Publications by authors named "Edward W Cowen"

128 Publications

Subsequent Cancers in Patients Affected with Moderate or Severe Chronic Graft-versus-Host Disease.

Transplant Cell Ther 2021 Aug 8. Epub 2021 Aug 8.

Immune Deficiency Cellular Therapy Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Electronic address:

Subsequent cancer (SC) is a significant cause of morbidity and mortality in long-term survivors after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Chronic graft-versus-host disease (cGVHD) and treatment-related immunosuppression have been recognized as risk factors for SC. This study sought to investigate the incidence and risk factors for SC in patients with established cGVHD, assessed separately for onset of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)-categorized into nonmelanoma skin cancer (NMSC)-and all cancers other than NMSC. Two hundred and four patients were enrolled in the prospective cross-sectional cGVHD Natural History Study and underwent comprehensive clinical evaluation. Patients were followed-up with an annual survey. The cumulative incidences of NMSC and cancers other than NMSC with competing risks were estimated separately, and transplantation- and cGVHD-related factors were assessed for association with outcomes using Gray's test and multivariable Cox models. The time period for all analyses began at 2 years postevaluation to restrict analyses to patients presumed to not have had SC present at evaluation. Nineteen patients were diagnosed with NMSC and 19 were diagnosed with cancers other than NMSC, with 10-year cumulative incidences of 15.5% (95% confidence interval, 9.0% to 27.6%) and 13.8% (95% CI, 8.2% to 20.8%), respectively. Age at transplantation (hazard ratio [HR], 1.94; 95% CI, 1.23 to 3.06) and higher C-reactive protein level at evaluation (HR, 9.49; 95% CI, 1.26 to 71.58) were jointly associated with NMSC, and gastrointestinal cGVHD at evaluation (HR, 0.26; 95% CI, 0.09 to 0.78) was associated with reduced risk of NMSC. T cell depletion at transplantation (HR, 3.09; 95% CI, 1.17 to 8.20), lymphoma as an indication for transplantation (HR, 3.96; 95% CI, 1.56 to 10.05), and oral cGVHD severity at evaluation (HR, 4.36; 95% CI, 1.52 to 12.46) were jointly associated with cancers other than NMSC. This study estimates the incidence of SC in a population of allo-HSCT recipients with severe cGVHD and identifies correlations with the subsequent development of SC. These factors seem to differ between NMSC and cancers other than NMSC. Further longitudinal investigations accounting for dynamic and cumulative processes are needed to improve our understanding and management of SC.
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http://dx.doi.org/10.1016/j.jtct.2021.08.001DOI Listing
August 2021

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. The 2020 Highly morbid forms report.

Transplant Cell Ther 2021 Jun 10. Epub 2021 Jun 10.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, University of Washington, Seattle, Washington.

Chronic graft-versus-host disease (GVHD) can be associated with significant morbidity, in part because of nonreversible fibrosis, which impacts physical functioning (eye, skin, lung manifestations) and mortality (lung, gastrointestinal manifestations). Progress in preventing severe morbidity and mortality associated with chronic GVHD is limited by a complex and incompletely understood disease biology and a lack of prognostic biomarkers. Likewise, treatment advances for highly morbid manifestations remain hindered by the absence of effective organ-specific approaches targeting "irreversible" fibrotic sequelae and difficulties in conducting clinical trials in a heterogeneous disease with small patient numbers. The purpose of this document is to identify current gaps, to outline a roadmap of research goals for highly morbid forms of chronic GVHD including advanced skin sclerosis, fasciitis, lung, ocular and gastrointestinal involvement, and to propose strategies for effective trial design. The working group made the following recommendations: (1) Phenotype chronic GVHD clinically and biologically in future cohorts, to describe the incidence, prognostic factors, mechanisms of organ damage, and clinical evolution of highly morbid conditions including long-term effects in children; (2) Conduct longitudinal multicenter studies with common definitions and research sample collections; (3) Develop new approaches for early identification and treatment of highly morbid forms of chronic GVHD, especially biologically targeted treatments, with a special focus on fibrotic changes; and (4) Establish primary endpoints for clinical trials addressing each highly morbid manifestation in relationship to the time point of intervention (early versus late). Alternative endpoints, such as lack of progression and improvement in physical functioning or quality of life, may be suitable for clinical trials in patients with highly morbid manifestations. Finally, new approaches for objective response assessment and exploration of novel trial designs for small populations are required.
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http://dx.doi.org/10.1016/j.jtct.2021.06.001DOI Listing
June 2021

Methods to Assess Disease Activity and Severity in Cutaneous Chronic Graft-versus-Host Disease: A Critical Literature Review.

