Functional and Cutaneous Treatment Outcomes With Intravenous Immunoglobulin for Eosinophilic Fasciitis: A Retrospective Study.

BACKGROUND: Eosinophilic fasciitis (EF) is a rare subtype of deep morphea with an elevated risk of functional impairment. No treatment algorithm has been established for adults with EF refractory to traditional corticosteroid or immunomodulatory treatments. Research on cutaneous and functional outcomes of alternative therapies, such as intravenous immunoglobulin (IVIG), remains scarce.  Objective: To describe the functional and cutaneous outcomes associated with IVIG in adults with treatment-refractory EF at a tertiary referral center. METHODS: We performed a retrospective chart review of 18 consecutive patients with EF identified through a billing code search seen within the UCSF Department of Dermatology between 2015 and 2022.  Results: Seven patients (41.2%) underwent at least one course of intravenous immunoglobulins (IVIG) during the study period. Of 6 patients with available follow-up data, 5 patients (83.3%) achieved both sustained cutaneous and functional improvement. In the IVIG cohort, 1 patient (16.7%) achieved complete response with relapse, 4 (66.7%) were partial responders, and 1 (16.7%) was a non-responder who required treatment with mepolizumab. CONCLUSION: Adverse effects of IVIG included headaches in 1 patient (14.3%) and rash in 2 patients (28.6%). There were no reported veno-occlusive or thromboembolic events associated with IVIG.  J Drugs Dermatol. 2024;23(4):8017.    doi:10.36849/JDD.8017e.

Research Fever in Dermatology-A Symptom of a Larger Problem.

This Viewpoint offers potential solutions to research "fever," which is characterized as a symptom of larger problems in our health care and educational systems rather than the fault of residency applicants.

Clinical and therapeutic course in head variants of linear morphea in adults: a retrospective review.

Parry Romberg Syndrome (PRS) and en coup de sabre (ECDS) are head variants of linear morphea with functional and structural implications. This study describes the clinical course, autoimmune co-morbidities, complications, and treatment of adults with PRS/ECDS at a tertiary referral center. We retrospectively reviewed the records of all 34 adult patients with PRS/ECDS identified through billing code search and seen by dermatologists at our institution between 2015 and 2021. Eight patients (23.5%) had ECDS, 8 (23.5%) had PRS, and 18 (52.9%) had overlap. Twenty-six patients (76.5%) reported ocular, oral, and/or neurologic symptoms, and 8 (23.5%) had concomitant autoimmune/inflammatory conditions. Sixteen patients (47.1%) had a skin biopsy, and 25 (73.5%) had imaging. Forty-six MRIs were obtained, of which 6 (13.0%) reported intracranial findings and 25 (54.3%) reported disease-related connective tissue damage. Twenty-four patients (70.6%) underwent systemic treatment during their disease course per available clinical records. Seventeen patients (70.8%) had improved or stable disease upon treatment completion, with an average duration of 22.2 months. Ten patients (41.7%) reported recurrence of disease following the treatment course. To address changes to facial contour, 6 patients (17.6%) opted for procedural treatments. One patient (16.7%) experienced morphea reactivation following a filler injection performed off-immunosuppression. Compared to findings in children, our study suggests adults with PRS/ECDS are more likely to have oral and ocular complications but experience less severe neurologic symptoms. While systemic treatments appear beneficial in most adult patients with PRS/ECDS, disease may recur following discontinuation.

Dapsone-induced methemoglobinemia and hemolysis in a woman without G6PD deficiency presenting with idiopathic urticaria.

