib (50 to 200 mg PO daily) in combination with fixed doses of decitabine (oral decitabine/cedazuridine: 35/100 mg/day or intravenous decitabine: 20 mg/m 2/day on days 1-5) in a 28-day treatment cycle. Close attention will be paid to treatment-emergent thrombocytopenia with protocol-driven treatment holds and dose modification strategies employed when platelet count drops below 50 x 10 9/L. After RP2D is determined, an additional 10 patients will be enrolled in the dose expansion phase. Patients with platelet count ≥ 25 x 10 9/L and < 75 x 10 9/L, will receive lead-in dosing with decitabine or decitabine/cedazuridine with the ability to add avapritinib if sufficient platelet thresholds are achieved. This study will open at 7 sites in the United States and is anticipated to open in January 2024.

Validation of sTREM-1 and IL-6 based algorithms for outcome prediction of COVID-19

BackgroundA prospective observational cohort study of COVID-19 patients in a single Emergency Department (ED) showed that sTREM-1- and IL-6-based algorithms were highly predictive of adverse outcome (Van Singer et al. J Allergy Clin Immunol 2021). We aim to validate the performance of these algorithms at ED presentation.MethodsThis multicentric prospective observational study of PCR-confirmed COVID-19 adult patients was conducted in the ED of three Swiss hospitals. Data of the three centers were retrospectively completed and merged. We determined the predictive accuracy of the sTREM-1-based algorithm for 30-day intubation/mortality. We also determined the performance of the IL-6-based algorithm using data from one center for 30-day oxygen requirement.Results373 patients were included in the validation cohort, 139 (37%) in Lausanne, 93 (25%) in St.Gallen and 141 (38%) in EOC. Overall, 18% (93/373) patients died or were intubated by day 30. In Lausanne, 66% (92/139) patients required oxygen by day 30. The predictive accuracy of sTREM-1 and IL-6 were similar compared to the derivation cohort. The sTREM-1-based algorithm confirmed excellent sensitivity (90% versus 100% in the derivation cohort) and negative predictive value (94% versus 100%) for 30-day intubation/mortality. The IL-6-based algorithm performance was acceptable with a sensitivity of 85% versus 98% in the derivation cohort and a negative predictive value of 60% versus 92%.ConclusionThe sTREM-1 algorithm demonstrated good reproducibility. A prospective randomized controlled trial, comparing outcomes with and without the algorithm, is necessary to assess its safety and impact on hospital and ICU admission rates. The IL-6 algorithm showed acceptable validity in a single center and need additional validation before widespread implementation.

Chronic or recurrent Campylobacter enteritis in primary immunodeficiency: a UK national case-series and review of the literature.