Transplant Cell Ther 2021 Sep 6;27(9):738-746. Epub 2021 Jun 6.

Department of Dermatology, Mayo Clinic, Rochester, Minnesota. Electronic address:

Chronic graft-versus-host disease (cGVHD), a potentially debilitating complication of hematopoietic cell transplantation, confers increased risk for mortality. Whereas treatment decisions rely on an accurate assessment of disease activity/severity, validated methods of assessing cutaneous cGVHD activity/severity appear to be limited. In this study, we aimed to identify and evaluate current data on the assessment of disease activity/severity in cutaneous cGVHD. Using modified PRISMA methods, we performed a critical literature review for relevant articles. Our literature search identified 1741 articles, of which 1635 were excluded as duplicates or failure to meet inclusion criteria. Of the included studies (n = 106), 39 (37%) addressed clinical and/or histopathologic parameters, 53 (50%) addressed serologic parameters, 8 (7.5%) addressed imaging parameters, and 6 (5.5%) addressed computer-based technologies. The only formally validated metric of disease activity/severity assessment in cutaneous cGVHD is the National Institutes of Health consensus scoring system, which is founded on clinical assessment alone. The lack of an objective marker for cGVHD necessitates further studies. An evaluation of the potential contributions of serologic, imaging, and/or computer-based technologies is warranted.
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http://dx.doi.org/10.1016/j.jtct.2021.05.030DOI Listing
September 2021

Adult diagnosis of congenital serine biosynthesis defect: A treatable cause of progressive neuropathy.

Am J Med Genet A 2021 07 4;185(7):2102-2107. Epub 2021 Jun 4.

National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.

A woman with ichthyosis, contractures, and progressive neuropathy represents the first case of phosphoserine aminotransferase deficiency diagnosed and treated in an adult. She has novel compound heterozygous mutations in the gene PSAT1. Treatment with high dose oral L-serine completely resolved the ichthyosis. Consideration of this diagnosis is important because early treatment with L-serine repletion can halt progression of neurodegeneration and potentially improve neurological disabilities. As exome sequencing becomes more widely implemented in the diagnostic evaluation of progressive neurodegenerative phenotypes, adult neurologists and geneticists will increasingly encounter later onset manifestations of inborn errors of metabolism classically considered in infancy and early childhood.
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http://dx.doi.org/10.1002/ajmg.a.62245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8330494PMC
July 2021

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IIa. The 2020 Clinical Implementation and Early Diagnosis Working Group Report.

Transplant Cell Ther 2021 07 9;27(7):545-557. Epub 2021 Apr 9.

Division of Stem Cell Transplantation and Cellular Therapy, Dana-Farber Cancer Institute, Boston, Massachusetts.

Recognition of the earliest signs and symptoms of chronic graft-versus-host disease (GVHD) that lead to severe manifestations remains a challenge. The standardization provided by the National Institutes of Health (NIH) 2005 and 2014 consensus projects has helped improve diagnostic accuracy and severity scoring for clinical trials, but utilization of these tools in routine clinical practice is variable. Additionally, when patients meet the NIH diagnostic criteria, many already have significant morbidity and possibly irreversible organ damage. The goals of this early diagnosis project are 2-fold. First, we provide consensus recommendations regarding implementation of the current NIH diagnostic guidelines into routine transplant care, outside of clinical trials, aiming to enhance early clinical recognition of chronic GVHD. Second, we propose directions for future research efforts to enable discovery of new, early laboratory as well as clinical indicators of chronic GVHD, both globally and for highly morbid organ-specific manifestations. Identification of early features of chronic GVHD that have high positive predictive value for progression to more severe manifestations of the disease could potentially allow for future pre-emptive clinical trials.
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http://dx.doi.org/10.1016/j.jtct.2021.03.033DOI Listing
July 2021

Predictors of hematologic malignancy relapse in patients with advanced chronic graft-versus-host disease.

Bone Marrow Transplant 2021 07 1;56(7):1584-1592. Epub 2021 Feb 1.

Immune Deficiency Cellular Therapy Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Building 10, Room CRC 4-3130, Bethesda, MD, 20892, USA.

