Cutaneous Subtypes Research Articles

The Miniature Macula-Ephelis

An ephelis is a miniature, benign, brown or tan cutaneous blemish which appears upon sun exposed surfaces. Genetic composition and cutaneous subtype of incriminated individual directs the emergence of ephelis. Generally spherical, ephelis demonstrates a localized area of hyperpigmentation contingent to magnitude of sun exposure. Superimposed stratified squamous epithelium exhibits hyperpigmentation of basal keratinocytes and elongation of rete ridges whereas quantifiable melanocytes remain unaltered. Ephelis requires segregation from conditions such as café-au-lait macules, junctional nevus, solar lentigo, melano-acanthoma, melanosis, moles, sun spots, liver spots and malignant epithelial neoplasms. The innocuous ephelis does not require treatment although protection from sun exposure is recommended.

Guzkowe zapalenie tętnic — obraz kliniczny, diagnostyka i leczenie

Polyarteritis nodosa (PAN) belongs to the group of medium vessel vasculitis. Two subtypes of the disease are classically distinguished — systemic variant and cutaneous variant. Systemic PAN is a potentially life-threatening disease, while cutaneous subtype is usually characterized by mild course. The review aims to summarize the symptomatology, diagnostics and treatment of PAN and to draw attention to the dermatological manifestations of the disease. Skin changes develop in 28–60% of patients with systemic PAN. The most common manifestations include palpable purpura, livedo reticularis and inflammatory nodules, and less commonly - urticarial lesions, transient erythema, distal necrosis, superficial phlebitis and splinter haemorrhages. Skin lesions in cutaneous PAN are typically located on the lower extremities, and less frequently — on the upper extremities or trunk. Painful nodules, livedo reticularis and ulcerations are the most frequent manifestations of cutaneous PAN. Ulcerations usually heal leaving ivory-white stellate scars ( atrophie blanche ) surrounded by telangiectasias. The diagnosis of both systemic and cutaneous subtype of the disease is based on diagnostic criteria. Management of systemic PAN consists of induction of remission and maintenance therapy. The choice of therapeutic option should be based on the severity of the disease and comorbidities, especially hepatitis B virus infection. Cutaneous PAN is characterized by a benign course with frequent relapses. First-line treatment usually consists of non-steroidal anti-inflammatory drugs, colchicine and dapsone. Considering frequent development of skin lesions in the course of PAN, knowledge of the clinical presentation, diagnosis and treatment of the condition is an important part of the everyday dermatological practice.

Dermatologic Manifestations, Histologic Features and Disease Progression among Cutaneous Lupus Erythematosus Subtypes: A Prospective Observational Study in Asians.

IntroductionCutaneous manifestations are central to the primary diagnosis of systemic lupus erythematosus (SLE). However, information on the clinical, histopathologic, and direct immunofluorescence (DIF) features among subtypes of cutaneous lupus erythematosus (CLE), as well as longitudinal prospective observational study to evaluate the natural history and the progression to SLE, is lacking among Asians. Our objectives are to summarize the differences in the clinical, histopathologic, and DIF characteristics and serological profiles between various subtypes of CLE, and to provide its natural history and the association with disease activity in our Asian population.MethodsA prospective observational study on CLE patients was performed between May 2016 and May 2020. Patients underwent full physical/dermatologic examination, skin biopsy for histology, and DIF. Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores and laboratory data were evaluated. Time schedule and characteristics for resolution and/or the disease progression to SLE were recorded in subsequent follow-ups.ResultsOf 101 biopsy-proven CLE patients, 25 had acute CLE (ACLE), 8 had subacute CLE (SCLE), 39 had chronic CLE (CCLE) only, 22 had CCLE with SLE, and 7 had LE-nonspecific cutaneous lesions only. Patients with exclusive CLE showed lower female preponderance, serological abnormalities, and correlation to systemic disease. However, when CLE was accompanied with any LE-nonspecific cutaneous manifestations, they were associated with high antinuclear antibody (ANA) titer, renal, hematologic, joint involvement, and greater SLEDAI score. Of 207 biopsy sections, SCLE/CCLE regardless of systemic involvement showed significantly higher percentage of superficial/deep perivascular and perieccrine infiltration than ACLE. On DIF, deposition of multiple immunoreactants was associated with higher systemic disease. Approximately 10% of CLE-only patients later developed SLE but had mild systemic involvement.ConclusionOur findings support that each CLE subtype has a diverse and unique character. Comprehensive understanding of the differences among CLE subtypes is important for achieving the correct diagnosis and providing appropriate disease monitoring and management.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13555-020-00471-y.