Clinical ImplicationsCampylobacter infection is an important diagnosis to consider in primary immunodeficiency patients with chronic or recurrent diarrhea, particularly in those with very low diagnostic immunoglobulin levels. Macrolides, aminoglycosides, and/or carbapenems are promising treatment options for this potentially debilitating condition. Campylobacter infection is an important diagnosis to consider in primary immunodeficiency patients with chronic or recurrent diarrhea, particularly in those with very low diagnostic immunoglobulin levels. Macrolides, aminoglycosides, and/or carbapenems are promising treatment options for this potentially debilitating condition. Campylobacter infection, usually by Campylobacter jejuni, is the most common cause of bacterial enteritis in the world. In healthy individuals, the infection is self-limiting, but in patients with immunodeficiency, recurrent or persistent symptomatic infection may occur. In this case series, we present a cohort of primary immunodeficiency patients with chronic or recurrent Campylobacter enteritis from the United Kingdom and review the previously published literature. To identify relevant cases, a request was circulated via the UK Clinical Immunology mailing list, which includes 41 centers. Primary immunodeficiency (PID) cases with confirmed Campylobacter in stool or colonic tissue, by culture or PCR, and symptoms of longer than 3-month duration or 3 or more symptomatic flares, were included. Successful clearance of the infection was defined as resolution of symptoms and no recurrence for at least 3 months. In parallel, a literature review was performed to identify previously published cases in PubMed, using the terms “chronic,” “recurrent,” “Campylobacter,” “enteritis,” “diarrhoea,” “immune deficiency,” “immunodeficiency,” and “hypogammaglobulinemia.” Six centers replied, reporting 13 cases of chronic or recurrent Campylobacter enteritis in total: 4 from Queen Elizabeth Hospital (Glasgow), 3 from Southmead Hospital (Bristol), 2 from Royal London Hospital (London), 1 from Frimley Park Hospital (Surrey), 1 from Derriford Hospital (Plymouth), 1 from Northern Care National Health Service Foundation Trust (Greater Manchester), and 1 from Gloucester Royal Hospital (Gloucester). Patients were all adults, aged 21 to 71 years, with the vast majority (n = 12) having common variable immunodeficiency (CVID, Table I). Laboratory investigations at diagnosis revealed undetectable (<0.1 g/L) serum IgA in 85% (11 of 13) of cases and IgM in 62% (8 of 13). Where data were available, very low (<1 g/L) pretreatment serum IgG was seen in 67% (6 of 9) of cases. Low circulating B cells (<0.1 × 109 cells/L), natural killer cells (<0.1 × 109 cells/L), and T cells (<0.67 × 109 cells/L) were seen in 58% (7 of 12), 33% (4 of 12), and 17% (2 of 12) of cases, respectively. In patients with normal B cells and where B-cell immunophenotyping was performed, 67% (2 of 3) had low (<2%) class-switched memory B cells (Table I).Table IUK cohort with PID and recurrent or persistent Campylobacter enteritis: Immunologic profileCaseImmune deficiencyComorbiditiesDiagnostic serum immunoglobulin levels (g/L) & postvaccination responses (where data are available)Diagnostic lymphocyte subsets (×109 cells/L)Immunoglobulin replacement (at Campylobacter diagnosis)Trough immunoglobulin level (at Campylobacter diagnosis)1CVIDBronchiectasis, proliferative bronchiolitis, asthma, obesity, raised alcohol intakeUndetectable IgA & IgMB cells 0.05, normal T & NK cellsIVIg 25 g every 3 wk8 g/L2CVIDExcised brain tumor with residual learning difficulties, previous B-cell lymphoma, pulmonary nodules, splenomegalyIgG 0.8, undetectable IgA & IgMB cells <0.01, T cells 0.15, NK cells <0.01IVIg 70 g every 2 wk13.1 g/L3CVIDIntermittent low-level CMV and EBV viremiaIgG 19 (units /mL), undetectable IgA, IgM 0.11B cells 0.02 T cells 0.14, NK cells 0.01 (class- switch memory B cells 0.9%, CD21 low B cells 6%)IVIg 30 g every 3 wk6.2 g/L4CVIDNoneUndetectable IgG, IgA, & IgM with poor response to Pneumococcal polysaccharide vaccineB cells <0.01, normal T cells, NK cells 0.03SCIg 20 g every week12.1 g/L5CVID (NFKB2 mutation)Asthma, chronic rhinosinusitisIgG 3.6, undetectable IgA, IgM 0.16 with poor response to Pneumococcal polysaccharide vaccineB cells 0.01, normal T & NK cellsIVIg 40 g every 3 wk10.9 g/L6CVIDBronchiectasis, hypersplenism, ulcerative colitisUndetectable IgA & IgMNASCIg 14 g every week11 g/L7XLA (btk mutation confirmed)BronchiectasisIgG 0.73, undetectable IgA, IgM 0.29B cells <0.01, normal T & NK cellsIVIg 40 g every 3 wk10.4 g/L8CVIDNoneIgG 0.7, undetectable IgA & IgM with poor response to Pneumococcal polysaccharide vaccineNormal B, T, & NK cells (class- switch memory B cells 1%)IVIg 35 g every 3 wk7.5 g/L9CVIDBronchiectasisIgG 3.8, IgA 0.53, IgM 0.61 with poor response to Pneumococcal polysaccharide vaccineNormal B, T, & NK cellsNo (patient declined)3.8 g/L10CVIDNoneUndetectable IgA & IgMB cells 0.03, normal T cells, NK cells 0.05IVIG 30 g every 3 wkNA11CVIDInterstitial lung disease, ischemic heart diseaseUndetectable IgG, IgM, & IgA with poor response to Pneumococcal polysaccharide vaccineNormal B, T, & NK cells (class- switch memory B cells 0.6%)No (began after Campylobacter diagnosis)<1.1 g/L12CVIDBronchiectasis, chronic sinusitisIgG 0.69, undetectable IgA & IgM with poor response to Pneumococcal polysaccharide vaccineNormal B, T, & NK cellsSCIg 12 g every week11.7 g/L13CVIDLiver nodular regenerative hyperplasia, monoclonal gammopathy of undetermined significanceIgG 3.37, IgA 0.38, IgM 0.25 with poor response to Pneumococcal polysaccharide vaccineNormal B, T, & NK cells (class-switch memory B cells 6.3%)No (patient declined)3.4 g/LCMV, Cytomegalovirus; EBV, Epstein Barr virus; IVIg, intravenous immunoglobulin; NA, not available; NK, natural killer; SCIg, subcutaneous immunoglobulin.Undetectable = <0.1 g/L for IgA & IgM, <1 g/L for IgG. Open table in a new tab CMV, Cytomegalovirus; EBV, Epstein Barr virus; IVIg, intravenous immunoglobulin; NA, not available; NK, natural killer; SCIg, subcutaneous immunoglobulin. Undetectable = <0.1 g/L for IgA & IgM, <1 g/L for IgG. The total duration of gastrointestinal symptoms varied from 10 months to 17 years, and symptoms were intermittent in 6 patients (Table II). Three patients also exhibited malabsorption and/or weight loss, and 4 had systemic symptoms and/or bacteremia. In all cases, Campylobacter jejuni was isolated, with 3 patients harboring strains that were resistant to multiple antibiotics. Detection was by stool culture in most (n = 11), but 2 patients were positive only by colonic tissue culture or PCR analysis. In certain patients, other potential causes of chronic diarrhea were detected, for example, colon inflammation, duodenal villous atrophy, and chronic norovirus infection (Table II). Clinically however, Campylobacter remained the most likely cause for their symptoms, with onset and resolution of the diarrhea coinciding with Campylobacter detection (Table II).Table IIUK cohort with PID and recurrent or persistent Campylobacter enteritis: Clinical features, microbiology, and antimicrobial therapyCaseAge at symptoms onset (y), sexGastrointestinal symptoms/ malabsorption, and durationNo. of Campylobacter- positive samplesOther GI investigationsSystemic symptomsUnsuccessful antibiotic courses (temporary or no clinical improvement)Successful antibiotic course (symptoms resolution & no recurrence for >3 mo)142, MChronic diarrhea for 10 mo10× Campylobacter jejuni (MCS stool, multiresistant)Stool: calprotectin normal; negative for other bacteria, parasites, Norovirus, Enterovirus;GI endoscopy: chronic active pancolitisNoneMultiple PO clarithromycin,IV ertapenem,IV meropenemIV 1 g once a day ertapenem for 4 wk with PO neomycin for 7 d255, MIntermittent diarrhea with malabsorption and weight loss for 8 y13× C jejuni (MCS stool, multiresistant)Stool: calprotectin >600 μg/g; Norovirus+, negative for other bacteria, parasites, Enterovirus;GI endoscopies: chronic villous atrophy in duodenum, widespread focal active colitisEpisodes of arthralgia, headache and fever but negative blood MCS for Clostridium difficilePO doxycycline, clarithromycin, azithromycin, ciprofloxacin,cotrimoxazoleIV 1 g once a day ertapenem for 4 wk with PO neomycin for 7 d353, MIntermittent diarrhea for 17 y3× C jejuni (MCS stool)Stool: Norovirus+ negative for other bacteria, parasites;GI endoscopies: antral gastritis, increased intraepithelial lymphocytes and substantial villous atrophy in duodenum, mild active chronic inflammation without granulomata in colonNone (blood MCS not tested)PO coamoxiclav, neomycin, rifaximin, immunoglobulin; IV meropenem, ertapenem(spontaneous resolution)460, MChronic diarrhea with malabsorption and weight /protein loss3× C jejuni (PCR & MCS stool, multiresistant)Stool: negative for other bacteria, parasites, Norovirus, Enterovirus, Adenovirus, Astrovirus, Rotavirus, Sapovirus;GI endoscopies: nil significantSeveral episodes of bacteremia (MCS confirmed)PO azithromycin; IV carbapenem, aminoglycoside, chloramphenicolIV meropenem & aminoglycoside, PO ciprofloxacin532, FChronic diarrhea for 2 y4× C jejuni (PCR & MCS stool)Stool: calprotectin 116 μg/g; Norovirus+, Helicobacter pylori+Negative for other bacteria, parasites, Enterovirus, Adenovirus, Astrovirus, Rotavirus, SapovirusNone (blood MCS not tested)NonePO azithromycin 500 mg once a day with ciprofloxacin 500 mg twice a day for 3 wk654, MChronic diarrhea for 10 mo3× C jejuni (2× MCS & 1× PCR stool)Stool: negative for other bacteria, parasitesNonePO erythromycin, azithromycin, coamoxiclav(ongoing infection)724, MIntermittent diarrhea for 3 y>10× C jejuni (MCS stool)Stool: H pylori+, calprotectin 500 μg/g; negative for other bacteria, parasites, Norovirus, Adenovirus, Astrovirus, Rotavirus, Sapovirus;GI endoscopy: colon cryptitis with crypt abscessesEpisode of suspected bacteremia (blood MCS not tested)PO ciprofloxacin, azithromycinIV meropenem for 10 d829, MIntermittent diarrhea for 12 y2× C jejuni (MCS stool)NoneNone (blood MCS not tested)NonePO clarithromycin926, FChronic diarrhea for 6 mo with weight loss1× C jejuni (MCS colonic tissue)Stool: calprotectin 907 μg/g; negative for other bacteria, parasites;GI endoscopy: severe inflammation in lamina propria with cryptitis, crypt abscess formation and prominent lymphoid follicles in right & transverse colon, mild chronic inflammatory infiltrate in left colon, negative CMV stainsFevers but negative blood MCS for C difficilePO ciprofloxacinPO azithromycin 500 mg once a day for 2 wk1060, MIntermittent diarrhea for 15 y with weight loss5× C jejuni (MCS stool)NoneNone (blood MCS not tested)NonePO erythromycin 500 mg 4 times a day for 2 wk1171, MIntermittent diarrhea for 8 y3× C jejuni (MCS stool)Stool: negative for other bacteria, parasites, Norovirus, Adenovirus, Astrovirus, Rotavirus, Sapovirus;GI endoscopy: normal colonNone (blood MCS not tested)PO clarithromycin 500 mg twice a day for 2 wk(patient passed away)1248, FIntermittent diarrhea for 4 y4× C jejuni (MCS stool)Stool: calprotectin >600 μg/g; negative for other bacteria, parasites, Norovirus, Adenovirus, Astrovirus, Rotavirus, SapovirusNone (blood MCS not tested)PO ciprofloxacin 500 mg twice a day for 2 wk, clarithromycin 3 d (not tolerated)PO ciprofloxacin 500 mg twice a day for 2 wk1355, FIntermittent diarrhea for 8 y2× C jejuni (MCS stool)Stool: negative for other bacteria, parasites, Norovirus, Adenovirus, Astrovirus, Rotavirus, Sapovirus;GI endoscopy: focal mild acute inflammation in cecumNone (blood MCS not tested)NonePO clarithromycin 500 mg twice a day for 1 wkF, female; GI, gastrointestinal; IV, intravenous; M, male; MCS, microscopy, culture & sensitivities, includes screen for Salmonella, Shigella, Giardia, Escherichia coli O157, Cryptosporidium, Giardia; PO, per os (by mouth); PCR, polymerase chain reaction. Open table in a new tab F, female; GI, gastrointestinal; IV, intravenous; M, male; MCS, microscopy, culture & sensitivities, includes screen for Salmonella, Shigella, Giardia, Escherichia coli O157, Cryptosporidium, Giardia; PO, per os (by mouth); PCR, polymerase chain reaction. Fifty-eight percent (7 of 12) of patients were on adequate immunoglobulin replacement (serum IgG trough ≥ 8 g/L) when they developed enteritis (Table I). In patients who successfully cleared the infection and had no relapse, oral macrolides (n = 5, azithromycin, clarithromycin, or erythromycin) and intravenous carbapenems (n = 4, meropenem or ertapenem) were most commonly used, followed by aminoglycosides (n = 3, eg, neomycin), oral ciprofloxacin (n = 3), and coamoxiclav (n = 1), either alone or in combination. A literature review identified 32 published cases of recurrent or persistent Campylobacter enteritis or multiple Campylobacter spp. stool isolation in PID (see Table E1 in this article’s Online Repository at www.jaci-inpractice.org). Most were in X-linked agammaglobulinemia (XLA, n = 17), whereas 5 were in CVID and 3 in Good syndrome. Based on their diagnosis, very low or absent circulating B cells were expected to be present in at least 69% (22 of 32) of these cases, 18 with agammaglobulinemia and 3 with Good syndrome. The total duration of symptoms varied from 3 months to 15 years and resulted in weight loss in 7 of 32 (22%) cases. Sixty-six percent (21 of 32) also developed Campylobacter bacteremia, in some cases recurrent. Most stool cultures revealed C jejuni (n = 25), with Campylobacter coli being isolated in 6 cases and 1 patient harboring both. At least 20 of 32 (63%) patients were on immunoglobulin replacement when they developed enteritis, and these cases were more likely to clear the infection (80% vs 58% those who were not). The institution of immunoglobulin therapy alone led to resolution of the infection in 3 of 32 (9%) patients.1Schønheyder H.C. Søgaard P. Frederiksen W. A survey of Campylobacter bacteremia in three Danish counties, 1989 to 1994.Scand J Infect Dis. 1995; 27: 145-148Crossref PubMed Scopus (0) Google Scholar,2Borleffs J.C.C. Schellekens J.F. Brouwer E. Rozenberg-Arska M. Use of an immunoglobulin M containing preparation for treatment of two hypogammaglobulinemic patients with persistent Campylobacter jejuni infection.Eur J Clin Microbiol Infect Dis. 1993; 12: 772-775Crossref PubMed Scopus (0) Google Scholar In those patients who successfully cleared the infection, oral macrolides were most commonly used (n = 10; erythromycin, clarithromycin, or azithromycin), followed by aminoglycosides (n = 5; neomycin, gentamicin, netilmicin, or kanamycin), carbapenems (n = 5; meropenem, biapenem, or imipenem), tetracyclines (n = 4; doxycycline or minocycline), metronidazole (n = 3), fosfomycin (n = 2), ciprofloxacin (n = 1), and piperacillin (n = 1). Antibiotics were administered for a duration of 4 or more weeks in 7 of 32 (22%) cases. Overall, recurrent or persistent Campylobacter enteritis may contribute to significant morbidity in patients with PID, including debilitating diarrhea, malabsorption, weight loss, electrolyte disturbances, and bacteremia. A high index of suspicion for Campylobacter infection should be kept in these