Malignancy relapse remains a major barrier to treatment success in patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Chronic graft-versus-host disease (cGVHD) markedly reduces hematologic malignancy relapse risk, but relapses still occur in these patients. Patients (n = 275) with moderate or severe cGVHD were enrolled on the National Cancer Institute (NCI) prospective cross-sectional natural history study (NCT00092235). Subjects were median 36 months after allo-HSCT and were followed subsequently for malignancy relapse and survival. Seventeen patients experienced relapse. In a multivariable model including time-dependent influences on relapse, risk factors associated with increased risk of relapse included shorter time from transplant to cGVHD evaluation (HR 0.279, 95% CI 0.078-0.995) and lower number of prior lines of systemic immunosuppressive therapy for cGVHD (HR 0.260, 95% CI 0.094-0.719). In a model excluding time-dependent influences on relapse risk, lower number of prior lines of systemic immunosuppressive therapy for cGVHD (HR 0.288, 95% CI 0.103-0.804), lower C4 complement level (HR 0.346, 95% CI 0.129-0.923), and higher body mass index (HR 3.222, 95% CI 1.156-8.974), were all associated with increased relapse risk. Parameters indicating cGVHD severity and activity are associated with risk of malignancy relapse. Classical predictors of relapse after allo-HSCT do not seem to be prognostic.
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http://dx.doi.org/10.1038/s41409-021-01211-2DOI Listing
July 2021

(RIG-I)-related disease is associated with tissue-specific interferon pathway activation.

J Med Genet 2021 Jan 25. Epub 2021 Jan 25.

Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.

Background: Singleton-Merten syndrome (SGMRT) is a rare immunogenetic disorder that variably features juvenile open-angle glaucoma (JOAG), psoriasiform skin rash, aortic calcifications and skeletal and dental dysplasia. Few families have been described and the genotypic and phenotypic spectrum is poorly defined, with variants in (DExD/H-box helicase 58) being one of two identified causes, classified as SGMRT2.

Methods: Families underwent deep systemic phenotyping and exome sequencing. Functional characterisation with in vitro luciferase assays and in vivo interferon signature using bulk and single cell RNA sequencing was performed.

Results: We have identified a novel variant c.1529A>T p.(Glu510Val) that segregates with disease in two families with SGMRT2. Patients in these families have widely variable phenotypic features and different ethnic background, with some being severely affected by systemic features and others solely with glaucoma. JOAG was present in all individuals affected with the syndrome. Furthermore, detailed evaluation of skin rash in one patient revealed sparse inflammatory infiltrates in a unique distribution. Functional analysis showed that the variant is a dominant gain-of-function activator of interferon pathways in the absence of exogenous RNA ligands. Single cell RNA sequencing of patient lesional skin revealed a cellular activation of interferon-stimulated gene expression in keratinocytes and fibroblasts but not in neighbouring healthy skin.

Conclusions: These results expand the genotypic spectrum of DDX58-associated disease, provide the first detailed description of ocular and dermatological phenotypes, expand our understanding of the molecular pathogenesis of this condition and provide a platform for testing response to therapy.
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http://dx.doi.org/10.1136/jmedgenet-2020-107447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310534PMC
January 2021

Rehabilitation Interventions in the Multidisciplinary Management of Patients With Sclerotic Graft-Versus-Host Disease of the Skin and Fascia.

Arch Phys Med Rehabil 2021 04 23;102(4):776-788. Epub 2020 Dec 23.

Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD.

Graft-versus-host disease (GVHD) is a multisystemic disorder that affects 30%-80% of patients who undergo allogeneic hematopoietic stem cell transplantation 10%-15% of GVHD patients develop sclerotic features affecting the skin or deeper tissues, leading to functional limitations and poor quality of life. There is limited literature regarding the indications and efficacy of specific rehabilitative interventions in sclerotic GVHD (sclGVHD). In this article, we summarize the current evidence supporting rehabilitation intervention in sclGVHD and offer our approach to the multidisciplinary management of this disease. In addition, we review techniques that have been employed in other sclerotic skin diseases (eg, iontophoresis, extracorporeal shock waves, botulinum toxin A, adipose derived stromal vascular fraction), but that require further validation in the sclGVHD setting. Ultimately, optimal care for this complex disease requires a multidisciplinary approach that includes a rehabilitation and adaptive program tailored to each patient's needs.
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http://dx.doi.org/10.1016/j.apmr.2020.10.141DOI Listing
April 2021

A randomized phase 2 trial of pomalidomide in subjects failing prior therapy for chronic graft-versus-host disease.