OCULAR ROSACEA AND ZOONOTIC DEMODICOSIS

Among the temporary skin ecto-parasites, Demodex folliculorum is a worm-like mite that infests hairfollicles in various mammals including man. Rosacea is a common skin disorder that may occur inadults of all ethnic backgrounds, but is most commonly diagnosed in individuals with fair skin. Ocularrosacea may present independently or in association with cutaneous subtypes of rosacea. This studyclarified the correlation between ocular rosacea and demodicosis folliculorum in family patients; twofemales of them were superimposed with secondary bacterial infection. The patients acquired in zoonoticinfestation from their pet dog. The pet dog was sent to the Governmental Veterinary Hospital atAbbassia and was treated with Ivermectin®.Specific ocular infections often required etiological diagnosis of combined consultant ophthalmologyand microbiology

Hierarchical Clustering of Cutaneous Melanoma Based on Immunogenomic Profiling.

Cutaneous melanoma is an aggressive malignancy with high heterogeneity. Several studies have been performed to identify cutaneous melanoma subtypes based on genomic profiling. However, few classifications based on assessments of immune-associated genes have limited clinical implications for cutaneous melanoma. Using 470 cutaneous melanoma samples from The Cancer Genome Atlas (TCGA), we calculated the enrichment levels of 29 immune-associated gene sets in each sample and hierarchically clustered them into Immunity High (Immunity_H, n=323, 68.7%), Immunity Medium (Immunity_M, n=135, 28.7%), and Immunity Low (Immunity_L, n=12, 2.6%) based on the ssGSEA score. The ESTIMATE algorithm was used to calculate stromal scores (range: -1,800.51–1,901.99), immune scores (range: -1,476.28–3,780.33), estimate scores (range: -2,618.28–5,098.14) and tumor purity (range: 0.216–0.976) and they were significantly correlated with immune subtypes (Kruskal–Wallis test, P < 0.001). The Immunity_H group tended to have higher expression levels of HLA and immune checkpoint genes (Kruskal–Wallis test, P < 0.05). The Immunity_H group had the highest level of naïve B cells, resting dendritic cells, M1 macrophages, resting NK cells, plasma cells, CD4 memory activated T cells, CD8 T cells, follicular helper T cells and regulatory T cells, and the Immunity_L group had better overall survival. The GO terms identified in the Immunity_H group were mainly immune related. In conclusion, immune signature-associated cutaneous melanoma subtypes play a role in cutaneous melanoma prognosis stratification. The construction of immune signature-associated cutaneous melanoma subtypes predicted possible patient outcomes and provided possible immunotherapy candidates.

Tumor Mutation Burden and Structural Chromosomal Aberrations Are Not Associated with T-cell Density or Patient Survival in Acral, Mucosal, and Cutaneous Melanomas.

Tumor mutation burden (TMB) has been proposed as a key determinant of immunogenicity in several cancers, including melanoma. The evidence presented thus far, however, is often contradictory and based mostly on RNA-sequencing data for the quantification of immune cell phenotypes. Few studies have investigated TMB across acral, mucosal, and cutaneous melanoma subtypes, which are known to have different TMB. It is also unknown whether chromosomal structural mutations [structural variant (SV) mutations] contribute to the immunogenicity in acral and mucosal melanomas where such aberrations are common. We stained 151 cutaneous and 35 acral and mucosal melanoma patient samples using quantitative IHC and correlated immune infiltrate phenotypes with TMB and other genomic profiles. TMB and SVs did not correlate with the densities of CD8+ lymphocytes, CD103+ tumor-resident T cells (Trm), CD45RO+ cells, and other innate and adaptive immune cell subsets in cutaneous and acral/mucosal melanoma tumors, respectively, including in analyses restricted to the site of disease and in a validation cohort. In 43 patients with stage III treatment-naïve cutaneous melanoma, we found that the density of immune cells, particularly Trm, was significantly associated with patient survival, but not with TMB. Overall, TMB and chromosomal structural aberrations are not associated with protective antitumor immunity in treatment-naïve melanoma.

High D-dimer plasma concentration in systemic sclerosis patients: Prevalence and association with vascular complications.