patients, particularly in those who have previously tested positive. Campylobacter can persist in the intestinal tract only giving intermittent symptoms and reinfection is commonly by the same microorganism.3Okada H. Kitazawa T. Harada S. Itoyama S. Hatakeyama S. Ota Y. et al.Combined treatment with oral kanamycin and parenteral antibiotics for a case of persistent bacteremia and intestinal carriage with Campylobacter coli.Intern Med. 2008; 47: 1363-1366Crossref Scopus (16) Google Scholar Furthermore, Campylobacter is difficult to grow even in specific culture media, and there are no validated consensus mechanisms to measure the bioburden in the gut flora, let alone eradication.4Buss J.E. Cresse M. Doyle S. Buchan B.W. Craft D.W. Young S. Campylobacter culture fails to correctly detect Campylobacter in 30% of positive patient stool specimens compared to non-cultural methods.Eur J Clin Microbiol Infect Dis. 2019; 38: 1087Crossref Scopus (25) Google Scholar Colonic tissue culture or stool PCR may thus be necessary in patients with ongoing symptoms.4Buss J.E. Cresse M. Doyle S. Buchan B.W. Craft D.W. Young S. Campylobacter culture fails to correctly detect Campylobacter in 30% of positive patient stool specimens compared to non-cultural methods.Eur J Clin Microbiol Infect Dis. 2019; 38: 1087Crossref Scopus (25) Google Scholar Other causes of chronic diarrhea should also be considered in these patients, particularly in those who remain symptomatic despite Campylobacter eradication. Most cases in our series were patients with CVID (12 of 13), in contrast to previously published cases where XLA was the most frequent diagnosis (17 of 32). This may echo improvements in patient management, with more patients being treated with adequate immunoglobulin replacement in recent years. The fact that fewer patients were suspected to be bacteremic in our cohort compared with previously published literature (31% vs 66%) also suggests the latter. The cases described above highlight the importance of humoral immunity in the prevention of chronicity or reinfection from Campylobacter spp. Previously published case reports suggest that patients who are on immunoglobulin therapy are more likely to clear the infection and immunoglobulin therapy alone led to eradication in a few cases. Most patients in our case series also had undetectable or very low diagnostic immunoglobulin levels. It is well established that most patients with CVID and XLA lack plasma cells in the lamina propria of their small and/or large intestine and this is important because the intestinal mucosa normally harbors the largest population of antibody-secreting plasma cells in the body.5Khan F. Person H. Dekio F. Ogawa M. Ho Hen Dunkin D. et al.Crohn’s-like enteritis in X-linked agammaglobulinemia: a case series and systematic review.J Allergy Clin Immunol Pract. 2021; 9: 3466-3478Abstract Full Text Full Text PDF Scopus (0) Google Scholar Interestingly, 58% of patients in our case series also had low or absent circulating B cells. This contrasts with what is known for CVID, where only 10% to 20% are expected to have low B cells.6Selenius J.S. Martelius T. Pikkarainen S. Siitonen S. Mattila E. Pietikäinen R. et al.Unexpectedly high prevalence of common variable immunodeficiency in Finland.Front Immunol. 2017; 8: 1190Crossref PubMed Scopus (39) Google Scholar This finding was echoed by the literature review, where 69% of patients were expected to have very low or absent circulating B cells based on their diagnosis. Low circulating B cells also seem to play an important role in the predisposition to other chronic gastrointestinal infections, like norovirus.7Grammatikos A. Moghaddas F. Reeve H. Johnston S. Gompels M. Albur M. Low circulating B cells in immunocompromised individuals are linked to poorer antibody responses to vaccines and a predisposition to viral infections.J Allergy Clin Immunol Global. 2023; 2: 111-113Abstract Full Text Full Text PDF Google Scholar Finally, 42% of patients in our case series had inadequate serum immunoglobulin trough levels when diagnosed with Campylobacter enteritis. These observations suggest that patients with CVID who are not maintained on adequate immunoglobulin replacement are at a higher risk of infection. In patients with CVID and low B cells in particular, higher IgG therapeutic targets may need to be considered. HIV-infected patients can also develop chronic or recurrent Campylobacter enteritis,8Molina J.M. Casin I. Hausfater P. Giretti E. Welker Y. Decazes J.M. et al.Campylobacter infections in HIV-infected patients: clinical and bacteriological features.AIDS. 1995; 9: 881-885Crossref PubMed Google Scholar but even in these patients, humoral immunity seems to play a key role: HIV patients who fail to clear the infection have poor Campylobacter-specific antibody responses while low CD4 T-cell levels do not seem to correlate with a worse outcome.9Perlman D.M. Ampel N.M. Schifman R.B. Cohn D.L. Patton C.M. Aguirre M.L. et al.Persistent Campylobacter jejuni infections in patients infected with the human immunodeficiency virus (HIV).Ann Intern Med. 1988; 108: 540-546Crossref PubMed Google Scholar In conclusion, Campylobacter enteritis is an important diagnosis to consider in patients with PID with chronic or recurrent diarrhea, particularly in those with very low diagnostic immunoglobulin levels. Diarrhea in CVID can be highly multifaceted and other potential causes should always be considered. We thank the patients for their collaboration and participation and the respective departments of the authors for supporting this study. Table E1Previously published cases of chronic/recurrent Campylobacter enteritis or Campylobacter spp. stool isolation in PIDLead author, year of publicationAge of onset (y), sexImmune deficiencyImmunoglobulin replacementSymptomsNo. of Campylobacter+ stool samplesFailed treatments (temporary or no clinical improvement)Definitive treatment (resulting in symptom resolution)Aguilar-Company et al,E1Aguilar-Company J. Los-Arcos I. Pigrau C. Rodríguez-Pardo D. Larrosa M.N. Rodríguez-Garrido V. et al.Potential use of fosfomycin-tromethamine for treatment of recurrent campylobacter species enteritis.Antimicrob Agents Chemother. 2016; 60: 4398-4400Crossref PubMed Scopus (9) Google Scholar 201664, FCVIDIVIg every 3 wkDiarrhea and hypovolemic shock1× Campylobacter jejuni, 1× Campylobacter coliNRPO fosfomycin 3 g every 48 h for 6 wkBarker et al,E2Barker C.R. Painset A. Swift C. Jenkins C. Godbole G. Maiden M.C.J. et al.Microevolution of Campylobacter jejuni during long-term infection in an immunocompromised host.Sci Rep. 2020; 1010109Crossref Scopus (11) Google Scholar 2020NRCVIDNRIntermittent diarrhea for 15 y25× C jejuniNRNRMerrick et al,E3Merrick B. Tamilarasan A.G. Luber R. Yong P.F.K. Cheent K. Irving P.M. et al.Recurrent Campylobacter jejuni infection in an immunodeficient patient treated with repeated faecal microbiota transplant (FMT)-A case report.Infect Dis Rep. 2022; 14: 56-62Crossref Scopus (0) Google Scholar 202270, FCVIDIVIg 20 g every 2 wkIntermittent diarrhea for 6 y, episode of bacteremia6× C jejuniPO clarithromycin, erythromycin, fosfomycin;IV meropenem; fecal microbiota transplantNRWard et al,E4Ward T.T. Klein K. Borthistle B.K. 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Claas E.C.J. van der Plas R.N. Kuijper E.J. Bredius R.G.M. Campylobacter jejuni bacteremia and Helicobacter pylori in a patient with X-linked agammaglobulinemia.Eur J Clin Microbiol Infect Dis. 2010; 29: 1315-1319Crossref PubMed Scopus (0) Google Scholar 201015, MXLAIVIg every 4 wkDiarrhea, weight loss, and 2 episodes of bacteremia for 18 mo2× C jejuniPO erythromycin;IV meropenemPO doxycycline for 4 wk and azithromycin for 2 wkVan der Meer et al,E7Van der Meer J.W.M. Mouton R.P. Daha M.R. Schuurman R.K.B. Campylobacter jejuni bacteraemia as a cause of recurrent fever in a patient with hypogammaglobulinaemia.J Infect. 1986; 12: 235-239Abstract Full Text PDF PubMed Google Scholar 198624, MXLANRDiarrhea, fever4× C jejuniPO cotrimoxazole, neomycin, doxycycline;IV gentamicinNRSchonheyder et al,E8Schønheyder H.C. Søgaard P. Frederiksen W. A survey of Campylobacter bacteremia in three Danish counties, 1989 to 1994.Scand J Infect Dis. 1995; 27: 145-148Crossref PubMed Scopus (0) Google Scholar 199523, MXLANRWeight loss and 2 episodes of bacteremia for 4 wk1× C coliPenicillinIV netilmicin for 10 d and IVIgTokuda et al,E9Tokuda K. Nishi J. Miyanohara H. Sarantuya J. Iwashita M. Kamenosono A. et al.Relapsing cellulitis associated with Campylobacter coli bacteremia in an agammaglobulinemic patient.Pediatr Infect Dis J. 2004; 23: 577-579Crossref PubMed Scopus (23) Google Scholar 200422, MXLAIVIg every 3 wk2 episodes of bacteremia in 5 mo2× C coliPO clarithromycin;IV ceftazidime, cefazolin, amikacin, panipenem/ betamipronPO kanamycin 750 mg 4 times a dayChusid et al,E10Chusid M.J. Coleman C.M. Dunne W.M. Chronic asymptomatic Campylobacter bacteremia in a boy with X-linked hypogammaglobulinemia.Pediatr Infect Dis J. 1987; 6: 943-944Crossref PubMed Google Scholar 198711, MXLAIVIg every 4 wkBacteremia for 6 wk>3× C coliNRPO erythromycin; IV erythromycin, gentamicin, piperacillinHagiya et al,E11Hagiya H. Kimura K. Nishi I. Yoshida H. Yamamoto N. Akeda Y. et al.Emergence of carbapenem non-susceptible campylobacter coli after long-term treatment against recurrent bacteremia in a patient with X-linked agammaglobulinemia.Intern Med. 2018; 57: 2077-2080Crossref Scopus (12) Google Scholar 201837, MXLAIVIg every 3 wk3 episodes of bacteremia in 12 mo1× C coliPO tebipenem;IV cefazolin, meropenemIV biapenem 600 mg twice a day;PO minocycline 100 mg twice a day for 2 wk, metronidazole 250 mg 4 times a day for 4 wkAriganello et al,E12Ariganello P. Angelino G. Scarselli A. Salfa I. della Corte M. de Matteis A. et al.Relapsing Campylobacter jejuni systemic infections in a child with X-Linked agammaglobulinemia.Case Rep Pediatr. 2013; 2013: 1-3Crossref Google Scholar 201311, MXLAIVIg every 4 wkIntermittent diarrhea, and 2 episodes of bacteremia for 12 mo1× C jejuniPO ciprofloxacin;IV ceftriaxone, vancomycinIV meropenem, clarithromycinRafi et al,E13Rafi A. Matz J. An unusual case of Campylobacter jejuni pericarditis in a patient with X-linked agammaglobulinemia.Ann Allergy Asthma Immunol. 2002; 89: 362-367Abstract Full Text PDF PubMed Google Scholar2002NRXLAIVIg every 4 wk2 episodes of bacteremia in 2 y1× C jejuniIV erythromycin, ceftazidimeNRBorleffs et al,E14Borleffs J.C.C. Schellekens J.F. Brouwer E. Rozenberg-Arska M. Use of an immunoglobulin M containing preparation for treatment of two hypogammaglobulinemic patients with persistent Campylobacter jejuni infection.Eur J Clin Microbiol Infect Dis. 1993; 12: 772-775Crossref PubMed Scopus (0) Google Scholar 199323, MXLAIVIg every 3 wk2 episodes of bacteremia in 6 mo2× C jejuniPO ciprofloxacin;IV imipenemIV pentaglobin 500 mL every 3 wkBorleffs et al,E14Borleffs J.C.C. Schellekens J.F. Brouwer E. Rozenberg-Arska M. Use of an immunoglobulin M containing preparation for treatment of two hypogammaglobulinemic patients with persistent Campylobacter jejuni infection.Eur J Clin Microbiol Infect Dis. 1993; 12: 772-775Crossref PubMed Scopus (0) Google Scholar 199325, MXLAIVIg every 3 wk3 episodes of bacteremia in 6 mo3× C jejuniPO ciprofloxacin;IV imipenem, erythromycinIV pentaglobin 500 mL every 3 wkKim et al,E15Kim Y. Shin J.A. Han S.B. Cho B. Jeong D.C. Kang J.H. et al.Recurrent Campylobacter jejuni bacteremia in a patient with hypogammaglobulinemia: A case report.Medicine. 2017; 96e7238Google Scholar 201718, MXLA (suspected)IVIg every 3 wkIntermittent diarrhea, and 4 episodes of bacteremia for 18 mo2× C jejuniPO amoxicillin/ clavulanate, roxithromycin, clarithromycin, doxycycline;IV cefazolin, meropenem, amikacinNRAutenrieth et al,E16Autenrieth I.B. Schuster V. Ewald J. Harmsen D. Kreth H.W. An unusual case of refractory Campylobacter jejuni infection in a patient with X-linked agammaglobulinemia: successful combined therapy with maternal plasma and ciprofloxacin.Clin Infect Dis. 1996; 23: 526-531Crossref PubMed Google Scholar 19967, MXLAIVIg every 4 wkIntermittent diarrhea, and 4 episodes of bacteremia for 18 moSeveral C jejuniIV amoxicillin, doxycycline, imipenem, pentaglobin;PO bovine colostrumPO ciprofloxacin 250 mg twice a day for 3 wk;IV maternal plasma for 5 wkArai et al,E17Arai A. Kitano A. Sawabe E. Kanegane H. Miyawaki T. Miura O. Relapsing Campylobacter coli bacteremia with reactive arthritis in a patient with X-linked agammaglobulinemia.Intern Med. 2007; 46: 605-609Crossref Scopus (22) Google Scholar 200735, MXLAIVIg every 4 wk4 episodes of bacteremia in 18 mo2× C coliIV cefepimeIV meropenem;PO minocyclineVan der Meer et al,E7Van der Meer J.W.M. Mouton R.P. Daha M.R. Schuurman R.K.B. Campylobacter jejuni bacteraemia as a cause of recurrent fever in a patient with hypogammaglobulinaemia.J Infect. 1986; 12: 235-239Abstract Full Text PDF PubMed Google Scholar 198624, MXLAIVIgIntermittent diarrhea, and 5 episodes of bacteremia for >1 y2× C jejuniPO cotrimoxazole, neomycin, doxycycline;IM gentamicinNRKerstens et al,E18Kerstens P.J.S.M. Endtz H.P. Meis J.F.G.M. Oyen W.J.G. Koopman R.J.I. van den Broek P.J. et al.Erysipelas-like skin lesions associated with Campylobacter jejuni septicemia in patients with hypogammaglobulinemia.Eur J Clin Microbiol Infect Dis. 1992; 11: 842-847Crossref PubMed Scopus (0) Google Scholar 199224, MXLASCIgIntermittent diarrhea, and 3 episodes of bacteremia for 5 y3× C jejuniPO erythromycin, amoxicillin, flucloxacillinIV imipenem 500 mg 4 times a day for 6 wkKerstens et al,E18Kerstens P.J.S.M. Endtz H.P. Meis J.F.G.M. Oyen W.J.G. Koopman R.J.I. van den Broek P.J. et al.Erysipelas-like skin lesions associated with Campylobacter jejuni septicemia in patients with hypogammaglobulinemia.Eur J Clin Microbiol Infect Dis. 1992; 11: 842-847Crossref PubMed Scopus (0) Google Scholar 199226, MXLASCIg2 episodes of bacteremia in 2 wk2× C jejuniPO erythromycin;IV amoxicillin, flucloxacillin, gentamicinIV imipenem 500 mg 4 times a day for 2 wkPines et al,E19Pines A. Goldhammer E. Bregman J. Kaplinsky N. Frankl O. Campylobacter enteritis associated with recurrent abortions in agammaglobulinemia.Acta Obstet Gynecol Scand. 1983; 62: 279-280Crossref PubMed Google Scholar 198328, FAgammaglobulinemiaIVIgDiarrhea, weight loss, for 3 mo2× C jejuniPO cotrimoxazolePO erythromycin 1 g thrice a day and metronidazole 500 mg 4 times a dayAguilar-Company et al,E1Aguilar-Company J. Los-Arcos I. Pigrau C. Rodríguez-Pardo D. Larrosa M.N. Rodríguez-Garrido V. et al.Potential use of fosfomycin-tromethamine for treatment of recurrent campylobacter species enteritis.Antimicrob Agents Chemother. 2016; 60: 4398-4400Crossref PubMed Scopus (9) Google Scholar 201683, FGood syndromeIVIg every 2 wkIntermittent diarrhea for 6 mo1× C coliPO amoxicillin /clavulanatePO fosfomycin 3 g every 48 h for 4 wkTarr et al,E20Tarr P.E. Sneller M.C. Mechanic L.J. Economides A. Eger C.M. Strober W. et al.Infections in patients with immunodeficiency with thymoma (Good syndrome). 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Harmful algal bloom aerosols and human health.