Blood 2021 02;137(7):896-907

Immune Deficiency Cellular Therapy Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Steroid-refractory chronic graft-versus-host disease (cGVHD) is a therapeutic challenge. Sclerotic skin manifestations are especially difficult to treat. We conducted a randomized phase 2 clinical trial (#NCT01688466) to determine the safety, efficacy, and preferred dose of pomalidomide in persons with moderate to severe cGVHD unresponsive to corticosteroids and/or subsequent lines of therapy. Thirty-four subjects were randomized to receive pomalidomide 0.5 mg per day orally (n = 17; low-dose cohort) or 2 mg per day at a starting dose of 0.5 mg per day increasing to 2 mg per day over 6 weeks (n = 17; high-dose cohort). The primary endpoint was overall response rate (ORR) at 6 months according to the 2005 National Institutes of Health cGVHD Response Criteria. Thirty-two patients had severe sclerotic skin and received a median of 5 (range, 2-10) previous systemic therapies. ORR was 47% (95% confidence interval, 30-65) in the intention-to-treat analyses. All were partial responses, with no difference in ORR between the cohorts. ORR was 67% (45%-84%) in the 24 evaluable subjects at 6 months. Nine had improvement in National Institutes of Health joint/fascia scores (P = .018). Median change from the baseline in body surface area involvement of skin cGVHD was -7.5% (-10% to 35%; P = .002). The most frequent adverse events were lymphopenia, infection, and fatigue. Eight subjects in the high-dose cohort had dose decreases because of adverse events. There was 1 death in the low-dose cohort from bacterial pneumonia. Our data indicate antifibrotic effects of pomalidomide and possible association with increases in concentrations of blood regulatory T-cell and interleukin-2. Pomalidomide 0.5 mg per day is a safe and effective therapy for advanced corticosteroid-refractory cGVHD.
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http://dx.doi.org/10.1182/blood.2020006892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918188PMC
February 2021

Acral petechial eruptions without gastrointestinal symptoms: Three cases of dermatitis herpetiformis.

JAAD Case Rep 2020 Sep 28;6(9):935-938. Epub 2020 Jul 28.

Uniformed Services University of the Health Sciences, Department of Dermatology, Bethesda, Maryland.

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http://dx.doi.org/10.1016/j.jdcr.2020.07.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475064PMC
September 2020

Calcinosis Cutis in the Setting of Chronic Skin Graft-Versus-Host Disease.

JAMA Dermatol 2020 07;156(7):814-817

Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland.

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http://dx.doi.org/10.1001/jamadermatol.2020.1157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344382PMC
July 2020

Voriconazole and the Risk of Keratinocyte Carcinomas Among Lung Transplant Recipients in the United States.

JAMA Dermatol 2020 07;156(7):772-779

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.

Importance: The antifungal medication voriconazole is used to prevent and treat aspergillosis, a major cause of mortality among recipients of lung transplants (hereinafter referred to as lung recipients). Small studies suggest that voriconazole increases risk of cutaneous squamous cell carcinoma (SCC).

Objective: To examine associations of voriconazole and other antifungal medications with risk of keratinocyte carcinomas (SCC and cutaneous basal cell carcinoma [BCC]) in lung recipients.

Design, Setting, And Participants: This population-based cohort study included non-Hispanic white patients (n = 9599) who underwent lung transplant in the United States from January 1, 2007, to December 31, 2016, identified through the national Scientific Registry of Transplant Recipients with data linkable to pharmacy claims. Data were analyzed from March 1, 2018, to February 13, 2019.

Exposures: Antifungal medication use, including voriconazole, itraconazole, posaconazole, and other antifungals, was ascertained from pharmacy claims and treated as a time-varying exposure (assessed every 30 days). Cumulative antifungal exposure was calculated as the total number of exposed months.

Main Outcomes And Measures: Primary outcomes were the first SCC or BCC reported to the transplant registry by transplant centers. Follow-up began at transplant and ended at SCC or BCC diagnosis, transplant failure or retransplant, death, loss to follow-up, or December 31, 2016. Cox proportional hazards regression models were used to estimate adjusted hazard ratios (AHRs) for each antifungal medication.