To determine the frequency of elevated D-dimer plasma concentration (>500 ng/mL) in patients with systemic sclerosis and evaluate its association with systemic sclerosis-specific microvascular and macrovascular complications. Retrospective observational study of patients with systemic sclerosis followed in a tertiary referral center with at least one measurement of D-dimer between 2010 and 2018. A total of 214 patients were analyzed. Mean age at inclusion was 55.1 ± 14.7 years; 180 (84.1%) were female; 74 (34.6%) had diffuse cutaneous systemic sclerosis. Anti-Scl70 and anti-centromere antibodies were positive in 74 (34.6%) and 75 (35.0%) patients, respectively. D-dimer level was elevated in 93 (43.5%) patients, independently of cutaneous subtype (44.6% in diffuse cutaneous systemic sclerosis vs 42.9% in limited cutaneous systemic sclerosis, p = 0.81). At least one microvascular complication was found in 108 (50.5%) patients: 105 (49.1%) with previous or current digital ulcers, 6 (2.8%) with renal crisis, and 4 (1.9%) with pulmonary arterial hypertension. Microvascular complications were more frequent in patients with elevated D-dimer (57.0% vs 45.5%, p = 0.09), significantly so after exclusion of patients with a history of cancer and/or venous thromboembolism (60.5% vs 44.8%, p = 0.04). Macrovascular complications were detected in 15 (7.0%) patients and were associated with a high D-dimer level (11.8% vs 3.3%, p = 0.03). Over a median follow-up of 2.3 years [1.1-3.3] after D-dimer measurement, new macrovascular complications occurred only in patients with high D-dimer (n = 8). High D-dimer levels are frequently found in systemic sclerosis patients and seem to be associated with the occurrence of macrovascular and microvascular complications after adjustment for confounding factors.

TCL-302: Immunohistochemical Characterization of Anaplastic Large Cell Lymphoma Using Tissue Microarray

Context: Anaplastic Large Cell Lymphoma (ALCL) is a type of mature T-cell lymphomas with systemic and primary cutaneous (PCALCL) subtypes. Systemic ALCL includes anaplastic lymphoma kinase (ALK)+ and ALK-. ALK+ usually has the NPM/ALK gene, which has favorable prognosis compared to ALK-. PCALCL is usually indolent. DUSP22 rearrangement in ALK-ALCL has a favorable outcome like ALK+, indicating alternate pathways of ALCL. Objective: Our primary aim was to compare protein expression levels of selected signaling molecules in oncogenic pathways of ALCL (JAK1, STAT3, DUSP22, ERB4, BLIMP1, SOCS3) among the three subtypes. We also correlated expression levels to ORR, PFS, DFS, and OS. Design: This is a retrospective study correlating protein expression levels of various antibodies across 27 patient tissue samples. Setting: The study was set at H. Lee Moffitt Cancer Center and Research Institute, an academic referral center. Patients or other participants: We identified 50 ALCL patients from 2000–2019. Twenty-seven tissue samples (6 ALK+, 10 ALK-, 8 PCALCL, 3 controls) met eligibility criteria, which included pathologist-reviewed diagnosis of ALCL subtypes (ALK+, ALK-, PCALCL) and consent to the Tissue Core database. Interventions: Replicate cores were taken and TMAs were constructed from formalin-fixed, paraffin-embedded lymph node or skin biopsies. IHC was performed with Abs to selected proteins. Stained TMA was scanned using Aperio™ ScanScope XT2 with a 200×/0.8NA objective lens at 5 min/slide via Basler tri-linear array detection. TMAs were analyzed using Aperio Nuclear V9 Default algorithm with thresholds for stain intensity: Strong = 130, Moderate = 188, Weak = 162 to determine the % positive biomarker stain within each core. Main outcome measures: The primary study outcome measurement was comparison of protein expression levels based on specific pathways known or hypothesized to be involved in ALCL pathogenesis. We hypothesized that these protein expression levels would correlate to time to event outcomes Results: PCALCL, ALK+, and ALK- subgroups demonstrated a significant difference in SOCS3 expression with mean and std respectively: 42.4% (0.153), 17.4% (0.089), and 21.0% (0.155);p=0.008. Among all pairs, ALK+ and PCALCL were statistically different (p=0.011). Patients with high BLIMP1 expression (% larger than median, 28.5%) regardless of ALCL subtype were associated with better mOS (not reached) compared to patients with low ( Conclusions: We identified a significant difference in expression of two Abs among three subtypes of ALCL. Increased BLIMP1 was associated with favorable prognosis and could potentially be a positive prognostic marker. Increased SOCS3 appears more prevalent in PCALCL than systemic ALCL, suggesting a potential utility in DDx. We plan to validate our results in a larger sample. Adding secondary markers like Bcl-2 can be used in the future to correlate expression levels and response to targeted agents, such as venetoclax. Funding: University of South Florida Graduate Medical Education Grant ($7500).