Harmful algal blooms (HABs) are increasing across many locations globally. Toxins from HABs can be incorporated into aerosols and transported inland, where subsequent exposure and inhalation can induce adverse health effects. However, the relationship between HAB aerosols and health outcomes remains unclear despite the potential for population-level exposures. In this review, we synthesized the current state of knowledge and identified evidence gaps in the relationship between HAB aerosols and human health. Aerosols from Karenia brevis, Ostreopsis sp., and cyanobacteria were linked with respiratory outcomes. However, most works did not directly measure aerosol or toxin concentrations and instead relied on proxy metrics of exposure, such as cell concentrations in nearby waterbodies. Furthermore, the number of studies with epidemiological designs was limited. Significant uncertainties remain regarding the health effects of other HAB species; threshold dose and the dose-response relationship; effects of concurrent exposures to mixtures of toxins and other aerosol sources, such as microplastics and metals; the impact of long-term exposures; and disparities in exposures and associated health effects across potentially vulnerable subpopulations. Additional studies employing multifaceted exposure assessment methods and leveraging large health databases could address such gaps and improve our understanding of the public health burden of HABs.

A Call for Discovery and Therapeutic Development for Cutaneous Neurofibromas

Skin is the calling card of humanity—the body’s first line of defense against external threats and a major part of a person’s identity. Diseases of the skin are common and a leading cause of nonfatal disease burden in humans (Hay et al., 2014Hay R.J. Johns N.E. Williams H.C. Bolliger I.W. Dellavalle R.P. Margolis D.J. et al.The global burden of skin disease in 2010: an analysis of the prevalence and impact of skin conditions.J Invest Dermatol. 2014; 134: 1527-1534Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Effectively addressing skin diseases not only halts or prevents physical illness, it often treats or prevents the common comorbidities of skin disease: depression, anxiety, and suicidal ideation (Hay et al., 2014Hay R.J. Johns N.E. Williams H.C. Bolliger I.W. Dellavalle R.P. Margolis D.J. et al.The global burden of skin disease in 2010: an analysis of the prevalence and impact of skin conditions.J Invest Dermatol. 2014; 134: 1527-1534Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar; Misery et al., 2018Misery L. Seneschal J. Reguiai Z. Merhand S. Héas S. Huet F. et al.Patient burden is associated with alterations in quality of life in adult patients with atopic dermatitis: results from the ECLA study.Acta Derm Venereol. 2018; 98: 713-714Crossref Scopus (18) Google Scholar). Such mental health diagnoses carry their own substantial disease burden and dramatically impact QOL for both the person and the community affected by chronic skin diseases (Dalgard et al., 2015Dalgard F.J. Gieler U. Tomas-Aragones L. Lien L. Poot F. Jemec G.B.E. et al.The psychological burden of skin diseases: A cross-sectional multicenter study among dermatological out-patients in 13 European countries.J Invest Dermatol. 2015; 135: 984-991Abstract Full Text Full Text PDF PubMed Scopus (520) Google Scholar). Accordingly, an important aspect of effectively treating or preventing skin disease is improving mental health comorbidities and QOL through therapeutic discovery (Kaundinya et al., 2022Kaundinya T. Rakita U. Guraya A. Abboud D.M. Croce E. Thyssen J.P. et al.Differences in psychometric properties of clinician- and patient-reported outcome measures for atopic dermatitis by race and skin tone: A systematic review.J Invest Dermatol. 2022; 142: 364-381Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar; Renert-Yuval et al., 2022Renert-Yuval Y. Correa da Rosa J. Garcet S. Pavel A.B. Bares J. Chima M. et al.Analysis of alopecia areata surveys suggests a threshold for improved patient-reported outcomes.Br J Dermatol. 2022; 187: 539-547Crossref Scopus (4) Google Scholar). Of course, to achieve that critical step, we must first understand disease pathophysiology, develop therapies on the basis of established biologic mechanisms, know the natural history of the disease, and validate meaningful outcome measures for therapeutic interventions. Successful generation of this enormous dataset can result in incredible benefits for people living with skin disease. Indeed, there has been a recent explosion of new drug therapies (including a raft of new biologic agents targeting specific mediators of disease pathobiology) for conditions such as atopic dermatitis, psoriasis, and vitiligo (Arkwright and Koplin, 2023Arkwright P.D. Koplin J.J. Impact of a decade of research into atopic dermatitis.J Allergy Clin Immunol Pract. 2023; 11: 63-71Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar; Chovatiya and Paller, 2021Chovatiya R. Paller A.S. JAK inhibitors in the treatment of atopic dermatitis.J Allergy Clin Immunol. 2021; 148: 927-940Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar; Malik and Guttman-Yassky, 2018Malik K. Guttman-Yassky E. Cytokine targeted therapeutics for alopecia areata: lessons from atopic dermatitis and other inflammatory skin diseases.J Investig Dermatol Symp Proc. 2018; 19: S62-S64Abstract Full Text Full Text PDF PubMed Google Scholar). Such developments give inspiration and direction for another skin condition that has been without therapeutic advance: cutaneous neurofibromas (cNFs). cNFs are the most common tumor in people with the autosomal dominant neurocutaneous condition, neurofibromatosis type 1 (NF1) (Guiraud et al., 2019Guiraud M. Bouroubi A. Beauchamp R. Bocquet A. Grégoire J.M. Rauly-Lestienne I. et al.Cutaneous neurofibromas: patients' medical burden, current management and therapeutic expectations: results from an online European patient community survey.Orphanet J Rare Dis. 2019; 14: 286Crossref PubMed Scopus (9) Google Scholar). Nearly all adults with NF1 are afflicted with cNFs ranging in number from a handful to several thousand tumors involving the skin of all regions of the body (Cannon et al., 2018Cannon A. Chen M.J. Li P. Boyd K.P. Theos A. Redden D.T. et al.Cutaneous neurofibromas in neurofibromatosis type I: A quantitative natural history study.Orphanet J Rare Dis. 2018; 13: 31Crossref PubMed Scopus (28) Google Scholar; Ehara et al., 2018Ehara Y. Yamamoto O. Kosaki K. Yoshida Y. Natural course and characteristics of cutaneous neurofibromas in neurofibromatosis 1.J Dermatol. 2018; 45: 53-57Crossref PubMed Scopus (14) Google Scholar). cNFs are intermittently painful and itchy and can compromise skin integrity. In all cases, cNFs are disfiguring, negatively impacting mental health and QOL (Guiraud et al., 2019Guiraud M. Bouroubi A. Beauchamp R. Bocquet A. Grégoire J.M. Rauly-Lestienne I. et al.Cutaneous neurofibromas: patients' medical burden, current management and therapeutic expectations: results from an online European patient community survey.Orphanet J Rare Dis. 2019; 14: 286Crossref PubMed Scopus (9) Google Scholar; Maguiness et al., 2021Maguiness S. Berman Y. Rubin N. Dodds M. Plotkin S.R. Wong C. et al.Measuring the effect of cutaneous neurofibromas on quality of life in neurofibromatosis type 1.Neurology. 2021; 97: S25-S31Crossref PubMed Scopus (1) Google Scholar). NF1 is the most common autosomal dominant neurocutaneous disease (estimated incidence of 1:3,000), and nearly 100% (roughly 2.5 million people worldwide) develop cNFs. Indeed, people living with NF1 report that cNFs are the manifestation that they find most distressing (Guiraud et al., 2019Guiraud M. Bouroubi A. Beauchamp R. Bocquet A. Grégoire J.M. Rauly-Lestienne I. et al.Cutaneous neurofibromas: patients' medical burden, current management and therapeutic expectations: results from an online European patient community survey.Orphanet J Rare Dis. 2019; 14: 286Crossref PubMed Scopus (9) Google Scholar; Maguiness et al., 2021Maguiness S. Berman Y. Rubin N. Dodds M. Plotkin S.R. Wong C. et al.Measuring the effect of cutaneous neurofibromas on quality of life in neurofibromatosis type 1.Neurology. 2021; 97: S25-S31Crossref PubMed Scopus (1) Google Scholar). Yet, historically, there has been a lack of dedicated effort to understand the pathophysiology, relevant preclinical and clinical endpoints, and potential therapies to prevent and treat cNFs. A committed effort to understanding and effectively treating NF1-associated cNFs will benefit not only people with NF1 but all people with dermal lesions that are associated with neuropathic irritation, itch, and disfigurement because the core elements of cNFs (Schwann cells, fibroblasts, mast cells, and macrophages) are shared across many skin conditions. The time is optimal for multidisciplinary investment in unraveling the elemental factors that contribute to cNF formation, their associated symptoms, and the many opportunities to prevent and treat these tumors and their comorbidities. The articles presented in this “Spotlight on Cutaneous Neurofibroma” reflect the work undertaken by a community of invested stakeholders (patients and caregivers, basic scientists, clinical scientists, dermatologists, neuro-oncologists, and regulatory experts) to explore key questions pertaining to developing effective therapeutics for cNFs in people with NF1. Individuals with expertise in various areas participated in the 2022 cNF symposium organized by the Neurofibromatosis Therapeutic Acceleration Program. Four teams focused on addressing core concepts in cNF Pathology and Biology, Therapeutic Targets for cNF Treatment, Preclinical Testing and Assays, and Human Clinical Trials: Therapeutic Strategy and Development. Through a review of published and unpublished data and leveraging the recent therapeutic advances for other NF1-associated tumors such as plexiform neurofibromas (pNFs) and optic pathway gliomas (Fangusaro et al., 2021Fangusaro J. Onar-Thomas A. Poussaint T.Y. Wu S. Ligon A.H. Lindeman N. et al.A phase II trial of selumetinib in children with recurrent optic pathway and hypothalamic low-grade glioma without NF1: A pediatric brain tumor consortium study.Neuro Oncol. 2021; 23: 1777-1788Crossref PubMed Scopus (0) Google Scholar; Gross et al., 2020Gross A.M. Wolters P.L. Dombi E. Baldwin A. Whitcomb P. Fisher M.J. et al.Selumetinib in children with inoperable plexiform neurofibromas.N Engl J Med. 2020; 382 ([published correction appears in N Eng J Med 2020;383:1290]): 1430-1442Crossref PubMed Scopus (243) Google Scholar) and positive outcomes for other skin conditions such as vitiligo and alopecia areata that were previously without meaningful therapeutic advance (Chovatiya and Paller, 2021Chovatiya R. Paller A.S. JAK inhibitors in the treatment of atopic dermatitis.J Allergy Clin Immunol. 2021; 148: 927-940Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar; Sheikh et al., 2022Sheikh A. Rafique W. Owais R. Malik F. Ali E. FDA approves Ruxolitinib (opzelura) for vitiligo therapy: A breakthrough in the field of dermatology.Ann Med Surg (Lond). 2022; 81104499Google Scholar), the teams addressed what is known as well as the knowledge gaps needing to be filled to support meaningful therapeutic development for NF1-associated cNFs. NF1 results from inactivating pathogenic variants in the NF1 gene, which is located on chromosome 17q11.2 (Brosseau et al., 2018Brosseau J.P. Liao C.P. Wang Y. Ramani V. Vandergriff T. Lee M. et al.NF1 heterozygosity fosters de novo tumorigenesis but impairs malignant transformation.Nat Commun. 2018; 9: 5014Crossref PubMed Scopus (31) Google Scholar; Carey et al., 1986Carey J.C. Baty B.J. Johnson J.P. Morrison T. Skolnick M. Kivlin J. The genetic aspects of neurofibromatosis.Ann N Y Acad Sci. 1986; 486: 45-56Crossref PubMed Google Scholar; Upadhyaya et al., 1997Upadhyaya M. Osborn M.J. Maynard J. Kim M.R. Tamanoi F. Cooper D.N. Mutational and functional analysis of the neurofibromatosis type 1 (NF1) gene.Hum Genet. 1997; 99: 88-92Crossref PubMed Scopus (90) Google Scholar). The gene product, neurofibromin, is widely expressed in almost all tissues but is most abundant in the central and peripheral nervous systems (Brosseau et al., 2018Brosseau J.P. Liao C.P. Wang Y. Ramani V. Vandergriff T. Lee M. et al.NF1 heterozygosity fosters de novo tumorigenesis but impairs malignant transformation.Nat Commun. 2018; 9: 5014Crossref PubMed Scopus (31) Google Scholar; Daston and Ratner, 1992Daston M.M. Ratner N. Neurofibromin, a predominantly neuronal GTPase activating protein in the adult, is ubiquitously expressed during development.Dev Dyn. 1992; 195: 216-226Crossref PubMed Google Scholar; Upadhyaya et al., 1997Upadhyaya M. Osborn M.J. Maynard J. Kim M.R. Tamanoi F. Cooper D.N. Mutational and functional analysis of the neurofibromatosis type 1 (NF1) gene.Hum Genet. 1997; 99: 88-92Crossref PubMed Scopus (90) Google Scholar). NF1 can result from a de novo or familial pathogenic variant and is transmitted in an autosomal dominant inheritance pattern. Roughly 50% of patients with NF1 have a spontaneous pathogenic variant since the NF1 gene has one of the highest rates of spontaneous variation (Carey et al., 1986Carey J.C. Baty B.J. Johnson J.P. Morrison T. Skolnick M. Kivlin J. The genetic aspects of neurofibromatosis.Ann N Y Acad Sci. 1986; 486: 45-56Crossref PubMed Google Scholar). Absence of functional neurofibromin contributes to the constitutive activation of RAS (Bollag et al., 1996Bollag G. Clapp D.W. Shih S. Adler F. Zhang Y.Y. Thompson P. et al.Loss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in haematopoietic cells.Nat Genet. 1996; 12: 144-148Crossref PubMed Scopus (481) Google Scholar). RAS is a commonly mutated oncogene that is implicated in most human cancers. Altered RAS regulation is also associated with a range of conditions affecting multiple organs termed the RASopathies (Matthews et al., 2022Matthews H. Vanneste M. Katsura K. Aponte D. Patton M. Hammond P. et al.Refining nosology by modelling variation among facial phenotypes: the RASopathies [epub ahead of print].J Med Genet. 2022; (accessed XXX)https://doi.org/10.1136/jmedgenet-2021-108366Crossref Scopus (1) Google Scholar). NF1 is one such Rasopathy because variants in the gene NF1 lead to reduced function of neurofibromin and dysregulation of RAS. This results in highly variable clinical manifestations ranging from the nearly universal cNFs (including the various forms of the most common, discreet cNFs or the rarer diffusely infiltrating dermal neurofibromas [Ortonne et al., 2018Ortonne N. Wolkenstein P. Blakeley J.O. Korf B. Plotkin S.R. Riccardi V.M. et al.Cutaneous neurofibromas: current clinical and pathologic issues.Neurology. 2018; 91: S5-S13Crossref PubMed Scopus (52) Google Scholar]) to the uncommon but potentially fatal sarcomas and gliomas in people with NF1. The contribution of altered regulation of RAS to cNF formation, growth, and maintenance is explored in detail in the article “RAS signaling gone awry in skin: the complex role of RAS in cutaneous neurofibroma pathogenesis, emerging biological insights” (Rhodes et al., 2023Rhodes S.D. McCormick F. Cagan R.L. Bakker A. Staedtke V. Ly I. et al.RAS signaling gone awry in skin: the complex role of RAS in cutaneous neurofibroma pathogenesis, emerging biological insights.J Investig Dermatol. 2023; Abstract Full Text Full Text PDF Scopus (0) Google Scholar). Although the specific RAS isoforms activated in cNF development have yet to be defined, RAS and its down and upstream effectors are leading targets for cNF therapeutic development (Figure 1a). Furthermore, there are compelling developments highlighting the relatively protective role of germline loss of NF1 against malignancy versus the causative role of somatic NF1 alterations in common cancers, including melanoma (Brosseau et al., 2018Brosseau J.P. Liao C.P. Wang Y. Ramani V. Vandergriff T. Lee M. et al.NF1 heterozygosity fosters de novo tumorigenesis but impairs malignant transformation.Nat Commun. 2018; 9: 5014Crossref PubMed Scopus (31) Google Scholar). These observations indicate that there may be a complex balance in RAS regulation between benign and malignant tumors that, once understood, can be therapeutically harnessed (Figure 1a). Key challenges in the treatment or prevention of cNFs are their multiplicity and variability in clinical and molecular features across people with NF1 and even across tumors in a single individual. There are many factors that contribute to the regulation of cNF multiplicity addressed in the article “Cutaneous Neurofibroma Heterogenetity: Factors that Influence Tumor Burden in Neurofibromatosis Type 1” (Jiang et al., 2023Jiang C. Mckay R. Lee S. Romo C. Blakeley J. Haniffa M. et al.Cutaneous neurofibroma heterogeneity: factors that influence tumor burden in neurofibromatosis type 1.J Investig Dermatol. 2023; Abstract Full Text Full Text PDF Google Scholar). First, biallelic inactivation of the NF1 gene in Schwann cells is critical for cNF formation (and indeed, the formation of all peripheral nerve tumors in people with NF1) (Brosseau et al., 2018Brosseau J.P. Liao C.P. Wang Y. Ramani V. Vandergriff T. Lee M. et al.NF1 heterozygosity fosters de novo tumorigenesis but impairs malignant transformation.Nat Commun. 2018; 9: 5014Crossref PubMed Scopus (31) Google Scholar; Chen et al., 2019Chen Z. Mo J. Brosseau J.P. Shipman T. Wang Y. Liao C.P. et al.Spatiotemporal loss of NF1 in Schwann cell lineage leads to different types of cutaneous neurofibroma susceptible to modification by the hippo pathway.Cancer Discov. 2019; 9: 114-129Crossref PubMed Scopus (44) Google Scholar; Radomska et al., 2019Radomska K.J. Coulpier F. Gresset A. Schmitt A. Debbiche A. Lemoine S. et al.Cellular origin, tumor progression, and pathogenic mechanisms of cutaneous neurofibromas revealed by mice with Nf1 knockout in boundary cap cells.Cancer Discov. 2019; 9: 130-147Crossref PubMed Scopus (31) Google Scholar; Staser et al., 2012Staser K. Yang F.C. Clapp D.W. Pathogenesis of plexiform neurofibroma: tumor-stromal/hematopoietic interactions in tumor progression.Annu Rev Pathol. 2012; 7: 469-495Crossref PubMed Scopus (69) Google Scholar). The cell of origin of cNFs is defined as a boundary cap cell (Radomska et al., 2019Radomska K.J. Coulpier F. Gresset A. Schmitt A. Debbiche A. Lemoine S. et al.Cellular origin, tumor progression, and pathogenic mechanisms of cutaneous neurofibromas revealed by mice with Nf1 knockout in boundary cap cells.Cancer Discov. 2019; 9: 130-147Crossref PubMed Scopus (31) Google Scholar) or a skin-derived precursor cell (Chen et al., 2019Chen Z. Mo J. Brosseau J.P. Shipman T. Wang Y. Liao C.P. et al.Spatiotemporal loss of NF1 in Schwann cell lineage leads to different types of cutaneous neurofibroma susceptible to modification by the hippo pathway.Cancer Discov. 2019; 9: 114-129Crossref PubMed Scopus (44) Google Scholar) derived from the embryonic dorsal nerve root and the dorsal root ganglion (DRG) (Figure 1b). These recent discoveries link NF1 loss and RAS regulation with neural and skin development and homeostasis; both helping to identify new targets and experimental endpoints for cNFs and highlighting the important interaction between skin and the peripheral nervous system (Figure 1b). Work is ongoing to define the spatial and temporal loss of somatic NF1 and how NF1 variants influence cNF behavior in skin and pNF in deep nerves. Another hallmark of cNFs is the infiltration of inflammatory cells. Recent efforts revealed that cNF development in murine models is a multistep process, involving a number of intersecting cellular and inflammatory processes (Chen et al., 2019Chen Z. Mo J. Brosseau J.P. Shipman T. Wang Y. Liao C.P. et al.Spatiotemporal loss of NF1 in Schwann cell lineage leads to different types of cutaneous neurofibroma susceptible to modification by the hippo pathway.Cancer Discov. 2019; 9: 114-129Crossref PubMed Scopus (44) Google Scholar; Radomska et al., 2019Radomska K.J. Coulpier F. Gresset A. Schmitt A. Debbiche A. Lemoine S. et al.Cellular origin, tumor progression, and pathogenic mechanisms of cutaneous neurofibromas revealed by mice with Nf1 knockout in boundary cap cells.Cancer Discov. 2019; 9: 130-147Crossref PubMed Scopus (31) Google Scholar). Mast cells play a key role in the development of pNFs (infiltrating tumors of the peripheral nerve) where they are recruited by the chemoattractant stem cell factor secreted by NF1 null Schwann cells (Liao et al., 2018Liao C.P. Booker R.C. Brosseau J.P. Chen Z. Mo J. Tchegnon E. et al.Contributions of inflammation and tumor microenvironment to neurofibroma tumorigenesis.J Clin Invest. 2018; 128: 2848-2861Crossref PubMed Scopus (78) Google Scholar; Staser et al., 2012Staser K. Yang F.C. Clapp D.W. Pathogenesis of plexiform neurofibroma: tumor-stromal/hematopoietic interactions in tumor progression.Annu Rev Pathol. 2012; 7: 469-495Crossref PubMed Scopus (69) Google Scholar). Early studies indicate that there is also increased mast cell density in cNFs versus in uninvolved skin (with relatively higher density in small cNFs, cNFs removed from people in early adulthood, and symptomatic cNFs), but their role in tumorigenesis is still unclear (Kallionpää et al., 2022Kallionpää R.A. Ahramo K. Martikkala E. Fazeli E. Haapaniemi P. Rokka A. et al.Mast cells in human cutaneous neurofibromas: density, subtypes, and association with clinical features in neurofibromatosis 1.Dermatology. 2022; 238: 329-339Crossref PubMed Scopus (0) Google Scholar). Macrophages are also abundant in cNFs compared to unaffected skin, and there is a proposed relationship between the recruitment and proliferation of macrophages in human cNFs and the expression of YAP and TAZ, core effectors in the Hippo pathway (Jia et al., 2020Jia J. Zhang H. He L. Zhang H. Shu M. Cutaneous neurofibroma cells with active YAP promotes proliferation of macrophages resulting in increased accumulation of macrophages by modulating CCL5 and TGF-β1.Oncol Rep. 2020; 43: 1319-1330Google Scholar). Chen et al., 2019Chen Z. Mo J. Brosseau J.P. Shipman T. Wang Y. Liao C.P. et al.Spatiotemporal loss of NF1 in Schwann cell lineage leads to different types of cutaneous neurofibroma susceptible to modification by the hippo pathway.Cancer Discov. 2019; 9: 114-129Crossref PubMed Scopus (44) Google Scholar showed that the HOXB7 lineage−derived cells were the source cells for both cNFs and pNFs in a Hoxb7-Cre;Nf1f/fl genetically engineered mouse model and that the Hippo pathway is a key modulator of both the (more common) discrete and (rarer) diffuse cNFs. They also showed that Hippo and MAPK pathway dysregulation interact in the setting of Nf1 loss to support both cNF and pNF development (Chen et al., 2019Chen Z. Mo J. Brosseau J.P. Shipman T. Wang Y. Liao C.P. et al.Spatiotemporal loss of NF1 in Schwann cell lineage leads to different types of cutaneous neurofibroma susceptible to modification by the hippo pathway.Cancer Discov. 2019; 9: 114-129Crossref PubMed Scopus (44) Google Scholar). Finally, in 36 cNF samples from 10 patients, genetic variation was observed in genes within the Hippo pathway (Faden et al., 2017Faden D.L. Asthana S. Tihan T. DeRisi J. Kliot M. Whole exome sequencing of growing and non-growing cutaneous neurofibromas from a single patient with neurofibromatosis type 1.PLoS One. 2017; 12e0170348Google Scholar; Gosline et al., 2017Gosline S.J. Weinberg H. Knight P. Yu T. Guo X. Prasad N. et al.A high-throughput molecular data resource for cutaneous neurofibromas.Sci Data. 2017; 4170045Crossref Scopus (13) Google Scholar). The specific relationship between NF1, Ras, cNF formation, and alterations in the Hippo pathway is yet to be elucidated. This is of particular interest for cNFs because there are several therapeutics (systemic and topical) that are effective for regulation of altered Jak–signal transducer and activator of transcription (STAT) signaling in skin conditions such as atopic dermatitis and psoriasis (Chovatiya and Paller, 2021Chovatiya R. Paller A.S. JAK inhibitors in the treatment of atopic dermatitis.J Allergy Clin Immunol. 2021; 148: 927-940Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar; Papp et al., 2021Papp K. Szepietowski J.C. Kircik L. Toth D. Eichenfield L.F. Leung D.Y.M. et al.Efficacy and safety of Ruxolitinib cream for the treatment of atopic dermatitis: results from 2 phase 3, randomized, double-blind studies.J Am Acad Dermatol. 2021; 85: 863-872Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar). The Jak−STAT pathway interacts with the Hippo pathway and may be a promising area of investigation for cNFs (Guo et al., 2021Guo P. Wang Z. Zhou Z. Tai Y. Zhang A. Wei W. et al.Immuno-hippo: research progress of the hippo pathway in autoimmune disease.Immunol Lett. 2021; 230: 11-20Crossref Scopus (4) Google Scholar; Rosmarin et al., 2020Rosmarin D. Pandya A.G. Lebwohl M. Grimes P. Hamzavi I. Gottlieb A.B. et al.Ruxolitinib cream for treatment of vitiligo: a randomised, controlled, phase 2 trial.Lancet. 2020; 396: 110-120Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar; Wang et al., 2018Wang E.H.C. Sallee B.N. Tejeda C.I. Christiano A.M. JAK inhibitors for treatment of alopecia areata.J Invest Dermatol. 2018; 138: 1911-1916Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar). Finally, there are emerging data about the relationship between neuronal tissue and other cell components in cNFs such as Schwann cells and the cells of the microenvironment. This includes potential contributions of neurturin and artemin signaling between aberrant C-fiber terminals and Schwann cells in the dermis contributing to both the initiation and propagation of early-stage cNFs (Rice et al., 2019Rice F.L. Houk G. Wymer J.P. Gosline S.J.C. Guinney J. Wu J. et al.The evolution and multi-molecular properties of NF1 cutaneous neurofibromas originating from C-fiber sensory endings and terminal Schwann cells at normal sites of sensory terminations in the skin.PLoS One. 2019; 14e0216527Crossref Scopus (10) Google Scholar). This finding is reminiscent of the critical role of cells derived from the DRG in cNF development in preclinical models of cNF (Chen et al., 2019Chen Z. Mo J. Brosseau J.P. Shipman T. Wang Y. Liao C.P. et al.Spatiotemporal loss of NF1 in Schwann cell lineage leads to different types of cutaneous neurofibroma susceptible to modification by the hippo pathway.Cancer Discov. 2019; 9: 114-129Crossref PubMed Scopus (44) Google Scholar; Radomska et al., 2019Radomska K.J. Coulpier F. Gresset A. Schmitt A. Debbiche A. Lemoine S. et al.Cellular origin, tumor progression, and pathogenic mechanisms of cutaneous neurofibromas revealed by mice with Nf1 knockout in boundary cap cells.Cancer Discov. 2019; 9: 130-147Crossref PubMed Scopus (31) Google Scholar) (Figure 1b). As addressed by Jiang et al., 2023Jiang C. Mckay R. Lee S. Romo C. Blakeley J. Haniffa M. et al.Cutaneous neurofibroma heterogeneity: factors that influence tumor burden in neurofibromatosis type 1.J Investig Dermatol. 2023; Abstract Full Text Full Text PDF Google Scholar, an improved understanding of the factors that contribute to cNF heterogeneity (cell specific, tissue intrinsic, and systemic) will enable therapeutic development for both prevention and treatment of cNFs. An important element in a functional pipeline for therapeutic discovery and development for cNFs is the availability of feasible and informative model systems relative to human disease. Fortunately, tremendous progress has been made in the development and validation of preclinical models and their use for therapeutic assessment. These models range from two-dimensional semi-immortalized cell cultures to three-dimensional cocultures, human induced pluripotent stem cells harboring NF1 gene sequence variations, and multiple in vivo models (fly, mouse, pig) (Figure 1c) (Chen et al., 2019Chen Z. Mo J. Brosseau J.P. Shipman T. Wang Y. Liao C.P. et al.Spatiotemporal loss of NF1 in Schwann cell lineage leads to different types of cutaneous neurofibroma susceptible to modification by the hippo pathway.Cancer Discov. 2019; 9: 114-129Crossref PubMed Scopus (44) Google Scholar; King et al., 2020King L.B. Boto T. Botero V. Aviles A.M. Jomsky B.M. Joseph C. et al.Developmental loss of neurofibromin across distributed neuronal circuits drives excessive grooming in Drosophila.PLoS Genet. 2020; 16e1008920Crossref Scopus (7) Google Scholar; Li et al., 2016Li H. Chang L.J. Neubauer D.R. Muir D.F. Wallace M.R. Immortalization of human normal and NF1 neurofibroma Schwann cells.Lab Invest. 2016; 96: 1105-1115Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar; Mazuelas et al., 2020Mazuelas H. Carrió M. Serra E. Modeling tumors of the peripheral nervous system associated with Neurofibromatosis type 1: reprogramming plexiform neurofibroma cells.Stem Cell Res. 2020; 49102068Crossref Scopus (6) Google Scholar; Mo et al., 2021Mo J. Anastasaki C. Chen Z. Shipman T. Papke J. Yin K. et al.Humanized neurofibroma model from induced pluripotent stem cells delineates tumor pathogenesis and developmental origins.J Clin Invest. 2021; 131e139807Crossref Scopus (24) Google Scholar; Radomska et al., 2019Radomska K.J. Coulpier F. Gresset A. Schmitt A. Debbiche A. Lemoine S. et al.Cellular origin, tumor progression, and pathogenic mechanisms of cutaneous neurofibromas revealed by mice with Nf1 knockout in boundary cap cells.Cancer Discov. 2019; 9: 130-147Crossref PubMed Scopus (31) Google Scholar; Stemmer-Rachamimov et al., 2004Stemmer-Rachamimov A.O. Louis D.N. Nielsen G.P. Antonescu C.R. Borowsky A.D. Bronson R.T. et al.Comparative pathology of nerve sheath tumors in mouse models and humans.Cancer Res. 2004; 64: 3718-3724Crossref PubMed Scopus (73) Google Scholar). The applicability of each of the models to specific questions pertinent to cNF therapeutic development is addressed in the article by Staedtke et al., 2023Staedtke V. Topilko P. Le L. Grimes K. Largaespada D.A. Cagan R.L. et al.Existing and Developing Preclinical Models for Neurofibromatosis Type 1-related cutaneous Neurofibromas.J Investig Dermatol. 2023; Abstract Full Text Full Text PDF Google Scholar, “Existing and Developing Preclinical Models for Neurofibromatosis Type 1-related Cutaneous Neurofibromas.” One important role of these models is to enable the investigation of the temporal and spatial influence of Nf1 variants on the behavior of the various cells that make up cNFs. As such, these models enable therapeutic discovery for the condition NF1 (cNFs and other manifestations) as well as skin conditions influenced by the RAS−MAP kinase pathways. Despite the nearly universal presence of cNFs in people with NF1, the natural history of cNFs is not fully elucidated. It is well-documented that cNFs become apparent later in life than pNFs and increase in number and perhaps size over decades (Cannon et al., 2018Cannon A. Chen M.J. Li P. Boyd K.P. Theos A. Redden D.T. et al.Cutaneous neurofibromas in neurofibromatosis type I: A quantitative natural history study.Orphanet J Rare Dis. 2018; 13: 31Crossref PubMed Scopus (28) Google Scholar; Ehara et al., 2018Ehara Y. Yamamoto O. Kosaki K. Yoshida Y. Natural course and

Unraveling Mechanisms of Autoimmune Skin Blistering: Applying Single-Cell Transcriptomics to Pemphigus B Cells