BACKGROUND: The appearance of bite cells associated with methemoglobinemia can be caused by oxidizing drugs such as dapsone in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency or high drug serum levels. Bite cells are often pathognomonic for oxidant injury in patients with G6PD deficiency and suggest active hemolysis. CASE PRESENTATION: We report a case of a woman with no prior history of G6PD deficiency who presented with anemia, methemoglobinemia and bite cells on peripheral blood smear after dapsone therapy for new onset idiopathic urticaria. Laboratory tests for G6PD, blood count and liver function were within normal limits prior to initiation of therapy. During the patient's hospital course, moderate methemoglobinemia and anemia were identified despite mildly increased serum G6PD level. These pathologies were reversed upon stopping dapsone therapy. CONCLUSION: This case highlights the potential for therapeutic levels of dapsone to induce side effects in patients without G6PD deficiency and highlights the importance of routine blood monitoring for anemia and hemolysis during the course of drug therapy.

Mycoplasma pneumoniae-Induced Rash and Mucositis in a Previously Healthy Man: A Case Report and Brief Review of the Literature.

We describe a case of a 33-year-old-male with Mycoplasma pneumoniae-induced rash and mucositis and review the literature on this newly described syndrome.

Correction: Non-invasive measurement of sclerosis in cutaneous cGVHD patients with the handheld device Myoton: a cross-sectional study.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Increased Incidence of Resistant Hypertension in Patients With Systemic Lupus Erythematosus: A Retrospective Cohort Study.

OBJECTIVE: To compare the risk of resistant hypertension (RHTN) in patients with systemic lupus erythematosus (SLE) and in controls without SLE, and to define factors associated with RHTN in patients with SLE. METHODS: We studied 1,044 patients with SLE and 5,241 control subjects using de-identified electronic health records from a tertiary care center. SLE was defined as ≥4 International Classification of Diseases, Ninth Revision codes for SLE and antinuclear antibody titer ≥1:160. RHTN was defined as uncontrolled blood pressure on 3 antihypertensive medications or requiring 4 or more antihypertensives to attain control. First, we compared the risk of RHTN between groups. Second, we examined the association between RHTN and all-cause mortality in patients with SLE. RESULTS: RHTN was nearly twice as prevalent in patients with SLE compared to control subjects (10.2% and 5.3%, respectively), with an incidence rate of 10.2 versus 6.1 cases per 1,000 person-years of observation (hazard ratio [HR] 1.72 [95% confidence interval 1.28-2.30]; P < 0.001, adjusted for age, sex, race, baseline end-stage renal disease [ESRD], creatinine, and calendar year). In patients with SLE, we found associations between RHTN and black race, lower renal function, hypercholesterolemia, and increased inflammatory markers. RHTN was associated with a significantly higher mortality risk (HR 2.91, P = 0.0005) after adjustment for age, sex, race, calendar year, creatinine, baseline ESRD, and number of visits. CONCLUSION: Patients with SLE have a higher risk of RHTN compared to frequency-matched controls, independent of multiple covariates. RHTN is an important comorbidity for clinicians to recognize in SLE, because it is associated with a higher risk of mortality.

A Unique Case of Burkholderia cepacia Prosthetic Mitral Valve Endocarditis and Literature Review.

Burkholderia cepacia prosthetic valve endocarditis (PVE) is extremely rare, with few cases in the literature. A report of a patient with PVE is described, followed by a literature review on B. cepacia PVE. A 38 year old man with poor dentition and a history of intravenous drug use (IVDU) and mitral valve replacement was found to have a mitral valve vegetation. Five sets of blood cultures on different days grew B. cepacia. Individual sets of blood cultures on different dates also isolated S. viridans (outside hospital culture), methicillin-resistant S. epidermidis (hospital day 1), and Bacillus spp. (hospital day 6). He was successfully treated with ceftazidime and levofloxacin as dual therapy for B. cepacia PVE, in addition to vancomycin for gram positive coverage. This case report and review highlights the possibility of B. cepacia PVE in immunocompetent patients with poor dentition, with the potential for a successful outcome following combination antimicrobial therapy.

The Anatomic Distribution of Skin Involvement in Patients with Incident Chronic Graft-versus-Host Disease.