UV biomarker genes for classification and risk stratification of cutaneous actinic keratoses and squamous cell carcinoma subtypes.

Currently, there is no sensitive molecular test for identifying transformation-prone actinic keratoses (AKs) and aggressive squamous cell carcinoma (SCC) subtypes. Biomarker-based molecular testing represents a promising tool for risk stratifying these lesions. We evaluated the utility of a panel of ultraviolet (UV) radiation-biomarker genes in distinguishing between benign and transformation-prone AKs and SCCs. The expression of the UV-biomarker genes in 31 SCC and normal skin (NS) pairs and 10 AK/NS pairs was quantified using the NanoString nCounter system. Biomarker testing models were built using logistic regression models with leave-one-out cross validation in the training set. The best model to classify AKs versus SCCs (area under curve (AUC) 0.814, precision score 0.833, recall 0.714) was constructed using a top-ranked set of 13 UV-biomarker genes. Another model based on a 15-gene panel was developed to differentiate histologically concerning from less concerning SCCs (AUC 1, precision score 1, recall 0.714). Finally, 12 of the UV-biomarker genes were differentially expressed between AKs and SCCs, while 10 genes were uniquely expressed in the more concerning SCCs. UV-biomarker gene subsets demonstrate dynamic utility as molecular tools to classify and risk stratify AK and SCC lesions, which will complement histopathologic diagnosis to guide treatment of high-risk patients.

Top-Down Proteomics of Human Saliva Discloses Significant Variations of the Protein Profile in Patients with Mastocytosis.

Mastocytosis is a myeloproliferative neoplasm causing abnormal clonal mast cell accumulation in different tissues, such as skin and bone marrow. A cutaneous subtype (CM) is distinguished from a systemic one (SM); SM patients can be grouped into SM with (SM+C) or without (SM-C) additional cutaneous lesions, and their classification is often challenging. This study was purposed to highlight variations in the salivary proteome of patients with different mastocytosis subtypes and compared to healthy controls. A top-down proteomics approach coupled to a label-free quantitation revealed salivary profiles in patients different from those of controls and a down-regulation of peptides/proteins involved in the mouth homeostasis and defense, such as statherin, histatins, and acidic proline-rich proteins (aPRPs), and in innate immunity and inflammation, such as the cathepsin inhibitors, suggesting a systemic condition associated with an exacerbated inflammatory state. The up-regulation of antileukoproteinase and S100A8 suggested a protective role against the disease status. The two SM forms were distinguished by the lower levels of truncated forms of aPRPs, statherin, P-B peptide, and cystatin D and the higher levels of thymosin β4 and α-defensins 1 and 4 in SM-C patients with respect to SM+C. Data are available via ProteomeXchange with identifier PXD017759.

116 A dynamic panel of UV signature genes for risk stratification of cutaneous actinic keratosis and squamous cell carcinoma subtypes

Actinic keratoses (AKs) are premalignant cutaneous lesions, with a small percentage (<5%) eventually developing into squamous cell carcinomas (SCCs). SCC is generally curable except a subset of aggressive SCCs characterized by increased tendency for recurrence and metastasis. Currently, there is no test for identifying high-risk AKs and aggressive SCC subtypes. Biomarker-based molecular testing represents a promising tool for risk stratifying these cutaneous lesions to guide clinical diagnosis and treatment.

Cutaneous lupus erythematosus: factors related to cutaneous activity and damage in a cohort of 260 patients from A Coruña, Spain.