Clinical Implications•Single-cell RNA sequencing of antigen-specific B cells results in novel, potentially druggable targets for therapy.•CD137L/CD137 signaling and BATF are critically involved in patients with active pemphigus.•Integration of published omics datasets on patients with pemphigus may hold great promise. •Single-cell RNA sequencing of antigen-specific B cells results in novel, potentially druggable targets for therapy.•CD137L/CD137 signaling and BATF are critically involved in patients with active pemphigus.•Integration of published omics datasets on patients with pemphigus may hold great promise. Autoimmunity against the skin is typically attributed to autoantibodies (with their corresponding B cells producing them) or T cells that react against autoantigens, resulting in disease that can be clinically and immunologically differentiated into distinct patterns in most patients (Gudjonsson et al., 2020Gudjonsson J.E. Kabashima K. Eyerich K. Mechanisms of skin autoimmunity: cellular and soluble immune components of the skin.J Allergy Clin Immunol. 2020; 146: 8-16Google Scholar). Among those, autoimmune skin conditions with potentially life-threatening blistering encompass entities from the pemphigus and pemphigoid groups, with the respective autoantigens being well-defined at the molecular level, facilitating research and diagnosis (Hammers and Stanley, 2016Hammers C.M. Stanley J.R. Mechanisms of disease: pemphigus and bullous pemphigoid.Annu Rev Pathol. 2016; 11: 175-197Google Scholar). In patients with pemphigus, autoantibodies against desmosomal transmembrane adhesion proteins desmoglein (DSG) 3 and DSG1 are formed and result in pathologies on the skin and/or mucous membranes that are explained by the presence or absence of those autoantibody reactivities: patients with mucosal-dominant pemphigus vulgaris (mPV) feature anti-DSG3 antibodies, whereas patients with mucocutaneous pemphigus vulgaris (mcPV) display anti-DSG3 and anti-DSG1 antibodies. In pemphigus foliaceus (PF), only the skin is affected, and patients show only anti-DSG1 antibodies in circulation. Intracellular signaling processes are involved in targeted keratinocytes, as evidenced by various cell biologic studies, complementing the direct steric effects mediated by these pathogenic autoantibodies (Hammers and Stanley, 2016Hammers C.M. Stanley J.R. Mechanisms of disease: pemphigus and bullous pemphigoid.Annu Rev Pathol. 2016; 11: 175-197Google Scholar). Although the role and pathogenicity of autoantibodies in these patients are increasingly understood, the characteristics of the B cells that produce them are not fully understood or elucidated. In their article published in the Journal of Investigative Dermatology, Egami et al., 2023Egami S. Watanabe T. Fukushima-Nomura A. Nomura H. Takahashi H. Yamagami J. et al.Desmoglein-specific B-cell-targeted single-cell analysis revealing unique gene regulation in patients with pemphigus [epub ahead of print].J Invest Dermatol. 2023; (accessed XXX)https://doi.org/10.1016/j.jid.2023.03.1661Google Scholar performed state-of-the-art single-cell transcriptomic analysis on autoimmune antigen-specific memory B cells from patients with pemphigus to unravel new pathways of pathophysiologic relevance. Over the past decade, much progress has been made in decoding autoimmune mechanisms at all stages of this paradigmatic model disease, with important input stemming from omics-based high-throughput technologies: antibody and/or B-cell receptor repertoires of patients with pemphigus were studied in great detail and partly over time by antibody phage display (Payne et al., 2005Payne A.S. Ishii K. Kacir S. Lin C. Li H. Hanakawa Y. et al.Genetic and functional characterization of human pemphigus vulgaris monoclonal autoantibodies isolated by phage display.J Clin Invest. 2005; 115: 888-899Google Scholar), Epstein−Barr virus−transformed hybridoma cells (Di Zenzo et al., 2012Di Zenzo G. Di Lullo G. Corti D. Calabresi V. Sinistro A. Vanzetta F. et al.Pemphigus autoantibodies generated through somatic mutations target the desmoglein-3 cis-interface.J Clin Invest. 2012; 122: 3781-3790Google Scholar), and single-cell cloning after sorting (Cho et al., 2019Cho A. Caldara A.L. Ran N.A. Menne Z. Kauffman R.C. Affer M. et al.Single-cell analysis suggests that ongoing affinity maturation drives the emergence of pemphigus vulgaris autoimmune disease.Cell Rep. 2019; 28: 909-922.e6Google Scholar), yielding information on clonal diversity, processes of affinity maturation, antigen-binding properties, and synergistic effects of mAbs in mediating tissue pathology. By including next-generation sequencing approaches into these repertoire analyses, subclass-specific autoantibody repertoires (i.e., IgG4/IgG1, IgA1/IgA2) could be studied, providing new insights into their origins and formation in human disease (Ellebrecht et al., 2018Ellebrecht C.T. Mukherjee E.M. Zheng Q. Choi E.J. Reddy S.G. Mao X. et al.Autoreactive IgG and IgA B cells evolve through distinct subclass switch pathways in the autoimmune disease pemphigus vulgaris.Cell Rep. 2018; 24: 2370-2380Google Scholar). Proteomics-based deconvolution of pemphigus autoantibody repertoires finally allowed for unprecedented tracking of single-serum autoantibodies over time in patients, suggesting a much more clonally diverse and diverse landscape of autoantibodies in pemphigus (Chen et al., 2017Chen J. Zheng Q. Hammers C.M. Ellebrecht C.T. Mukherjee E.M. Tang H.Y. et al.Proteomic analysis of pemphigus autoantibodies indicates a larger, more diverse, and more dynamic repertoire than determined by B cell genetics.Cell Rep. 2017; 18: 237-247Google Scholar). Early genomic works applied microarrays to identify signatures of pemphigus vulgaris (PV)−associated differentially expressed genes (DEGs), comparing PBMCs from patients of differing clinical activity with those from controls (Dey-Rao et al., 2013Dey-Rao R. Seiffert-Sinha K. Sinha A.A. Genome-wide expression analysis suggests unique disease-promoting and disease-preventing signatures in pemphigus vulgaris.Genes Immun. 2013; 14: 487-499Google Scholar). Similar techniques were then used on single antigen-specific B cells to identify molecular effects of treatment, revealing pattern differences in IL1β and CD27 gene expression in the corticosteroid and rituximab treatment groups (Hébert et al., 2019Hébert V. Petit M. Maho-Vaillant M. Golinski M.L. Riou G. Derambure C. et al.Modifications of the transcriptomic profile of autoreactive B cells from pemphigus patients after treatment with rituximab or a standard corticosteroid regimen.Front Immunol. 2019; 10: 1794Google Scholar) or increases in the surface expression of the KCNN4 potassium channel on B cells after rituximab administration (Caillot et al., 2018Caillot F. Derambure C. Berkani N. Riou G. Maho-Vaillant M. Calbo S. et al.Long-term increase of Kcnn4 potassium channel surface expression on B cells in pemphigus patients after rituximab treatment.J Invest Dermatol. 2018; 138: 2666-2668Google Scholar). Total RNA sequencing of peripheral blood CD3−CD19+ lymphocytes from patients with pemphigus beautifully confirmed murine experimental data on reduced FcγRIIB signaling as an important driver for pathogenic class switching of autoantibodies also in human disease development (Nomura et al., 2022Nomura H. Wada N. Takahashi H. Kase Y. Yamagami J. Egami S. et al.IgM to IgG class switching is a necessary step for pemphigus phenotype induction in desmoglein 3-specific B cell receptor knock-in mouse.J Immunol. 2022; 208: 582-593Google Scholar). A trove of new transcriptomics data has been generated recently by studying lesional pemphigus skin samples that, in ectopic lymphoid-like structures, contain autoreactive B and T cells. Total RNA sequencing−based and microarray-based analyses not only led to the identification of an IL-17+ T-cell−governed autoimmune response (extending the concept of pemphigus just being a classical T helper 2−driven disease [Holstein et al., 2021Holstein J. Solimani F. Baum C. Meier K. Pollmann R. Didona D. et al.Immunophenotyping in pemphigus reveals a TH17/TFH17 cell-dominated immune response promoting desmoglein1/3-specific autoantibody production.J Allergy Clin Immunol. 2021; 147: 2358-2369Google Scholar]) but also to new potential epigenetic regulators (Huang et al., 2022Huang Z.X. Qu P. Wang K.K. Zheng J. Pan M. Zhu H.Q. Transcriptomic profiling of pemphigus lesion infiltrating mononuclear cells reveals a distinct local immune microenvironment and novel lncRNA regulators.J Transl Med. 2022; 20: 182Google Scholar) and new insights into the in vivo biology of autoimmune B cells (Zhou et al., 2020Zhou S. Liu Z. Yuan H. Zhao X. Zou Y. Zheng J. et al.Autoreactive B cell differentiation in diffuse ectopic lymphoid-like structures of inflamed pemphigus lesions.J Invest Dermatol. 2020; 140: 309-318.e8Google Scholar). Single-cell−sequencing technologies allow for the detection of pathologic dysregulations even in small subpopulations of cells, with regard to changes on the genetic, transcriptional, epigenetic, or proteomic levels, depending on the methodology applied. This technique can either be applied to complex samples (with preserved cellular heterogeneity) or to samples enriched for specific cell types, such as B cells. This latter approach was applied by Egami et al., 2023Egami S. Watanabe T. Fukushima-Nomura A. Nomura H. Takahashi H. Yamagami J. et al.Desmoglein-specific B-cell-targeted single-cell analysis revealing unique gene regulation in patients with pemphigus [epub ahead of print].J Invest Dermatol. 2023; (accessed XXX)https://doi.org/10.1016/j.jid.2023.03.1661Google Scholar on peripheral blood samples from three patients with pemphigus (one with PF, one with mcPV, and one with mPV), resulting in 103 DSG-specific sorted B cells and 128 non−DSG-specific sorted B cells as input material for single-cell RNA sequencing. For the one patient with PF, additional DSG1-specific B cells (31) were single-cell sorted after treatment, for comparison with 37 cells before treatment from that patient. The authors show that with their sorting and sequencing approach, B-cell receptor repertoire data can be obtained, also serving as an internal technical control for their experimentation. The authors then go on to identify, among upregulated DEGs, signatures of CD137L-mediated T-cell costimulation (with CD137L expression on antigen-specific B cells confirmed by flow cytometry), B-/T-cell differentiation (e.g., BATF), and inflammation (e.g., S100A8/A9, CCL3). In light of earlier published works and their translational potential, these findings are particularly intriguing. CD137L/CD137 signaling is involved in follicular T helper cell activation, a cell type recently implicated in pemphigus pathophysiology (Holstein et al., 2021Holstein J. Solimani F. Baum C. Meier K. Pollmann R. Didona D. et al.Immunophenotyping in pemphigus reveals a TH17/TFH17 cell-dominated immune response promoting desmoglein1/3-specific autoantibody production.J Allergy Clin Immunol. 2021; 147: 2358-2369Google Scholar). Moreover, the transcription factor BATF is known to be expressed in B cells, directly controlling activation-induced cytidine deaminase and thus acting as a regulator of class-switch recombination and somatic hypermutation (Ise et al., 2011Ise W. Kohyama M. Schraml B.U. Zhang T. Schwer B. Basu U. et al.The transcription factor BATF controls the global regulators of class-switch recombination in both B cells and T cells.Nat Immunol. 2011; 12: 536-543Google Scholar). Comparing DEGs before and after immunosuppressive treatment in a patient with PF, the authors identified, as expected, downregulation of genes and signaling implied in B-cell−mediated antibody production (i.e., CD27, peroxisome proliferator–activated receptor, APRIL), consistent with improvements in clinical activity and decreased serum antibody titers from treatment with corticosteroids and azathioprine. Studying cellular mechanisms of autoimmunity is challenging, especially so when rare diseases such as PV or PF are concerned; yet, at the same time, these conditions are very well-characterized with regard to their autoantigens, positioning them as model diseases for (theoretically) unbiased identification of new pathways and, potentially, treatment targets. As shown, Egami et al., 2023Egami S. Watanabe T. Fukushima-Nomura A. Nomura H. Takahashi H. Yamagami J. et al.Desmoglein-specific B-cell-targeted single-cell analysis revealing unique gene regulation in patients with pemphigus [epub ahead of print].J Invest Dermatol. 2023; (accessed XXX)https://doi.org/10.1016/j.jid.2023.03.1661Google Scholar succeeded in establishing an appropriate methodology for the isolation of antigen-specific B cells and subsequent single-cell RNA sequencing, holding great potential for translation into personalized medicine and studying more patients with PV, PF, and other dermatologic autoimmune diseases as well. From this and other works, it also becomes clear that the resulting datasets are becoming increasingly complex (and less intuitively accessible), requiring sophisticated bioinformatic analyses and the close collaboration of clinician scientists, basic researchers, informaticians, and statisticians. Finally, another future challenge (and chance) lies in the integration of various single-cell and non-single-cell omic datasets concerning one particular disease or group of diseases from laboratories worldwide, and to conclude and appropriately test promising treatment targets resulting from these strides. Christoph M. Hammers: http://orcid.org/0000-0001-5631-2415 The author states no conflict of interest. Desmoglein-Specific B-Cell−Targeted Single-Cell Analysis Revealing Unique Gene Regulation in Patients with PemphigusJournal of Investigative DermatologyPreviewAutoreactive B cells are assumed to play a critical role in pemphigus; however, the characteristics of these cells are not yet fully understood. In this study, 23 pemphigus vulgaris or pemphigus foliaceus samples were used to isolate circulating desmoglein (DSG)-specific B cells. Transcriptome analysis of the samples was performed at the single-cell level to detect genes involved in disease activity. DSG1- or DSG3-specific B cells from three patients’ differentially expressed genes related to T cell costimulation (CD137L) as well as B-cell differentiation (CD9, BATF, TIMP1) and inflammation (S100A8, S100A9, CCR3), compared with nonspecific B cells from the same patients. Full-Text PDF Open Access

IL-34 Exerts Anti-Inflammatory Activities on Keratinocytes and Is Downregulated in Psoriatic-Inflamed Skin

Interleukin-34 (IL-34) is expressed by keratinocytes in the skin and plays a role in Langerhans cell (LC) homeostasis through its binding to the colony-stimulating factor 1 receptor (CSF-1R) ( Greter et al., 2012 Greter M. Lelios I. Pelczar P. Hoeffel G. Price J. Leboeuf M. et al. Stroma-derived interleukin-34 controls the development and maintenance of langerhans cells and the maintenance of microglia. Immunity. 2012; 37: 1050-1060 Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar ; Wang et al., 2012 Wang Y. Szretter K.J. Vermi W. Gilfillan S. Rossini C. Cella M. et al. IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nat Immunol. 2012; 13: 753-760 Crossref PubMed Scopus (652) Google Scholar ). In recent years, a growing body of literature has reported its overexpression during inflammation in tissues and/or in the serum of patients with rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel diseases or Sjogren’s syndrome, in association with disease severity ( Munoz-Garcia et al., 2021 Munoz-Garcia J. Cochonneau D. Teletchea S. Moranton E. Lanoe D. Brion R. et al. The twin cytokines interleukin-34 and CSF-1: masterful conductors of macrophage homeostasis. Theranostics. 2021; 11: 1568-1593 Crossref PubMed Scopus (31) Google Scholar ). By contrast, some immunoregulatory properties of IL-34 have also been described in other physiopathological contexts, either by controlling the expression of proinflammatory cytokines or by promoting M2 macrophage differentiation and Treg cell functions ( Guillonneau et al., 2017 Guillonneau C. Bézie S. Anegon I. Immunoregulatory properties of the cytokine IL-34. Cell Mol Life Sci. 2017; 74: 2569-2586 Crossref PubMed Scopus (67) Google Scholar ). Although IL-34 is mainly produced in the skin, very few studies have investigated its expression, regulation and role during skin inflammation and it is still unclear whether IL-34 has a beneficial or a deleterious role. Li et al. reported low serum concentrations of IL-34 in psoriasis patients similar to those of healthy controls ( Li et al., 2017 Li J. Liu L. Rui W. Li X. Xuan D. Zheng S. et al. New Interleukins in Psoriasis and Psoriatic Arthritis Patients: The Possible Roles of Interleukin-33 to Interleukin-38 in Disease Activities and Bone Erosions. Dermatology. 2017; 233: 37-46 Crossref PubMed Scopus (67) Google Scholar ), without investigating IL-34 tissue expression. By contrast, Esaki et al. reported a reduced IL-34 expression in skin lesions of atopic dermatitis (AD) patients, suggesting that IL-34 could have immunoregulatory properties in the skin ( Esaki et al., 2015 Esaki H. Ewald D.A. Ungar B. Rozenblit M. Zheng X. Xu H. et al. Identification of novel immune and barrier genes in atopic dermatitis by means of laser capture microdissection. J Allergy Clin Immunol. 2015; 135: 153-163 Abstract Full Text Full Text PDF PubMed Google Scholar ).

PA12 A case of pustular psoriasis in epidermolytic ichthyosis: coincidence or common pathway?