Little is known about the anatomic distribution of cutaneous chronic graft-versus-host disease (cGVHD). Using data from the cGVHD Consortium Improving Outcomes Assessment Study, we describe the frequency and extent of erythema and superficial and deep sclerosis in 8 anatomic sites in patients with incident disease (ie, new cGVHD diagnosis within 3 months of study entry) receiving systemic therapy. Of 339 patients with incident disease, 182 (54%) had skin involvement. When an extremity was involved, the same type of disease was present contralaterally in 92% of cases, revealing a high level of symmetry. As anticipated, erythema was the most common incident feature; however, sclerotic skin involvement at the time of cGVHD diagnosis was more common than has been suggested by previous studies. Erythema occurred in 155 (85%) and sclerosis in 53 (29%) of the patients with skin involvement (46% and 16%, respectively, of the entire cohort of 339 incident cGVHD cases). Erythema was least common on the lower extremities (n = 71; 39% of patients with skin involvement). Moveable sclerosis was rare on the head, neck, and scalp (n = 4; 2%). Deep sclerosis did not occur in this region, and instead was most likely to occur on the upper extremities (n = 14; 8%) and lower extremities (n = 14; 8%). More than one-half of patients with erythema (n = 107; 58.7%) had diffuse involvement (4 or more of 8 sites involved), compared with less than one-third of those with sclerosis (n = 16; 30.2%).

Machine learning reveals chronic graft-versus-host disease phenotypes and stratifies survival after stem cell transplant for hematologic malignancies.

The application of machine learning in medicine has been productive in multiple fields, but has not previously been applied to analyze the complexity of organ involvement by chronic graft-versus-host disease. Chronic graft-versus-host disease is classified by an overall composite score as mild, moderate or severe, which may overlook clinically relevant patterns in organ involvement. Here we applied a novel computational approach to chronic graft-versus-host disease with the goal of identifying phenotypic groups based on the subcomponents of the National Institutes of Health Consensus Criteria. Computational analysis revealed seven distinct groups of patients with contrasting clinical risks. The high-risk group had an inferior overall survival compared to the low-risk group (hazard ratio 2.24; 95% confidence interval: 1.36-3.68), an effect that was independent of graft-versus-host disease severity as measured by the National Institutes of Health criteria. To test clinical applicability, knowledge was translated into a simplified clinical prognostic decision tree. Groups identified by the decision tree also stratified outcomes and closely matched those from the original analysis. Patients in the high- and intermediate-risk decision-tree groups had significantly shorter overall survival than those in the low-risk group (hazard ratio 2.79; 95% confidence interval: 1.58-4.91 and hazard ratio 1.78; 95% confidence interval: 1.06-3.01, respectively). Machine learning and other computational analyses may better reveal biomarkers and stratify risk than the current approach based on cumulative severity. This approach could now be explored in other disease models with complex clinical phenotypes. External validation must be completed prior to clinical application. Ultimately, this approach has the potential to reveal distinct pathophysiological mechanisms that may underlie clusters. Clinicaltrials.gov identifier: NCT00637689.

Reproducibility of the durometer and myoton devices for skin stiffness measurement in healthy subjects.

BACKGROUND: Clinical assessment of skin stiffness is unreliable in many applications. The durometer, an industrial device to measure hardness, has previously been applied in scleroderma. The Myoton is a noninvasive handheld device for assessing soft tissue biomechanical parameters. MATERIALS AND METHODS: We evaluated the reproducibility of both devices in six healthy subjects in the volar forearm, dorsal forearm, upper arm, shin, and calf bilaterally. The intraclass correlation coefficient (ICC) was used as a measure of reproducibility among three observers. RESULTS: The interobserver intraclass correlation coefficient (ICC) of overall stiffness for the Myoton was 0.74 [95% confidence interval (CI) 0.45-1.00] and 0.71 [0.39-1.00] for the durometer. Coefficient of variation (CV) for the Myoton was 6.4% [range 1.3-12.1] and 7.6% [range 4.4-13.8] for the durometer. Myoton and durometer values had a Pearson correlation of 0.69. The intraobserver Myoton ICC was 0.89 [0.74-1.00] and CV 3.1% [range 1.6-5.0]. The 95% confidence minimal detectable change by the Myoton for a single observer is 32.4 N/m, which is 7.6% of the average subject's overall stiffness. CONCLUSION: The Myoton demonstrated high reproducibility, particularly in the overall stiffness parameter, and merits further investigation to assess disease progression and treatment efficacy.