Cutaneous lupus erythematosus is a chronic autoimmune disease that can leave important sequelae. To determine the factors that predict the activity and damage of the skin disease, and the impact of tobacco on the efficacy of antimalarials using the Cutaneous Lupus Erythematosus Disease Area and Severity Index. A consecutive case series was performed on 260 patients with cutaneous lupus erythematosus (α = 0.05; precision ± 6.5%). We carried out a descriptive analysis of the variables included, with a multivariate analysis to measure the association of variables with the Cutaneous Lupus Erythematosus Disease Area and Severity Index activity and damage (p value < 0.05). The Cutaneous Lupus Erythematosus Disease Area and Severity Index activity was greater in smokers than non-smokers (4.0 ±5.3 vs 1.2 ±3.4, p = 0.006). No significant differences were observed in the Cutaneous Lupus Erythematosus Disease Area and Severity Index activity when the efficacy of antimalarials was analyzed between smokers and non-smokers. Cutaneous Lupus Erythematosus Disease Area and Severity Index damage was higher in smokers than in non-smokers (2.0 ± 3.6 vs 1.2 ± 2.6, p = 0.029). Cutaneous Lupus Erythematosus Disease Area and Severity Index activity was associated with: (a) being an active smoker (odds ratio 3.04, 95% confidence interval 1.68-5.51, p < 0.001; regression coefficient 2.05, 95% confidence interval 0.69-3.42, p = 0.003); (b) the chronic cutaneous lupus erythematosus subtype (odds ratio 1.98, 95% confidence interval 1.02-3.84, p = 0.044); and (c) C-reactive protein increase (≥0.5 mg/dL) (regression coefficient 2.56, 95% confidence interval 0.40-4.71, p = 0.020). Cutaneous Lupus Erythematosus Disease Area and Severity Index damage was associated with: (a) the activity (regression coefficient 0.11, 95% confidence interval 0.01-0.20, p = 0.024); (b) the chronic cutaneous lupus erythematosus subtype (regression coefficient 2.46, 95% confidence interval 1.37-3.56, p < 0.001); (c) the use of topical treatment (regression coefficient 1.31, 95% confidence interval 0.01-2.61, p = 0.049); and (d) systemic treatment (regression coefficient 1.44, 95% confidence interval 0.35-2.53, p < 0.010). Smoking is related to an increase risk and a greater activity of cutaneous lupus erythematosus. The chronic cutaneous lupus erythematosus subtype and an increased C-reactive protein level were also associated with a higher disease activity. The sequelae were related to the activity, the chronic cutaneous lupus erythematosus subtype, and the use of topical and systemic treatment. The impact of tobacco on the efficacy of antimalarials may be caused by an increase in the severity of the disease more than by resistance in smokers.

Toripalimab for the treatment of melanoma

ABSTRACT Introduction Immune therapies have dramatically changed the treatment landscape for melanoma in the past decade. Ipilimumab, nivolumab, and pembrolizumab have been approved by U.S. Food and Drug Administration for the treatment of metastatic melanoma sequentially. Toripalimab, a humanized IgG4 monoclonal antibody against programmed cell death protein-1 (PD-1), was approved by National Medical Product Administration in China in 2018 as second-line therapy for metastatic melanoma. Areas covered This is a comprehensive review of the literature and studies of toripalimab in melanoma, including clinical trials and translational research. Expert opinion Toripalimab is not inferior to pembrolizumab as a second-line therapy for metastatic melanoma. Prospective validated predictive markers are lacking. Programmed cell death ligand 1 expression and tumor mutational burden are two common recognized biomarkers, but the predictability of these markers requires additional improvement. A number of studies have confirmed that PD-1 inhibitors, including toripalimab, are not as effective in mucosal and acral melanomas as in non-acral cutaneous subtype. Toripalimab in combination with tyrosine kinase inhibitor axitinib has shown a promising result for metastatic mucosal melanoma. It is crucial to explore the mechanisms underlying the varying biological behavior of melanoma subtypes, which may also provide clues of innate and acquired resistance to PD-1 blockade.

Pseudotumoral calcinosis in systemic sclerosis: Data from systematic literature review and case series from two referral centres

ObjectivesWe aimed to clarify the definition, distribution, clinical association and outcomes of large calcinosis in patients with systemic sclerosis (SSc). MethodsWe conducted a systematic literature review (SLR) focusing on SSc-related large calcified masses. Upon updating the terminology and definition, all cases of “pseudotumoral” calcinosis seen at the Cochin and Padova University Hospitals were reviewed. ResultsThe SLR yielded 30 SSc cases, with large calcified masses mainly defined as “tumoral” or “pseudotumoral”. Among the 629 SSc cases included in the Cochin and Padova cohorts, 19 (3%) living and 7 deceased patients were affected by pseudotumoral calcinosis; among these, the great majority had a severe vascular phenotype. The mean age in the whole population (56 cases) was 59 ± 11.4 years with a median disease duration at calcinosis onset of 7 (5–10) years. Twenty-five out of 56 patients (44.6%) had the diffuse cutaneous form of SSc. Anti-topisomerase I and anticentromere were found equally. Pseudotumoral calcinosis were commonly symmetrical and the size ranged from 2 to 15.5 cm. Most patients had multiple site involvement: 52% hand/wrist, 29% shoulders and elbows, 20% hips and 25% spinal calcinosis. Fistulization/ulceration and infections were reported in 32% and 23% of cases, respectively; nerve compression was found in 40% of spinal calcinosis and in one patient with limb calcinosis. There was no clear evidence of clinical and radiological improvement with any treatment. A partial improvement was seen in 7 patients that underwent surgery. ConclusionPseudotumoral calcinosis may occur in about 3% of SSc patients, commonly symmetrical and in multiple sites without differences regarding the cutaneous subtypes but often in those with a severe vascular phenotype. Medical treatment seems ineffective, whereas a surgical approach may be considered.