Abstract An 8-year-old boy with epidermolytic ichthyosis (EI) due to a heterozygous KRT1 mutation presented with a striking bullous skin eruption. Microbiological swabs were sent, and oral antibiotics were prescribed for suspected bullous impetigo. He deteriorated clinically, developing a fever and more extensive pustular rash reminiscent of generalized pustular psoriasis (GPP). Skin biopsies from two distinct cutaneous sites revealed histology strongly supportive of pustular psoriasis. Oral ciclosporin was commenced in addition to intensive topical emollient therapy. Following widespread desquamation, the pustular eruption fully resolved. Recurrence upon weaning of ciclosporin necessitated the introduction of ustekinumab. The rash remains controlled on this therapy. The EI is caused by heterozygous mutations in KRT1 or KRT10, and presents at birth with erythroderma and widespread skin denudation. The erythema and skin fragility abate in early childhood, giving way to prominent hyperkeratosis. Severe palmoplantar keratoderma is seen in those with KRT1 mutations. The GPP is a rare but life-threatening condition characterized by sterile pustules with or without systemic involvement. Interleukin (IL)-36-mediated inflammatory signalling plays a pathogenic role, as evidenced by loss of function mutations in IL36RN, which encodes an IL-36 receptor antagonist (Marrakchi S, Guigue P, Renshaw BR et al. Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis. N Engl J Med 2011; 365:620–8), and the efficacy of IL-36 receptor inhibitor spesolimab in a recent phase II trial. Both EI and GPP are rare, and the confluence of these entities in this case is striking. Four other cases in the literature describe a GPP-like eruption in patients with congenital ichthyoses. The coexistence of these conditions might be explained by their immunological profiles. Studies of the skin of patients with congenital ichthyoses have shown immune dysregulation with T helper 17/IL-23 skewing, and upregulation of associated inflammatory cytokines, including IL-36γ. The latter encodes for an IL-36 receptor agonist (Paller AS, Renert-Yuval Y, Suprun M et al. An IL-17-dominant immune profile is shared across the major orphan forms of ichthyosis. J Allergy Clin Immunol 2017; 139:152–65). Thus, increased IL-36 receptor agonist activity in congenital ichthyosis could theoretically lead to GPP in genetically predisposed individuals with already upregulated IL-36 receptor-mediated signalling.

Tralokinumab shows clinical improvement in patients with prurigo nodularis-like phenotype atopic dermatitis: A multicenter, prospective, open-label case series study

There are several phenotypes of atopic dermatitis (AD). 1 Girolomoni G. de Bruin-Weller M. Aoki V. et al. Nomenclature and clinical phenotypes of atopic dermatitis. Ther Adv Chronic Dis. 2021; 2620406223211002979 Google Scholar The prurigo nodularis (PN)-like phenotype occurs in nearly one-half of the patients with AD. 1 Girolomoni G. de Bruin-Weller M. Aoki V. et al. Nomenclature and clinical phenotypes of atopic dermatitis. Ther Adv Chronic Dis. 2021; 2620406223211002979 Google Scholar In all AD phenotypes, chronic itch usually leads to an itch-scratch cycle with the development of secondary lesions. These include, in the PN-like phenotype, excoriated hyperkeratotic, intensely itchy papules and nodules in areas accessible to scratch. 1 Girolomoni G. de Bruin-Weller M. Aoki V. et al. Nomenclature and clinical phenotypes of atopic dermatitis. Ther Adv Chronic Dis. 2021; 2620406223211002979 Google Scholar An emergent role of the type 2 cytokines, including interleukin (IL) 4, IL-13, IL-31, and IL-5, has been suggested in the pathogenesis underlying AD itch. IL-13 is a potent enhancer of the neuronal response to different itch stimuli. 2 Miron Y. Miller P.E. Hughes C. et al. Mechanistic insights into the antipruritic effects of lebrikizumab, an anti–IL-13 mAb. J Allergy Clin Immunol. 2022; 150: 690-700 Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar Tralokinumab, a fully human IgG4 monoclonal antibody neutralizing IL-13, is a novel treatment that has demonstrated safety and efficacy in clinical trials in treating adult patients with moderate-to-severe AD. 3 Wollenberg A. Blauvelt A. Guttman-Yassky E. et al. Tralokinumab for moderate-to-severe atopic dermatitis: results from two 52-week, randomized, double-blind, multicentre, placebo-controlled phase III trials (ECZTRA 1 and ECZTRA 2). Br J Dermatol. 2021; 184: 437-449 Crossref PubMed Scopus (170) Google Scholar In our open-label, retrospective case series study, tralokinumab improved clinical manifestations in 2 patients presenting with PN-like phenotype. 4 Pezzolo E. Naldi L. Tralokinumab in the treatment of resistant atopic dermatitis: an open-label, retrospective case series study. J Eur Acad Dermatol Venereol. 2023; 37: e644-e645 Crossref Scopus (2) Google Scholar Therefore, we prospectively investigated tralokinumab efficacy and safety in treating for at least 16 weeks, 17 adult patients with moderate-to-severe PN-like phenotype AD at 5 dermatology tertiary referral centers, from July 2021 to November 2022. Patients were eligible for treatment with tralokinumab after failing the first-line approved biologic treatment dupilumab, without achieving eczema area and severity index (EASI)-50 after 16 weeks of treatment. Written informed consent was obtained for each patient. At baseline, patients (mean age, 60.75 years; 76.5% women) presented moderate-to-severe PN-like phenotype AD and with means (ranges) EASI of 27.2 (16-45), Investigator Global Assessment (IGA) of 3.7 (3-4), numeric rating scale (NRS)-itch of 9.8 (8-10), NRS-sleeplessness of 8.9 (6-10), and dermatology life and quality index (DLQI) of 16.3 (14-24). Seventy percent of patients used concomitant topical corticosteroids at baseline. Patients reached EASI-50 within 4 weeks, EASI-75 within 12 weeks, and EASI-90 within 32 weeks (mean EASI reduction from 27.2-1.7, P <.001) (Fig 1). The mean NRS-itch and sleeplessness and DLQI values significantly decreased as early as week 4 (P <.001) and progressively reduced after 16-week continuous treatment. Tralokinumab resulted in complete or almost complete clinical remission (IGA 0 or 1) in 76% (13/17) of patients, in 47% (8/17) within week 12, in 23% within week 32, and 6% within week 64, and an at least 2-grade IGA reduction in the others (24%) (Fig 2). Both patients with 16-weeks treatment observation (8/17) and patients with 32 or 64 weeks of continuous treatment (9/17) maintained clinical efficacy without reporting any serious adverse effect. 5 Licata G, Tancredi V, Pezzolo E, et al. Efficacy and safeness of tralokinumab in patients with atopic dermatitis who developed conjunctivitis under dupilumab: a case series. J Eur Acad Dermatol Venereol. Published online April 5, 2023. https://doi.org/10.1111/jdv.19108 Google Scholar Mild conjunctivitis represented the main adverse effect (12%), followed by injection-site reaction, localized urticaria, and mild herpetic stomatitis. Fig 2Atopic dermatitis severity assessed by the Investigator Global Assessment score at different times. IGA, Investigator Global Assessment. View Large Image Figure Viewer Download Hi-res image