A Prospective Trial of Extracorporeal Photopheresis for Chronic Graft-versus-Host Disease Reveals Significant Disease Response and No Association with Frequency of Regulatory T Cells.

Extracorporeal photopheresis (ECP) is an accepted treatment for chronic graft-versus-host disease (cGVHD); however, the mechanism of action is unclear. We conducted a prospective multicenter clinical trial to assess ECP response rates using the 2005 National Institutes of Health (NIH) consensus criteria and to assess the relationship between regulatory T cells (Tregs) and treatment response (NCT01324908). Eighty-three patients with any NIH subtype of cGVHD were enrolled, irrespective of number of prior lines of treatment, and 6 were subsequently excluded because of the absence of follow-up from cancer relapse, infection, or study withdrawal. Study outcomes were provider-assessed response and formal response by 2005 NIH criteria. Peripheral blood samples were collected at prespecified study visits and were analyzed by flow cytometry for Tregs. In a heavily pretreated cohort of patients, with a median of 2 prior lines of therapy, 62.3% of patients had a provider-assessed response to ECP and 43.5% had response by NIH criteria. These assessments showed only a slight agreement (kappa statistic, .09). In a logistic regression model that included previously identified risk factors such as bilirubin, platelet count, and time from transplant to study entry, no clinical factors were associated with the provider's response assessment. Furthermore, there was no significant difference in percentage of Tregs in blood leukocytes at study entry and completion or in overall change in Treg frequency between ECP responders and nonresponders. ECP was associated with a clinically significant decrease in median prednisone dose (.36 to .14 mg/kg, P < .001) from study entry to last visit and a significant decrease in global severity of cGVHD and total body surface area with erythematous rash. Overall, ECP was able to deliver response using NIH response criteria in a highly pretreated cohort with moderate and severe cGVHD independent of most previous risk factors for adverse outcomes of cGVHD.

Characteristics and treatment of African-American and European-American patients with resistant hypertension identified using the electronic health record in an academic health centre: a case-control study.

OBJECTIVE: To identify patients with hypertension with resistant and controlled blood pressure (BP) using electronic health records (EHRs) in order to elucidate practices in the real-world clinical treatment of hypertension and to enable future genetic studies. DESIGN: Using EHRs, we developed and validated algorithms to identify patients with resistant and controlled hypertension. SETTING: An academic medical centre in Nashville, Tennessee. POPULATION: European-American (EA) and African-American (AA) patients with hypertension. MAIN OUTCOME MEASURES: Demographic characteristics: race, age, gender, body mass index, outpatient BPs and the history of diabetes mellitus, chronic kidney disease stage 3, ischaemic heart disease, transient ischaemic attack, atrial fibrillation and sleep apnoea. MEDICATION TREATMENT: All antihypertensive medication classes prescribed to a patient at the time of classification and ever prescribed following classification. RESULTS: The algorithms had performance metrics exceeding 92%. The prevalence of resistant hypertension in the total hypertensive population was 7.3% in EA and 10.5% in AA. At diagnosis, AA were younger, heavier, more often female and had a higher incidence of type 2 diabetes and higher BPs than EA. AA with resistant hypertension were more likely to be treated with vasodilators, dihydropyridine calcium channel blockers and alpha-2 agonists while EA were more likely to be treated with angiotensin receptor blockers, renin inhibitors and beta blockers. Mineralocorticoid receptor antagonists use was increased in patients treated with more than four antihypertensive medications compared with patients treated with three (12.4% vs 2.6% in EA, p<0.001; 12.3% vs 2.8% in AA, p<0.001). The number of patients treated with a mineralocorticoid receptor antagonist increased to 37.4% in EA and 41.2% in AA over a mean follow-up period of 7.4 and 8.7 years, respectively. CONCLUSIONS: Clinical treatment of resistant hypertension differs in EA and AA patients. These results demonstrate the feasibility of identifying resistant hypertension using an EHR.