Results: Among the 9793 lung transplants in 9599 recipients included in the analysis, median age at transplant was 59 (interquartile range [IQR], 48-65) years, 5824 (59.5%) were male, and 5721 (58.4%) reported ever smoking. During a median follow-up of 3.0 (IQR, 1.4-5.0) years after transplant, 1031 SCCs (incidence, 322 per 10 000 person-years) and 347 BCCs (incidence, 101 per 10 000 person-years) were reported. Compared with lung recipients with no observed voriconazole use, those with 1 to 3 months of voriconazole use experienced increased AHR for SCC of 1.09 (95% CI, 0.90-1.31); 4 to 7 months, 1.42 (95% CI, 1.16-1.73); 8 to 15 months, 2.04 (95% CI, 1.67-2.50); and more than 15 months, 3.05 (95% CI, 2.37-3.91). Ever itraconazole exposure was associated with increased SCC risk (AHR, 1.20; 95% CI, 1.00-1.45). For BCC, risk was not associated with voriconazole use but was increased with itraconazole use (AHR, 1.74; 95% CI, 1.27-2.37) or posaconazole use (AHR, 1.55; 95% CI, 1.00-2.41).

Conclusions And Relevance: In this study, voriconazole use was associated with increased SCC risk among lung recipients, especially after prolonged exposure. Further research evaluating the risk-benefit ratio of shorter courses or alternative medications in transplant recipients at high risk for SCC should be considered.
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http://dx.doi.org/10.1001/jamadermatol.2020.1141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221851PMC
July 2020

Use of teledermatology by dermatology hospitalists is effective in the diagnosis and management of inpatient disease.

J Am Acad Dermatol 2021 Jun 7;84(6):1547-1553. Epub 2020 May 7.

Department of Dermatology, Mayo Clinic, Rochester, Minnesota.

Background: Patient outcomes are improved when dermatologists provide inpatient consultations. Inpatient access to dermatologists is limited, illustrating an opportunity to use teledermatology. Little is known about the ability of dermatologists to accurately diagnose disease and manage inpatients with teledermatology, particularly when using nondermatologist-generated clinical data.

Methods: This prospective study assessed the ability of teledermatology to diagnose disease and manage 41 dermatology consultations from a large urban tertiary care center, using internal medicine referral documentation and photographs. Twenty-seven dermatology hospitalists were surveyed. Interrater agreement was assessed by the κ statistic.

Results: There was substantial agreement between in-person and teledermatology assessment of the diagnosis with differential diagnosis (median κ = 0.83), substantial agreement in laboratory evaluation decisions (median κ = 0.67), almost perfect agreement in imaging decisions (median κ = 1.0), and moderate agreement in biopsy decisions (median κ = 0.43). There was almost perfect agreement in treatment (median κ = 1.0), but no agreement in follow-up planning (median κ = 0.0). There was no association between raw photograph quality and the primary plus differential diagnosis or primary diagnosis alone.

Limitations: Selection bias and single-center nature.

Conclusions: Teledermatology may be effective in the inpatient setting, with concordant diagnosis, evaluation, and management decisions.
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http://dx.doi.org/10.1016/j.jaad.2020.04.171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204758PMC
June 2021

Somatic SMAD3-activating mutations cause melorheostosis by up-regulating the TGF-β/SMAD pathway.

J Exp Med 2020 05;217(5)

Section on Heritable Disorders of Bone and Extracellular Matrix, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.

Melorheostosis is a rare sclerosing dysostosis characterized by asymmetric exuberant bone formation. Recently, we reported that somatic mosaicism for MAP2K1-activating mutations causes radiographical "dripping candle wax" melorheostosis. We now report somatic SMAD3 mutations in bone lesions of four unrelated patients with endosteal pattern melorheostosis. In vitro, the SMAD3 mutations stimulated the TGF-β pathway in osteoblasts, enhanced nuclear translocation and target gene expression, and inhibited proliferation. Osteoblast differentiation and mineralization were stimulated by the SMAD3 mutation, consistent with higher mineralization in affected than in unaffected bone, but differing from MAP2K1 mutation-positive melorheostosis. Conversely, osteoblast differentiation and mineralization were inhibited when osteogenesis of affected osteoblasts was driven in the presence of BMP2. Transcriptome profiling displayed that TGF-β pathway activation and ossification-related processes were significantly influenced by the SMAD3 mutation. Co-expression clustering illuminated melorheostosis pathophysiology, including alterations in ECM organization, cell growth, and interferon signaling. These data reveal antagonism of TGF-β/SMAD3 activation by BMP signaling in SMAD3 mutation-positive endosteal melorheostosis, which may guide future therapies.
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http://dx.doi.org/10.1084/jem.20191499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201932PMC
May 2020

Quality of Life in Patients With Skin of Color and Chronic Graft-vs-Host Disease.