The Importance of Patient-Focused Drug Development in Pemphigus and Pemphigoid

Clinical Implications•Pemphigus and pemphigoid can be severe life-threatening diseases that cause significant burden on the day-to-day lives of patients.•Access to therapy can remain an issue for patients because rituximab is only clinically approved for pemphigus vulgaris, so most therapies are prescribed off label.•Patients must weigh the burden of disease versus burden of therapy. The goal of therapy is to control disease without serious side effects.•Given the side effects of steroids, minimal therapy is the primary goal of therapy, and complete remission of disease is secondary. New therapies do not have to be perfect, as long as they provide meaningful benefits to patients.•Validated tools for measuring disease activity in pemphigus and pemphigoid have been published. The five-point Investigator’s Global Assessment scales in pemphigus and pemphigoid are not validated.•The definition of clear or almost clear disease is overly stringent and not fair compared with the endpoints used for clinical trials in other autoimmune diseases with pathophysiology similar to that of pemphigus. Clinical trial data indicate that patients’ QOL can be restored despite not achieving clear or almost clear disease activity. Clinical trials should use endpoints that reflect meaningful benefits to patients and consider the physical and psychological impact of treatments.•There has been a steady increase in clinical trials in pemphigus and pemphigoid over the last several years. The International Pemphigus and Pemphigoid Foundation seeks to continue its collaboration with the patient community, industry, and the United States Food and Drug Administration to improve access to treatment and QOL for all people affected with pemphigus and pemphigoid.Developing new treatments for intractable diseases is essential to improve patients’ health and QOL. The United States Food and Drug Administration (FDA) evaluates the safety and efficacy of treatments to ensure that the benefits of a new product outweigh its risks. Understanding what patients look for in new drugs and how patients and caregivers view the risks of therapy can help to identify areas of unmet need and guide the drug development process. Over the last decade, the FDA has incorporated patients’ perspectives and experiences into drug development process through Patient Listening Sessions and Patient-Focused Drug Development (PFDD) meetings. In contrast to Patient Listening Sessions, which are not open to the public, PFDD meetings aim to ensure that patients’ experiences, needs, and priorities are captured and meaningfully incorporated into drug development and evaluation. From the patient's perspective, PFDD meetings raise awareness and engagement in the patient community by discussing patient perspectives on the burden of disease, clinical trial participation, and risk−benefit tradeoffs of drugs used to treat their condition. From the drug development perspective, PFDD meetings can help the FDA to conduct risk−benefit assessments, advise drug sponsors on their development programs, and identify areas of unmet need or potential trial endpoints. Patients are the experts in these meetings, sharing their lived experiences so that clinicians and researchers can better understand the unmet needs of the patient community and develop tools that better assess the benefits of patient therapies. A summary of PFDD meetings relevant to dermatology is listed in Table 1.Table 1FDA and EL-PFDD Meetings Relevant to DermatologyDisease or ConditionType of MeetingMeeting DateAmyloidosisEL-PFDD Meeting16 November 2015PsoriasisFDA-led PFDD Meeting17 March 2016Alopecia areataFDA-led PFDD Meeting11 September 2017LupusEL-PFDD Meeting25 September 2017Hereditary angioedemaFDA-led PFDD Meeting25 September 2017HyperhidrosisEL-PFDD Meeting13 November 2017Hypereosinophilic syndromesEL-PFDD Meeting23 March 2018Pachyonychia congenitaEL-PFDD Meeting6 April 2018Dermatitis (eczema)EL-PFDD Meeting23 September 2019Systemic sclerosisFDA-led PFDD Meeting13 October 2020VitiligoFDA-led PFDD Meeting8 March 2021Gorlin syndromeEL-PFDD Meeting8 October 2021Pemphigus and pemphigoidEL-PFDD Meeting25 January 2023Abbreviations: EL, externally led; FDA, United States Food and Drug Administration; PFDD, Patient-Focused Drug Development.Data were obtained from https://www.fda.gov/industry/prescription-drug-user-fee-amendments/condition-specific-meeting-reports-and-other-information-related-patients-experience. Open table in a new tab •Pemphigus and pemphigoid can be severe life-threatening diseases that cause significant burden on the day-to-day lives of patients.•Access to therapy can remain an issue for patients because rituximab is only clinically approved for pemphigus vulgaris, so most therapies are prescribed off label.•Patients must weigh the burden of disease versus burden of therapy. The goal of therapy is to control disease without serious side effects.•Given the side effects of steroids, minimal therapy is the primary goal of therapy, and complete remission of disease is secondary. New therapies do not have to be perfect, as long as they provide meaningful benefits to patients.•Validated tools for measuring disease activity in pemphigus and pemphigoid have been published. The five-point Investigator’s Global Assessment scales in pemphigus and pemphigoid are not validated.•The definition of clear or almost clear disease is overly stringent and not fair compared with the endpoints used for clinical trials in other autoimmune diseases with pathophysiology similar to that of pemphigus. Clinical trial data indicate that patients’ QOL can be restored despite not achieving clear or almost clear disease activity. Clinical trials should use endpoints that reflect meaningful benefits to patients and consider the physical and psychological impact of treatments.•There has been a steady increase in clinical trials in pemphigus and pemphigoid over the last several years. The International Pemphigus and Pemphigoid Foundation seeks to continue its collaboration with the patient community, industry, and the United States Food and Drug Administration to improve access to treatment and QOL for all people affected with pemphigus and pemphigoid. Abbreviations: EL, externally led; FDA, United States Food and Drug Administration; PFDD, Patient-Focused Drug Development. Data were obtained from https://www.fda.gov/industry/prescription-drug-user-fee-amendments/condition-specific-meeting-reports-and-other-information-related-patients-experience. On January 25, 2023, the International Pemphigus and Pemphigoid Foundation hosted an externally led PFDD meeting with the FDA in collaboration with international patient advocacy organizations PEM Friends (United Kingdom), Association Pemphigus Pemphigoïde France, and Pemphigus/Pemphigoid Friends Association (Japan). This commentary discusses patient and physician perspectives relevant to PFDD in pemphigus and pemphigoid. Pemphigus vulgaris and pemphigus foliaceus are autoimmune blistering diseases caused by autoantibodies directed against desmosomal adhesion proteins (Schmidt et al., 2019Schmidt E. Kasperkiewicz M. Joly P. Pemphigus.Lancet. 2019; 394: 882-894Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar). Pemphigoid encompasses a group of autoimmune blistering diseases caused by autoantibodies directed against various adhesion proteins of the dermal−epidermal junction (Egami et al., 2020Egami S. Yamagami J. Amagai M. Autoimmune bullous skin diseases, pemphigus and pemphigoid.J Allergy Clin Immunol. 2020; 145: 1031-1047Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar). Pemphigus and pemphigoid are orphan diseases. The rarity of the disease as well as limited access to specialty centers with experts in autoimmune blistering diseases often results in delays in diagnosis. The main complaints of patients are pruritus (particularly for bullous pemphigoid), pain from oral and genital erosions, dysphagia and weight loss, insomnia, fatigue, corticosteroid side effects, stigmatization from visible blisters and scarring, anxiety over the danger of treatment, and fear of relapse and having to take corticosteroids again. Pemphigoid can lead to erosions and scarring of the skin in addition to the eyes, larynx, esophagus, and genitourinary mucosa, in some cases resulting in blindness or death. Patients have elevated mortality relative to age-matched controls (Langan et al., 2008Langan S.M. Smeeth L. Hubbard R. Fleming K.M. Smith C.J. West J. Bullous pemphigoid and pemphigus vulgaris--incidence and mortality in the UK: population based cohort study.BMJ. 2008; 337: a180Crossref PubMed Scopus (472) Google Scholar). In addition, difficulties due to disease or complications of treatment can lead patients to lose work, income, and QOL (Sebaratnam et al., 2012Sebaratnam D.F. McMillan J.R. Werth V.P. Murrell D.F. Quality of life in patients with bullous dermatoses.Clin Dermatol. 2012; 30: 103-107Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar). Treatments for pemphigus and pemphigoid aim to stop the production of autoantibodies and inflammation. Corticosteroids are clinically approved for the treatment of pemphigus. Rituximab is clinically approved only for the pemphigus vulgaris subtype. Other therapies are prescribed off label for pemphigus, such as oral immunosuppressives and intravenous Ig. All therapies for pemphigoid (including immunosuppressives, anti-inflammatory agents, intravenous Ig, and mAbs such as omalizumab or dupilumab) are prescribed off label. The ideal goals of treatment are to have complete healing of blisters and resolution of the functional impairment associated with the disease, improve QOL, prevent disease recurrence, and limit treatment side effects related to corticosteroids and immunosuppressants. The efficacy of rituximab and corticosteroids for pemphigus is supported by two pivotal randomized controlled trials, indicating 40−90% rates of complete remission off corticosteroids with the use of maintenance rituximab infusions every 6 months (Chen et al., 2020Chen D.M. Odueyungbo A. Csinady E. Gearhart L. Lehane P. Cheu M. et al.Rituximab is an effective treatment in patients with pemphigus vulgaris and demonstrates a steroid-sparing effect.Br J Dermatol. 2020; 182: 1111-1119Crossref PubMed Scopus (40) Google Scholar; Joly et al., 2017Joly P. Maho-Vaillant M. Prost-Squarcioni C. Hebert V. Houivet E. Calbo S. et al.First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial.Lancet. 2017; 389: 2031-2040Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar; Werth et al., 2021Werth V.P. Joly P. Mimouni D. Maverakis E. Caux F. Lehane P. et al.Rituximab versus mycophenolate mofetil in Patients with pemphigus vulgaris.N Engl J Med. 2021; 384: 2295-2305Crossref PubMed Scopus (35) Google Scholar). Real-world data have described temporal outcomes of rituximab therapy for pemphigus vulgaris when used as part of standard clinical care, indicating that 43% of patients who receive repeated cycles of rituximab for relapsed or refractory disease achieve complete remission off corticosteroids (Tovanabutra et al., 2022Tovanabutra N. Bax C.E. Feng R. Kushner C.J. Payne A.S. Temporal outcomes after rituximab therapy for pemphigus vulgaris.J Invest Dermatol. 2022; 142: 1058-1064.e7Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar). Limitations of rituximab and corticosteroids include their transient therapeutic effect, which necessitates repeated infusions for disease control. Chronic immune suppression can lead to serious infections and impaired response to vaccines. Studies have shown increased mortality from COVID-19 in patients with autoimmune blistering disease treated with immunosuppressive therapies (French study Group on auto immune bullous skin diseases, and the French network of rare diseases in Dermatology, 2022Joly P. French study Group on auto immune bullous skin diseases, and the French network of rare diseases in Dermatology (FIMARAD)Incidence and severity of COVID-19 in patients with autoimmune blistering skin diseases: A nationwide study.J Am Acad Dermatol. 2022; 86: 494-497Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar). As a result, many patients feel that they can no longer safely do the things they used to do, such as gatherings with family and friends, vacation or work travel, dining out, and working in indoor office spaces. This has led to substantial social and professional isolation, in some cases forcing patients to seek other lines of work. In addition, chronic corticosteroid use can lead to numerous side effects, including weight gain, mood swings, insomnia, bruising, and stretch marks, in addition to serious medical complications such as hypertension, diabetes, glaucoma, cataracts, and bone fractures. These limitations highlight several unmet needs in pemphigus and pemphigoid therapy. The main problems in pemphigus management are relapsing and refractory disease, which require higher cumulative steroid doses and result in more side effects from therapy. Physicians and patients must remain vigilant for rare and potentially life-threatening infections due to immunosuppressive treatments. Patients are in need of drugs that are safe and well-tolerated, which avoid chronic immune suppression and the need for regular blood work. Oral, topical, or subcutaneous routes of administration would be beneficial to patients who may have difficulty arranging travel or logistics for intravenous infusions. Drugs that work fast to control disease would be important because most drugs for pemphigus and pemphigoid take several months to have therapeutic effects. For QOL, patients want to avoid the use of corticosteroids. Validated disease activity scales for pemphigus and pemphigoid have been developed over the last 15 years by an international panel of medical experts, who have performed studies to compare the reliability with the validity of different disease activity instruments (Hébert et al., 2019Hébert V. Boulard C. Houivet E. Duvert Lehembre S. Borradori L. Della Torre R. et al.Large international validation of ABSIS and PDAI pemphigus severity scores.J Invest Dermatol. 2019; 139: 31-37Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar; Masmoudi et al., 2021Masmoudi W. Vaillant M. Vassileva S. Patsatsi A. Quereux G. Moltrasio C. et al.International validation of the Bullous pemphigoid Disease Area Index severity score and calculation of cut-off values for defining mild, moderate and severe types of bullous pemphigoid.Br J Dermatol. 2021; 184: 1106-1112Crossref PubMed Scopus (26) Google Scholar; Murrell et al., 2012Murrell D.F. Daniel B.S. Joly P. Borradori L. Amagai M. Hashimoto T. et al.Definitions and outcome measures for bullous pemphigoid: recommendations by an international panel of experts.J Am Acad Dermatol. 2012; 66: 479-485Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar; Rosenbach et al., 2009Rosenbach M. Murrell D.F. Bystryn J.C. Dulay S. Dick S. Fakharzadeh S. et al.Reliability and convergent validity of two outcome instruments for pemphigus.J Invest Dermatol. 2009; 129: 2404-2410Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar). These studies have identified indices with high inter-rater and intrarater reliability, such as the Pemphigus Disease Area Index (PDAI) and the Bullous Pemphigoid Disease Area Index (BPDAI). Using the consensus-based standards for the selection of health measurement instruments, the PDAI and BPDAI perform better than the PASI or eczema activity and severity index (EASI), which have been used by the FDA for drug approvals in their respective diseases. Patients would value 50% or 75% improvement in pemphigus or pemphigoid disease activity, similar to endpoints that have previously led to drug approvals for atopic dermatitis (EASI-50) and psoriasis (PASI-75). A major challenge for pemphigus and pemphigoid drug development is that recent clinical trials in pemphigus and pemphigoid are being required by FDA to use an endpoint of clear or almost clear disease using a five-point Investigator’s Global Assessment (IGA) scale. However, IGAs have not been validated for pemphigus and pemphigoid. Validated instruments that separate disease activity from damage and are sensitive to changes in disease activity are better to show a response to therapy than IGA five-point scales. Past experience with a similar scale known as the Physician Global Assessment (PGA) shows that the PGA is far less reliable than autoimmune bullous disease−specific instruments (Rosenbach et al., 2009Rosenbach M. Murrell D.F. Bystryn J.C. Dulay S. Dick S. Fakharzadeh S. et al.Reliability and convergent validity of two outcome instruments for pemphigus.J Invest Dermatol. 2009; 129: 2404-2410Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar). In addition, in current IGA scales for pemphigus and pemphigoid, a single blister would be classified as mild disease and would prevent a patient from achieving the endpoint of clear or almost clear disease. For example, a patient with near total oral mucosal blistering (PDAI score = 42) could experience complete disease clearance with therapy but could develop one transient small blister (PDAI score = 1) on the day of the clinical trial assessment, which can easily occur given the skin and mucosal fragility in patients with pemphigus and pemphigoid. Despite a nearly 98% improvement in PDAI score, the single blister would result in an IGA score of 2 and would be counted as a treatment failure. Hence, the IGA definition of clear or almost clear disease is overly strict given the burden of disease and the risks and limitations of current therapies. Endpoints for pemphigus and pemphigoid clinical trials should be comparable with those used for other similar autoimmune diseases such as myasthenia gravis, which have received drug approvals on the basis of a two-point reduction in disease activity scales, without the requirement for complete or near complete disease clearance (Howard et al., 2021Howard Jr., J.F. Bril V. Vu T. Karam C. Peric S. Margania T. et al.Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): a multicentre, randomised, placebo-controlled, phase 3 trial.Lancet Neurol. 2021; 20 ([published correction appears in Lancet Neurol 2021;20:e5]): 526-536Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar). Less stringent criteria for almost clear including up to three small blisters or a PDAI/BPDAI activity score of up to 5 should be considered, or endpoints could be based on a minimal clinically important difference or percentage reduction in disease-specific activity scores. Consensus outcome definitions and endpoints for pemphigus and pemphigoid have been published (Murrell et al., 2012Murrell D.F. Daniel B.S. Joly P. Borradori L. Amagai M. Hashimoto T. et al.Definitions and outcome measures for bullous pemphigoid: recommendations by an international panel of experts.J Am Acad Dermatol. 2012; 66: 479-485Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar, Murrell et al., 2008Murrell D.F. Dick S. Ahmed A.R. Amagai M. Barnadas M.A. Borradori L. et al.Consensus statement on definitions of disease, end points, and therapeutic response for pemphigus.J Amer Acad Dermatol. 2008; 58: 1043-1046Abstract Full Text Full Text PDF PubMed Scopus (430) Google Scholar), which included definitions of complete or partial remission of systemic therapy or minimal doses of systemic therapy. These consensus definitions were intended to assess standard-of-care therapies (mainly oral immunosuppressives) because they were published before clinical trials for pemphigus and pemphigoid were in development in the United States. Endpoints for clinical trials may include complete or partial remission on minimal steroid doses or off steroids while remaining on the investigational therapy being evaluated. In pivotal clinical trials of rituximab for pemphigus, the last rituximab infusion was performed 6 months before assessment of the primary endpoint, a logical timepoint because the effect of rituximab on total B-cell counts lasts longer than 6 months. In the context of rituximab and corticosteroids, off therapy means off steroids for 8 weeks—this definition was not intended to indicate that clinical trials of other therapies with different mechanisms of action must achieve disease remission off the investigational therapy being tested. For example, medications with a shorter pharmacodynamic effect than rituximab (such as efgartigimod, whose effects on IgG begin to reverse within a week of stopping the drug) need to be continued to the endpoint to see the steroid-sparing effect. Minimal steroid doses for endpoints should also be considered carefully because prednisone doses of 10 mg or greater can have a substantial therapeutic effect. The oral Bruton’s tyrosine kinase inhibitor rilzabrutinib failed to show a significant difference compared with placebo in a phase 3 trial for pemphigus when a minimal steroid dose of 10 mg daily was evaluated in the comparator arm. A minimal steroid dose of 5 mg daily or a weight-based dose such as 0.1 mg/kg/day may be more appropriate to show a difference compared with steroids alone. Defining meaningful improvement is critical. In the PEMPHIX phase 3 randomized controlled trial of rituximab and corticosteroids, 40% of patients achieved the primary endpoint of complete remission off steroids. However, 87.2% of clinicians and 80.9% of patients rated the disease as very much improved at week 52, despite not having sustained a complete response to therapy. In the nomacopan clinical trial in bullous pemphigoid, a 75% reduction in BPDAI score was associated with a 100% improvement in QOL in some patients. These data indicate that patients’ QOL can be restored despite not achieving complete remission of disease activity. Hence, requiring complete disease clearance or an IGA endpoint of clear or almost clear for clinical trials in pemphigus and pemphigoid is not tied to meaningful response for patients. The use of nonvalidated and insensitive IGA scales will ultimately impede drug development for pemphigus and pemphigoid and prevent effective therapies from getting to patients. Dozens of patients with pemphigus and pemphigoid shared their experiences living with the disease. Current therapies present barriers to care that add to the already overwhelming burden patients face from the symptoms of the disease. Patients often have to try multiple therapies to find one that achieves disease remission. Many drugs used to treat pemphigus and pemphigoid have to be prescribed off label, which can create financial difficulty and delays in treatment. Additional and better treatment options are needed. Other challenges included delay in diagnosis, the physical and mental toll of the disease on themselves and their family, debilitating pain and itch from widespread lesions, limited access to blistering disease specialists or therapy, and the need to seek other lines of work owing to constraints imposed by disease or its therapy. The impact of disease on their QOL, patient perspectives on the limitations of current therapies, what characteristics they would look for in a new drug, and what outcomes of therapy are desirable were discussed. The PFDD meeting aims to highlight the physical, psychological, and emotional impact of disease on patients to identify what is most important to those living with these diseases. After the PFDD meeting, a Voice of the Patient Meeting Report will be published, summarizing input shared by patients and their caregivers, along with results of the patient polls and survey (https://www.fda.gov/industry/prescription-drug-user-fee-amendments/condition-specific-meeting-reports-and-other-information-related-patients-experience). Rebecca Strong: http://orcid.org/0009-0007-8957-3655 Dedee F. Murrell: http://orcid.org/0000-0003-2971-0199 PD is an employee with the International Pemphigus & Pemphigoid Foundation. PJ is a consultant for Roche, Amgen, Principia Biopharma, Argenx, AstraZeneca, Thermo Fisher, Sanofi Regeneron, Janssen, and Akari. DFM is a consultant/investigator for Roche, GlaxoSmithKline, Novartis, Principia Bio, Immune Pharmaceuticals, Eli Lilly, Sanofi, argenx, Astra Zeneca, Bristol Myers Squibb, Genentech, Janssen, Pfizer, and Regeneron. VPW is a consultant for AbbVie/Abbott, AnaptysBio, Argenx, Astra Zeneca, Biogen, Bristol Myers Squibb, Eli Lilly, EMD Serono, Galderma, Genentech, Gilead, GlaxoSmithKline, Horizon Therapeutics, Janssen, Kirin, Merck/Merck Sharp & Dohme, Nektar, Novartis, Octapharma, Pfizer, Principia, Regeneron, Rome Pharmaceuticals, and Sanofi and received grant/research support from Amgen, argenx, Biogen, Corbus, CSL Behring, Genentech, Horizon Therapeutics, Pfizer, Regeneron, and Syntimmune. ASP holds equity, grants, payments, and patent licensing from Cabaletta Bio and consults for Janssen. We would like to thank Amethyst Yale, Anna Lane, and the patients with pemphigus and pemphigoid who graciously gave their time and shared their experiences.

Abnormal Newborn Screening for Severe Combined Immunodeficiency due to CD4 T cell lymphopenia associated with Heterozygous FOXN1 Variants in the Forkhead Domain

FOXN1 performs a pivotal role in the development of thymic epithelium. Homozygous FOXN1 deficiency results in T-B+NK+ SCID while FOXN1 haploinsufficiency is associated with T cell lymphopenia and nail dystrophy. We report two patients with variants of uncertain significance (VUS) in FOXN1 who presented with lymphopenia detected on newborn screening.Patient A is a 17-month-old female born to non-consanguineous parents who presented with lowT-cell receptor excision circles (TRECs). At 2 weeks old, her lymphocyte subset panel revealed low T cells, but normal B and NK cells (Table 1). Follow up at 3 months revealed uptrending T cells and significantly decreased B cells. She had no concerning clinical features or infections at that time. By 6 months, her T cells were again downtrending, but her B cells had normalized. She required antibiotics for acute otitis media, which quickly resolved. At 15 months, T cell lymphopenia persisted (Figure 2). Her infection history was reassuring, developmental milestones met and physical exam notable only for spooned nails.Patient B is a 4-month-old female also born to non-consanguineous parents presenting with low TRECs. Initial workup at 5 days revealed T cell lymphopenia, but normal B and NK cells (Table 1). At 2 months, CD4 lymphopenia persisted though CD8T cells normalized (Figure 2). She had a self-limiting upper respiratory infection, but otherwise unremarkable infection history. Development and physical exam were normal.A targeted 429-gene panel for inborn errors of immunity revealed heterozygous FOXN1 VUSs in both Patient A (c.890T > G, p.Ile297Ser) and Patient B (c.890T > C, p.Ile297Thr). Patient A's variant was not present in population databases. Patient B's variant has been observed (gnomAD frequency of 0.007%) but not present in population databases for the patient's ethnicities. Surprisingly, both are located at the same position within the Forkhead domain (Figure 1). Algorithms to predict the effect of missense changes on FOXN1 protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all predicted these variants as likely to be disruptive. Further understanding of the phenotypes associated with heterozygous FOXN1 variants of uncertain significance is crucial to guiding diagnostics, treatment, and prognosis. Table 1Lymphocyte panel results at original presentation (Patient A: 2 weeks old, Patient B: 5 days old). Reference ranges obtained from J Allergy Clin Immunol, Volume 112, Number 5, pp 973–980, November 2003VariantCD4+ CD45RA+ (Naïve CD4+ T Cells, cells/μL)CD4+ CD45RO+ (Memory CD4+ T cells, cells/μL)CD8+ T Cells (cells/μL)CD19+ B Cells (cells/μL)CD16+ CD56+ (NK Cells, cells/μL)Patient Ac.890T>G (p.Ile297Ser)633100518423700Patient Bc.890T>C (p.Ile297Thr)569126122610311Ref range (0–3 months)1200–370060–900560–1700300–2000170–1700 [Display omitted] [Display omitted]

Associations between serum per- and polyfluoroalkyl substances and asthma morbidity in the National Health and Nutrition Examination Survey (2003-18).

Per- and polyfluoroalkyl substances (PFAS) are a class of chemicals widely used in manufacturing and are highly resistant to degradation, so they accumulate in the environment. Serum concentrations of these so-called forever chemicals have been associated with impairment of innate and adaptive immune responses. The relationship between serum PFAS levels and asthma morbidity has not been studied. We tested the association between serum PFAS concentration and asthma exacerbations. We performed secondary analysis of data from the National Health and Nutrition Examination Survey (NHANES, 2003-18). We fit multivariable logistic regression models to estimate odds ratios and 95% CIs for asthma exacerbation in the prior 12 months, given serum concentrations of PFAS. Models were adjusted for relevant covariates. Of 1101 participants with self-reported current asthma and available serum PFAS data, we observed that higher serum perfluorooctanoic and perfluorodecanoic acids were associated with greater odds of asthma attacks in the previous 12 months (respectively, adjusted odds ratio 1.16, 95% CI 1.01, 1.33; and adjusted odds ratio 1.21, 95% CI 1.03, 1.43). After stratification by age, the association between perfluorooctanoic acid and asthma attacks was significant in the 12-18-year-old group only (adjusted odds ratio 1.56, 95% CI 1.06, 2.31). No significant relationships were observed between PFAS and asthma-related emergency department visits. After correction for multiple comparison testing, none of the associations reached the threshold of significance. The role of these bioaccumulative forever chemicals in susceptibility to asthma attacks warrants further examination in longitudinal studies. (J Allergy Clin Immunol Global 2023;2:100078.).

Prevelance of Common Aeroallergens in Allergic Rhinitis and its Correlation with Bronchial Asthma: A Study on 798 Patients by Skin Prick Test.

Allergic rhinitis affects 30% of the Indian population (Dey et al. in Int Arch Allergy Immunol 178:60-65, 2019). Patients can be sensitive to single or multiple allergens. Polysensitization is more common (Bousquet et al. in Ann Epidemiol 20:797-803, 2010; Arbes et al. in J Allergy Clin Immunol 116:377-383, 2005). Sensitization to multiple allergens may have a role in the severity and the association of Asthma in such patients. A total of 798 patients with allergic rhinitis (SFAR ≥ 7) were included. Disease severity and associated symptoms were evaluated using questionnaire. Each patient underwent a Skin prick test with an allergen panel of 35 allergens each (Annesi-Maesano et al. in Allergy 57:107-114, 2002) and the results were evaluated to study the association of asthma and severity of Allergic rhinitis. Data consisting of 389 (48.7%) males and 409 (51.3%) females were assessed. A total of 82.2% of the study population of symptomatic patients were sensitized to at least one of the allergens. Seventy patients (8.78%) had associated asthma. Forty-four patients were polysensitized and fifteen were mono sensitized. Among polysensitized patients, 36 patients had sensitization to at least 6 different allergens. Dermatophagoides pteronyssinus was the most common allergen among asthma patients. This study provides a thorough knowledge of locally prevalent aeroallergens which is essential for the prompt diagnosis and treatment of allergic patients. Skin prick test can be a non-invasive vital tool in analyzing patterns of allergen exposure, the prevalence of allergen, sensitizing potential of different allergens in that specific geographic area.

Could an electronic tool to assess asthma control with a 1-day timeframe be useful for clinical management?