BRAF and MEK inhibitor therapy eliminates Nestin-expressing melanoma cells in human tumors.

Little is known about the in vivo impacts of targeted therapy on melanoma cell abundance and protein expression. Here, 21 antibodies were added to an established melanoma mass cytometry panel to measure 32 cellular features, distinguish malignant cells, and characterize dabrafenib and trametinib responses in BRAFV600mut melanoma. Tumor cells were biopsied before neoadjuvant therapy and compared to cells surgically resected from the same site after 4 weeks of therapy. Approximately 50,000 cells per tumor were characterized by mass cytometry and computational tools t-SNE/viSNE, FlowSOM, and MEM. The resulting single-cell view of melanoma treatment response revealed initially heterogeneous melanoma tumors were consistently cleared of Nestin-expressing melanoma cells. Melanoma cell subsets that persisted to week 4 were heterogeneous but expressed SOX2 or SOX10 proteins and specifically lacked surface expression of MHC I proteins by MEM analysis. Traditional histology imaging of tissue microarrays from the same tumors confirmed mass cytometry results, including persistence of NES- SOX10+ S100ß+ melanoma cells. This quantitative single-cell view of melanoma treatment response revealed protein features of malignant cells that are not eliminated by targeted therapy.

Umbilical Cord Coiling in High-risk Pregnancies: Associations With Determinants of Adverse Birth Outcomes and Iron Status.

Abnormal umbilical cord coiling has been associated with adverse neonatal outcomes, but the etiology of these findings remains poorly characterized. This study was undertaken to examine associations between cord coiling and maternal iron (Fe) status and to identify potential determinants of hypo- and hypercoiling in 2 higher risk obstetric groups: pregnant adolescents (≤18 years, n = 92) and adult women carrying twins (n = 49), triplets (n = 11), or quadruplets (n = 1). Umbilical cords were classified as hypo-, normo-, or hypercoiled using digital photographs to assess gross appearance. Hypocoiling and hypercoiling were observed in 44% (n = 86/195) and 13% (n = 26/195) of the combined study population. The prevalence of hypocoiling among women carrying multiples was over 3-fold higher than the prevalence in singleton pregnancies based on the published data. Within the entire study population, hypocoiling was associated with a lower gestational age at birth when compared to normocoiling and hypercoiling (36.3 ± 3.6 weeks [n = 86] vs 37.8 ± 2.7 [n = 83], P < .01, and 38.2 ± 2.6 [n = 26], P < .01, respectively), whereas hypercoiling was associated with significantly lower serum ferritin when compared to normocoiling ( P < .01) and hypocoiling ( P < .001). In the multiples cohort only, hypercoiling was significantly associated with multiparity ( P < .01) and lower birth weight ( P < .05). Further studies are needed to identify the determinants and consequences of cord coiling.

Generating Quantitative Cell Identity Labels with Marker Enrichment Modeling (MEM).

Multiplexed single-cell experimental techniques like mass cytometry measure 40 or more features and enable deep characterization of well-known and novel cell populations. However, traditional data analysis techniques rely extensively on human experts or prior knowledge, and novel machine learning algorithms may generate unexpected population groupings. Marker enrichment modeling (MEM) creates quantitative identity labels based on features enriched in a population relative to a reference. While developed for cell type analysis, MEM labels can be generated for a wide range of multidimensional data types, and MEM works effectively with output from expert analysis and diverse machine learning algorithms. MEM is implemented as an R package and includes three steps: (1) calculation of MEM values that quantify each feature's relative enrichment in the population, (2) reporting of MEM labels as a heatmap or as a text label, and (3) quantification of MEM label similarity between populations. The protocols here show MEM analysis using datasets from immunology and oncology. These MEM implementations provide a way to characterize population identity and novelty in the context of computational and expert analyses. © 2018 by John Wiley & Sons, Inc.