JAMA Dermatol 2020 05;156(5):589-590

Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland.

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http://dx.doi.org/10.1001/jamadermatol.2019.4857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042814PMC
May 2020

Clinical characteristics and cytokine biomarkers in patients with chronic graft-vs-host disease persisting seven or more years after diagnosis.

Am J Hematol 2020 04 25;95(4):387-394. Epub 2020 Jan 25.

Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Chronic graft-versus-host disease (cGVHD) is the leading late complication after allogeneic hematopoietic stem cell transplantation (HSCT). Many patients receive multiple lines of systemic therapy until cGVHD resolves, but about 15% remain on systemic treatment for more than 7 years after cGVHD diagnosis. This study describes the clinical and biological factors of patients who present with cGVHD persisting for ≥7 years (persistent cGVHD). Patients with persistent cGVHD (n = 38) and those with cGVHD for <1 year (early cGVHD) (n = 83) were enrolled in a prospective cross-sectional natural history study. Patients in the persistent cGVHD group were a median of 10.2 years from cGVHD diagnosis (range 7-27 years). Fifty-eight percent of persistent cGVHD patients (22/38) were receiving systemic immunosuppression, compared to 88% (73/83) in the early cGVHD group. In multivariable analysis, bone marrow (BM) stem cell source, presence of ENA autoantibodies, higher NIH lung score, higher platelet counts, and higher IgA levels were significantly associated with persistent cGVHD. A high sensitivity panel of serum biomarkers including seven cytokines diagnostic for cGVHD was analyzed and showed significantly lower levels of BAFF and CXCL10 in patients with persistent cGVHD. In conclusion, standardly accepted clinical measures of disease severity may not accurately reflect disease activity in patients with persistent cGVHD. However, many patients with persistent cGVHD are still receiving systemic immunosuppression despite lacking evidence of disease activity. Development of reliable clinical biomarkers of cGVHD activity may help guide future systemic treatments.
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http://dx.doi.org/10.1002/ajh.25717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453587PMC
April 2020

Motor ability, function, and health-related quality of life as correlates of symptom burden in patients with sclerotic chronic graft-versus-host disease receiving imatinib mesylate.

Support Care Cancer 2020 Aug 6;28(8):3679-3689. Epub 2019 Dec 6.

Rehabilitation Medicine Department, Clinical Center, National Institutes of Health, MSC 1604, 10 Center Drive, Bethesda, MD, 20892, USA.

Purpose: To explore improvement in motor ability, function, health-related quality of life (HRQOL), and symptom severity in patients with sclerotic chronic graft-versus-host disease (ScGVHD) in response to treatment as well as the relationship among changes on such measures.

Methods: This study was a secondary analysis of data from 13 individuals with severe ScGVHD enrolled in a clinical trial evaluating the efficacy of imatinib mesylate (clinicaltrials.gov identifier: NCT00702689). Self-reported, clinician-reported, and performance-based indicators of motor ability, function, HRQOL, and symptom severity were assessed at baseline and 6 months following the administration of imatinib mesylate.

Results: Participants did not show statistically significant improvement on any measures over time. Approximately one-third of patients displayed clinically significant improvement on measures of motor ability (palmar pinch strength, dominant hand, 30.8%), functioning (Manual Ability Measure-36, 41.7%), HRQOL (Short Form 36 [SF-36] Mental Component Summary, 33.3%), and symptom severity (Lee Symptom Scale, 38.5%). Improvement in cGVHD symptom burden was correlated with improvement in function (Assessment of Motor and Process Skills [AMPS] and Disabilities of the Arm, Shoulder, and Hand [DASH] scores) and HRQOL (SF-36 Physical Component Summary scores).

Conclusions: Findings suggest the potential utility of administering patient-reported and performance-based functional measures, such as the DASH and the AMPS, to patients with cGVHD. By understanding the functional consequences of ScGVHD, interdisciplinary teams of health care providers, including rehabilitation professionals, can work to improve long-term outcomes.
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http://dx.doi.org/10.1007/s00520-019-05207-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274957PMC
August 2020

Clinical Evaluation of Melorheostosis in the Context of a Natural History Clinical Study.