Asthma is a heterogeneous disease defined in part by a history of respiratory symptoms that vary over time and in intensity. Therefore, symptom assessment is at the core of asthma management,1Reddel HK Bacharier LB Bateman ED et al.Global Initiative for Asthma Strategy 2021: executive summary and rationale for key changes.Am J Respir Crit Care Med. 2022; 205: 17-35Crossref PubMed Scopus (60) Google Scholar and leveraging mobile health (mHealth) apps to remotely monitor it is a promising strategy in clinical practice and research, especially because most of the population owns a smartphone in the present day.2Pew Research CenterMobile technology and home broadband 2021.https://pewresearch-org-preprod.go-vip.co/internet/2021/06/03/mobile-technology-and-home-broadband-2021/Date: June 3, 2021Date accessed: February 7, 2023Google Scholar However, the wide variety of mobile apps available for asthma with different purposes, such as health education, symptom recording, or medication reminders,3Himes BE Leszinsky L Walsh R Hepner H Wu AC Mobile health and inhaler-based monitoring devices for asthma management.J Allergy Clin Immunol Pract. 2019; 7: 2535-2543Summary Full Text Full Text PDF PubMed Scopus (29) Google Scholar could lead to fragmented information. In The Lancet Digital Health, Bernardo Sousa-Pinto and colleagues4Sousa-Pinto B Jácome C Pereira A M et al.Development and validation of an electronic daily control score for asthma (e-DASTHMA): a real-world direct patient data study.Lancet Digit Health. 2023; (published online March 3.)https://doi.org/10.1016/S2589-7500(23)00020-1Google Scholar present the development and validation of a score for electronic daily asthma control (e-DASTHMA). They describe the analysis of 135 635 1-day observations from 1662 users of the MASK-air app who were treated for asthma. First, they developed a set of data-driven scores based on reported asthma symptoms (from a 0–100 visual analogue scale [VAS]) and medication administered, and assessed their construct validity, test–retest reliability, and responsiveness. Second, they performed an external validation using a cohort of patients with physician-diagnosed asthma who reported the daily effect of asthma symptoms on work or school activities through another app (InspirerMundi). This external validation also included a comparison of the developed scores with the Global Initiative for Asthma (GINA) patient classification rated by the physician, through area under the receiver operating characteristic curves. e-DASTHMA was referred to as a digital biomarker that can complement existing instruments that measure asthma control within longer time frames (1–4 weeks). This study4Sousa-Pinto B Jácome C Pereira A M et al.Development and validation of an electronic daily control score for asthma (e-DASTHMA): a real-world direct patient data study.Lancet Digit Health. 2023; (published online March 3.)https://doi.org/10.1016/S2589-7500(23)00020-1Google Scholar uses a novel approach to measure asthma control by focusing on both symptoms and medication administered during a single day. Existing questionnaires either do not have a specific question about medication (the Asthma Control Test5Schatz M Sorkness CA Li JT et al.Asthma control test: reliability, validity, and responsiveness in patients not previously followed by asthma specialists.J Allergy Clin Immunol. 2006; 117: 549-556Summary Full Text Full Text PDF PubMed Scopus (895) Google Scholar and Asthma Control Questionnaire6Juniper EF Byrne PMO Guyatt GH Ferrie PJ King DR Development and validation of a questionnaire to measure asthma control.Eur Respir J. 1999; 14: 902-907Crossref PubMed Scopus (1817) Google Scholar) or have a single question that only addresses the need to increase medication (Control of Allergic Rhinitis and Asthma Test7Fonseca JA Nogueira-Silva L Morais-Almeida M et al.Validation of a questionnaire (CARAT10) to assess rhinitis and asthma in patients with asthma.Allergy. 2010; 65: 1042-1048Crossref PubMed Scopus (117) Google Scholar). e-DASTMA, however, specifically asks about the medication administered that day. For example, consider two people with asthma reporting the same amount of symptoms (VAS 30), but with different treatments. The patient who took an inhaled corticosteroid with formoterol that day would have a e-DASTHMA score of 25·6, and the patient who took an inhaled corticosteroid and a short-acting β-agonist would have a score of 32·8, which according to the cutoff point for e-DASTHMA (≥28·9) indicates worse asthma control. Hence, the second patient would be a candidate for a treatment change according to the GINA stepwise approach1Reddel HK Bacharier LB Bateman ED et al.Global Initiative for Asthma Strategy 2021: executive summary and rationale for key changes.Am J Respir Crit Care Med. 2022; 205: 17-35Crossref PubMed Scopus (60) Google Scholar after assessing other aspects of asthma management, such as treatment adherence or inhaler technique. We agree with the authors that e-DASTHMA would avoid recall biases and might allow for the better identification of exacerbations than other asthma control tools with longer time frames. However, a 1-day time frame does not imply reporting every day, which would be burdensome and could jeopardise feasibility. In fact, in this study,4Sousa-Pinto B Jácome C Pereira A M et al.Development and validation of an electronic daily control score for asthma (e-DASTHMA): a real-world direct patient data study.Lancet Digit Health. 2023; (published online March 3.)https://doi.org/10.1016/S2589-7500(23)00020-1Google Scholar 2955 patients were excluded because they did not provide data in 3 different months on the MASK-air app (only reporting 5 days on average), whereas the included participants reported 82 days on average (10% of the number of days of the study period). Is this a poor response rate for a tool with a 1-day timeframe? Would completing e-DASTHMA only when symptoms worsen be enough to generate valuable information for decision making? It should be considered that the users are patients with a chronic condition, which is already a burden per se. The term digital biomarker has generated controversy and currently does not have a consensus.8Montag C Elhai JD Dagum P On blurry boundaries when defining digital biomarkers: how much biology needs to be in a digital biomarker?.Front Psychiatry. 2021; 12740292Crossref Scopus (7) Google Scholar Biomarker has been defined as a characteristic measured as an indicator of biological or pathogenic processes, or responses to an exposure or intervention (eg, molecular, histological, radiographical, or physiological characteristics), and it does not include an assessment of how an individual feels, functions, or survives.9FDA-NIH Biomarker Working GroupBEST (Biomarkers, EndpointS, and other Tools) resource.https://www.ncbi.nlm.nih.gov/books/NBK338449/?report=readerDate accessed: February 10, 2023Google Scholar Hence, a patient-reported outcome measure, such as reported symptoms and medication, does not fit the definition of a biomarker. Therefore, despite the value of using a daily asthma control score constructed from patient-reported variables collected through an mHealth app, it is questionable whether it can be considered a digital biomarker. To avoid confusion or creating false expectations about the methods used, we would recommend to use the term indirect digital biomarker, a concept previously proposed8Montag C Elhai JD Dagum P On blurry boundaries when defining digital biomarkers: how much biology needs to be in a digital biomarker?.Front Psychiatry. 2021; 12740292Crossref Scopus (7) Google Scholar to encompass digital footprints linked to symptoms that might act as latent variables indirectly linked to a biological variable. In summary, this study shows the use of real-world data obtained via an mHealth app to create e-DASTHMA, a promising tool for the assessment of asthma control over a 1-day period. Further research is needed to support the content validity (based on expert panel judgements) and suitability for implementing e-DASTHMA in research and clinical practice. Financial support for this comment was provided through grants by the Generalitat de Catalunya (AGAUR 2021 SGR 00624) and by the Universidad de Costa Rica (OAICE-85–2019). Development and validation of an electronic daily control score for asthma (e-DASTHMA): a real-world direct patient data studye-DASTHMA is a good tool for the daily assessment of asthma control. This tool can be used as an endpoint in clinical trials as well as in clinical practice to assess fluctuations in asthma control and guide treatment optimisation. Full-Text PDF Open Access

Bringing dietary therapy for eosinophilic oesophagitis under scientific scrutiny

In The Lancet Gastroenterology & Hepatology, Kara L Kliewer and colleagues report results from the first major multicentre, randomised trial of dietary therapy in patients with eosinophilic oesophagitis. 1 Kliewer KL Gonsalves N Dellon ES et al. One-food versus six-food elimination diet therapy for the treatment of eosinophilic oesophagitis: a multicentre, randomised, open-label trial. Lancet Gastroentrol Hepatol. 2023; (published online Feb 27.)https://doi.org/10.1016/S2468-1253(23)00012-2 Google Scholar The detailed study of patient outcomes, along with the assessment of transcriptomic and other markers, give valuable insights into the benefits and limitations of dietary therapy. Their objective evidence shows that the value of dietary therapy, in particular the six-food elimination diet (6FED), might have been overestimated in previous studies. 2 Gonsalves N Yang GY Doerfler B Ritz S Ditto AM Hirano I Elimination diet effectively treats eosinophilic esophagitis in adults; food reintroduction identifies causative factors. Gastroenterology. 2012; 142: 1451-1459 Summary Full Text Full Text PDF PubMed Scopus (480) Google Scholar , 3 Lucendo AJ Arias A Gonzalez-Cervera J et al. Empiric 6-food elimination diet induced and maintained prolonged remission in patients with adult eosinophilic esophagitis: a prospective study on the food cause of the disease. J Allergy Clin Immunol. 2013; 131: 797-804 Summary Full Text Full Text PDF PubMed Scopus (305) Google Scholar , 4 Infante J Modolell I Alcedo J et al. Step-up empiric elimination diet for pediatric and adult eosinophilic esophagitis: the 2-4-6 study. J Allergy Clin Immunol. 2018; 141: 1365-1372 Summary Full Text Full Text PDF PubMed Scopus (140) Google Scholar In their study, histological remission to less than 15 eosinophils per high-power field (eos/hpf) occurred in only 23 (34%) of 67 patients on the one-food elimination diet (1FED; eliminating animal milk) and 25 (40%) of 62 patients on the 6FED at 6 weeks. Kliewer and colleagues also show that the margin between 1FED and 6FED is not significant in terms of both histological remission and symptom improvement. Given the complexity of life when trying to avoid six foods and the great difficulty in sustaining such an effort for more than a year, this evidence on the value of keeping dietary therapy simple is important. As well as being easier to comply with, a single-food elimination diet (or perhaps a two-food elimination diet avoiding milk and wheat 2 Gonsalves N Yang GY Doerfler B Ritz S Ditto AM Hirano I Elimination diet effectively treats eosinophilic esophagitis in adults; food reintroduction identifies causative factors. Gastroenterology. 2012; 142: 1451-1459 Summary Full Text Full Text PDF PubMed Scopus (480) Google Scholar ) requires fewer repeat endoscopies than the seven endoscopies needed to determine which foods are relevant in the multifood approach. One-food versus six-food elimination diet therapy for the treatment of eosinophilic oesophagitis: a multicentre, randomised, open-label trialHistological remission rates and improvements in histological and endoscopic features were similar after 1FED and 6FED in adults with eosinophilic oesophagitis. 6FED had efficacy in just less than half of 1FED non-responders and steroids had efficacy in most 6FED non-responders. Our findings indicate that eliminating animal milk alone is an acceptable initial dietary therapy for eosinophilic oesophagitis. Full-Text PDF

Perioperative Considerations in Patients With Mast Cell Activation Syndrome

Mast Cell Activation Syndrome (MCAS) is a hypersensitivity disorder, and subset of Mast Cell Disease, which has become increasingly recognized over the past three decades. Since the first case reports were published in the late 1980s, 1 Akin C Valent P Metcalfe DD. Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol. 2010; 126 (e4): 1099-1104 Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar , 2 Roberts LJ. Carcinoid syndrome and disorders of systemic mast-cell activation including systemic mastocytosis. Endocrinol Metab Clin North Am. 1988; 17: 415-436 Abstract Full Text PDF PubMed Google Scholar significant advancements have been made to better understand MCAS characteristics and determine effective treatment strategies. With improvements in recognition and modification of diagnostic criteria, it is estimated that up to 17% of the population has MCAS, 3 Buttgereit T Gu S Carneiro-Leão L et al. Idiopathic mast cell activation syndrome is more often suspected than diagnosed – a prospective real-life study. Allergy. 2022; 77: 2794-2802 Crossref Scopus (2) Google Scholar , 4 Afrin LB Ackerley MB Bluestein LS et al. Diagnosis of mast cell activation syndrome: a global “consensus-2”. Diagnosis (Berl). 2020; 8: 137-152 Crossref PubMed Scopus (34) Google Scholar highlighting the importance of clinician education regarding this recently identified disorder. To better understand the pathophysiology of MCAS—and the pharmacologic interventions effective in its management—it is important to first begin by discussing the normal activity of mast cells.

An emerging new respiratory pathogen, Lophomonas blattarum, found in bronchoalveolar lavage in an immunodeficient patient with asthma

Infections with unusual organisms are frequently found in patients with primary and acquired immunodeficiency. It is estimated that 1 in 1200 individuals in the United States have a diagnosis of primary immunodeficiency, with common variable immunodeficiency (CVID) accounting for approximately 35% of the cases. 1 Boyle JM Buckley RH. Population prevalence of diagnosed primary immunodeficiency diseases in the United States. J Clin Immunol. 2007; 27: 497-502 Crossref PubMed Scopus (317) Google Scholar CVID is a heterogeneous disorder that is primarily a defect of the humoral immune system, although approximately 50% of patients have T cell defects as well. Patients with CVID have increased susceptibility to infections, particularly of the upper and lower respiratory tract, and increased incidence of autoimmune diseases and neoplasms. 2 Bonilla FA Kahn DA Ballas ZK Chinen J Frank MM Hsu JT et al. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. 2015; 136 (1186-1205.e1-e78) Abstract Full Text Full Text PDF PubMed Scopus (394) Google Scholar Common pathogens causing respiratory tract infections in CVID include Streptococcus pneumoniae, Haemophilus influenza, and Staphylococcus aureus.2 Bonilla FA Kahn DA Ballas ZK Chinen J Frank MM Hsu JT et al. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. 2015; 136 (1186-1205.e1-e78) Abstract Full Text Full Text PDF PubMed Scopus (394) Google Scholar Although parasitic infections can occur, the most often described is Giardia infection of the gastrointestinal tract. 2 Bonilla FA Kahn DA Ballas ZK Chinen J Frank MM Hsu JT et al. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. 2015; 136 (1186-1205.e1-e78) Abstract Full Text Full Text PDF PubMed Scopus (394) Google Scholar Infections with other parasites particularly of the respiratory tract have rarely been described. Lophomonas blattarum is a flagellated protozoa found in the gut of cockroaches and termites which has been found to cause rare bronchopulmonary infections, although there are no published cases in the United States to date. 3 Martinez-Girón R Cornelis van Woerden H. Lophomonas blattarum and bronchopulmonary disease. J Med Microbiol. 2013; 62: 1641-1648 Crossref Scopus (35) Google Scholar ,4 Chaudhury A Parija SC. Lophomonas blattarum: a new flagellate causing respiratory tract infections. Trop Parasitol. 2020; 10: 7-11 Google Scholar The most often reported symptoms of L blattarum infection are fever and productive cough. The infection is usually responsive to treatment with metronidazole. 3 Martinez-Girón R Cornelis van Woerden H. Lophomonas blattarum and bronchopulmonary disease. J Med Microbiol. 2013; 62: 1641-1648 Crossref Scopus (35) Google Scholar ,4 Chaudhury A Parija SC. Lophomonas blattarum: a new flagellate causing respiratory tract infections. Trop Parasitol. 2020; 10: 7-11 Google Scholar

Recurrent wheezing phenotypes after severe bronchiolitis and progression to asthma

Recurrent wheezing, a common diagnosis after severe bronchiolitis, has multiple phenotypes of uncertain relation to childhood asthma. Among infants hospitalized for bronchiolitis, we investigated the relation of three 2020 recurrent wheezing phenotypes by age 4 years to asthma by age 6 years. In a 17-center cohort study of infants hospitalized with bronchiolitis, we investigated the National Heart, Lung, and Blood Institute (NHLBI) 2020-defined recurrent wheezing phenotype and 2 additional phenotypes based on this definition: multitrigger and severe. As a sensitivity analysis, we examined the NHLBI 2007 recurrent wheezing phenotype. We calculated the proportion of study subjects who developed asthma by age 6 years and used multivariable logistic regression to examine characteristics associated with the highest-risk 2020 phenotype. Of 921 infants, 632 (69%) developed NHLBI 2020 recurrent wheezing, 734 (80%) developed multitrigger wheezing, and 165 (18%) developed severe wheezing by age 4 years; in addition, 296 (32%) developed NHLBI 2007-defined recurrent wheezing by age 3 years. Of 862 children with sufficient data (94%), 239 (28%) developed asthma by age 6 years. The proportions of children who progressed to asthma were as follows: 33% of those with NHLBI 2020-defined wheezing, 33% of those with multitrigger wheezing, 54% of those with severe wheezing, and 52% of those with NHLBI 2007-defined recurrent wheezing. The children with the severe phenotype who developed asthma had the associated characteristics preterm birth, child eczema, maternal asthma, and non-respiratory syncytial virus infection. Most infants with severe bronchiolitis developed the NHLBI 2020-defined recurrent wheezing phenotype by age 4 years. Depending on the phenotype, 33% to 54% will develop asthma by age 6 years. Future research will examine whether earlier treatment of high-risk phenotypes will improve wheezing symptoms and potentially prevent childhood asthma. (J Allergy Clin Immunol Global 2023;2:84-7.).