JBMR Plus 2019 Aug 26;3(8):e10214. Epub 2019 Jul 26.

Clinical and Investigative Orthopedics Surgery Unit National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH Bethesda MD USA.

Melorheostosis is a rare dysostosis involving cortical bone overgrowth that affects the appendicular skeleton. Patients present with pain, deformities, contractures, range of motion limitation(s), and limb swelling. It has been described in children as well as adults. We recently identified somatic mosaicism for gain-of-function mutations in in patients with melorheostosis. Despite these advances in genetic understanding, there are no effective therapies or clinical guidelines to help clinicians and patients in disease management. In a study to better characterize the clinical and genetic aspects of the disease, we recruited 30 adults with a radiographic appearance of melorheostosis and corresponding increased uptake on F-NaF positron emission tomography (PET)/CT. Patients underwent physical exam, imaging studies, and laboratory assessment. All patients underwent nerve conduction studies and ultrasound imaging of the nerve in the anatomic distribution of melorheostosis. We found sensory deficits in approximately 77% of patients, with evidence of focal nerve entrapment in five patients. All patients reported pain; 53% of patients had changes in skin overlying the affected bone. No significant laboratory abnormalities were noted. Our findings suggest that patients with melorheostosis may benefit from a multidisciplinary team of dermatologists, neurologists, orthopedic surgeons, pain and palliative care specialists, and physical medicine and rehabilitation specialists. Future studies focused on disease management are needed. © 2019 The Authors. Published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbm4.10214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715778PMC
August 2019

Trichomegaly induced by topical tacrolimus for the treatment of periorbital vitiligo: A brief report of a new adverse effect.

Pediatr Dermatol 2019 Jul 9;36(4):e95-e96. Epub 2019 May 9.

DermAssociates/US Dermatology Partners, PC, Rockville, Maryland.

Trichomegaly is a known adverse effect of systemic administration of cyclosporine but is less commonly associated with systemic tacrolimus or with topical calcineruin inhibitors. In this report, we describe the first case, to our knowledge, of trichomegaly due to long-term use of topical tacrolimus for periocular vitiligo.
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http://dx.doi.org/10.1111/pde.13825DOI Listing
July 2019

Birt-Hogg-Dubé syndrome initially diagnosed as tuberous sclerosis complex.

JAAD Case Rep 2019 Apr 5;5(4):368-371. Epub 2019 Apr 5.

Department of Dermatology, Uniformed Services University of the Health Sciences, Bethesda, Maryland.

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http://dx.doi.org/10.1016/j.jdcr.2019.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453834PMC
April 2019

Decoding Skin Involvement in Chronic Graft-vs-Host Disease.

Authors:
Edward W Cowen

JAMA Dermatol 2019 07;155(7):777-778

Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland.

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http://dx.doi.org/10.1001/jamadermatol.2019.0354DOI Listing
July 2019

Recurrent fevers, progressive lipodystrophy, and annular plaques in a child.

J Am Acad Dermatol 2019 Jan 8;80(1):291-295. Epub 2018 Sep 8.

Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland. Electronic address:

KEY TEACHING POINTS.
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http://dx.doi.org/10.1016/j.jaad.2018.08.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132105PMC
January 2019

Understanding the evolving phenotype of vascular complications in telomere biology disorders.

Angiogenesis 2019 02 25;22(1):95-102. Epub 2018 Aug 25.

Dyskeratosis Congenita Outreach, Inc., New York, NY, USA.

Vascular complications such as bleeding due to gastrointestinal telangiectatic anomalies, pulmonary arteriovenous malformations, hepatopulmonary syndrome, and retinal vessel abnormalities are being reported in patients with telomere biology disorders (TBDs) more frequently than previously described. The international clinical care consortium of telomere-associated ailments and family support group Dyskeratosis Congenita Outreach, Inc. held a workshop on vascular abnormalities in the TBDs at the National Cancer Institute in October 2017. Clinicians and basic scientists reviewed current data on vascular complications, hypotheses for the underlying biology and developed new collaborations to address the etiology and clinical management of vascular complications in TBDs.
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http://dx.doi.org/10.1007/s10456-018-9640-7DOI Listing
February 2019

Distinct Clinical and Pathological Features of Melorheostosis Associated With Somatic MAP2K1 Mutations.

J Bone Miner Res 2019 01 14;34(1):145-156. Epub 2018 Sep 14.

Clinical and Investigative Orthopedics Surgery Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA.

Melorheostosis is a rare hyperostotic disease of the long bones classically characterized by a "dripping candle-wax" radiographic appearance. We recently described somatic activating mutations in MAP2K1 as a cause of melorheostosis. Here, we report distinguishing characteristics of patients with MAP2K1-positive melorheostosis. Fifteen unrelated patients with radiographic appearance of melorheostosis underwent paired biopsies of affected and unaffected bone for whole-exome sequencing, histology, and cell culture. Eight patients with mutations in MAP2K1 in affected bone were compared to the seven MAP2K1-negative patients to identify distinguishing characteristics. Patients with MAP2K1-positive melorheostosis had a distinct phenotype with classic "dripping candle-wax" appearance on radiographs (p = 0.01), characteristic vascular lesions on skin overlying affected bone (p = 0.01), and higher prevalence of extraosseous mineralization and joint involvement (p = 0.04 for both). Melorheostotic bone from both MAP2K1-positive and MAP2K1-negative patients showed two zones of distinct morphology-an outer segment of parallel layers of primary lamellar bone and a deeper zone of intensely remodeled highly porous osteonal-like bone. Affected bone from MAP2K1-positive patients showed excessive osteoid (p = 0.0012), increased number of osteoblasts (p = 0.012) and osteoclasts (p = 0.04), and increased vascularity on histology in comparison to paired unaffected bone which was not seen in affected bone in most MAP2K1-negative patients. The identification of a distinct phenotype of patients with MAP2K1-positive melorheostosis demonstrates clinical and genetic heterogeneity among patients with the disease. Further studies are needed to better understand the underlying pathophysiology and associated skin findings. © 2018 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577747PMC
January 2019

Impact of the 2014 NIH chronic graft-versus-host disease scoring criteria modifications assessed in a large cohort of severely affected patients.

Bone Marrow Transplant 2019 01 8;54(1):76-84. Epub 2018 Aug 8.

Experimental Transplantation and Immunology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA.

In 2005, the National Institutes of Health (NIH) chronic graft-versus-host disease (cGVHD) consensus project provided diagnosis and staging criteria, based mostly on clinical experience and expert opinion. These criteria were revised in 2014, aiming to provide enhanced specificity and clarity. However, the impact of 2014 changes to the original NIH cGVHD severity scoring criteria has not been reported. In this study, 284 patients, prospectively enrolled on the National Cancer Institute's cross-sectional cGVHD natural history study, were scored using the 2005 NIH cGVHD criteria and then rescored according to the 2014 modifications. In comparing the two criteria, 2014 cGVHD global severity scoring resulted in a tendency toward being categorized as milder scores (75 vs. 72% of severe score per 2014, p = 0.0009), with a statistically significant shift in NIH liver and lung scores toward milder categories (p < 0.0001). 2005 and 2014 NIH global severity scores showed a significant association with reduced grip strength (p < 0.0001), reduced joint range of motion (p = 0.0003), and the subspecialist evaluation score (p < 0.0001). Poor survival prediction of the severe NIH lung score is also retained in the new criteria (p = 0.0012). These findings support the use of 2014 cGVHD scoring criteria in continuous efforts to develop better classification systems.
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http://dx.doi.org/10.1038/s41409-018-0224-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268758PMC
January 2019

Immunotherapy and Skin Side Effects.

JAMA Dermatol 2018 Jun;154(6):744

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http://dx.doi.org/10.1001/jamadermatol.2018.0269DOI Listing
June 2018

JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies.

J Clin Invest 2018 07 11;128(7):3041-3052. Epub 2018 Jun 11.

National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, Maryland, USA.

Background: Monogenic IFN-mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease.

Methods: Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes-associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed.

Results: Eighteen patients were treated for a mean duration of 3.0 years (1.5-4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93-1.78) to 0.25 (IQR, 0.1-0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31-1.09) to 0.11 mg/kg/day (IQR, 0.02-0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients' quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia.

Conclusion: Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment.

Trial Registration: ClinicalTrials.gov NCT01724580 and NCT02974595.

Funding: This research was supported by the Intramural Research Program of the NIH, NIAID, and NIAMS. Baricitinib was provided by Eli Lilly and Company, which is the sponsor of the expanded access program for this drug.
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http://dx.doi.org/10.1172/JCI98814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026004PMC
July 2018
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