Increased Mortality in Asians With Systemic Sclerosis in Northern California.

ObjectiveThe objective of this study is to evaluate racial/ethnic differences in disease manifestations and survival in a US cohort of patients with systemic sclerosis (SSc), with a focus on Asian patients.MethodsA retrospective cohort study was conducted among Kaiser Permanente Northern California adults with an incident SSc diagnosis by a rheumatologist from 2007 to 2016, confirmed by a chart review to fulfill 2013 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria. Self‐reported race/ethnicity was categorized as non‐Hispanic white, Asian, Hispanic, and black. Disease manifestations and survival were compared, using white patients as the reference.ResultsA total of 609 patients with incident SSc were identified: 89% were women, and 81% had limited cutaneous SSc, with a mean age at diagnosis of 55.4 ± 14.8 years. The racial/ethnic distribution was 51% non‐Hispanic white (n = 310), 25% Hispanic (n = 154), 16% Asian (n = 96), and 8% black (n = 49). Compared with white patients, black patients had a greater prevalence of diffuse disease (14.5% vs. 44.9%; P < 0.001), and Asians had higher rates of anti‐U1‐RNP antibodies (32.1% vs. 11.9%; P = 0.005). Nine‐year overall survival rates following SSc diagnosis were lower in Asian (52.3%), black (52.2%), and Hispanic patients (68.2%) compared with white patients (75.8%). Pulmonary hypertension and infections were the leading causes of death in Asian patients. Asian race was associated with higher mortality on univariable (hazard ratio [HR] 1.83 [95% confidence interval (CI) 1.08‐2.99]; P = 0.020) and multivariable analyses (HR 1.80 [95% CI 0.99‐3.16]; P = 0.047) when adjusting for age, sex, body mass index, cutaneous subtype, smoking status, interstitial lung disease, pulmonary hypertension, renal crisis, and malabsorption syndrome.ConclusionAsian patients with SSc in this US cohort had increased mortality compared with white patients. These patients warrant close monitoring for disease progression.

Differential cardiovascular responses to cutaneous afferent subtypes in a nociceptive intersegmental spinal reflex

Electrical stimulation to segmental dorsal cutaneous nerves (DCNs) activates a nociceptive sensorimotor reflex and the same afferent stimulation also evokes blood pressure (BP) and heart rate (HR) responses in rats. To investigate the relationship between those cardiovascular responses and the activation of nociceptive afferents, we analyzed BP and HR responses to electrical stimulations at each DCN from T6 to L1 at 0.5 mA to activate A-fiber alone or 5 mA to activate both A- and C-fibers at different frequencies. Evoked cardiovascular responses showed a decrease and then an increase in BP and an increase and then a plateau in HR. Segmentally, both cardiovascular responses tended to be larger when evoked from the more rostral DCNs. Stimulation frequency had a larger effect on cardiovascular responses than the rostrocaudal level of the DCN input. Stimulation strength showed a large effect on BP changes dependent on C-fibers whereas HR changes were dependent on A-fibers. Additional A-fiber activation by stimulating up to 4 adjacent DCNs concurrently, but only at 0.5 mA, affected HR but not BP. These data support that cutaneous nociceptive afferent subtypes preferentially contribute to different cardiovascular responses, A-fibers to HR and C-fibers to BP, with temporal (stimulation frequency) and spatial (rostrocaudal level) dynamics.

Thalidomide and Lenalidomide for Refractory Systemic/Cutaneous Lupus Erythematosus Treatment: A Narrative Review of Literature for Clinical Practice.

Thalidomide has shown exceptional results in systemic/cutaneous lupus erythematosus(SLE/CLE). Recently, lenalidomide has been also prescribed for SLE/CLE treatment. Literature regarding efficacy/adverse events for these drugs is scarce with a single systematic review and meta-analysis focused solely on thalidomide for refractory cutaneous lupus subtypes. We, therefore, addressed in this narrative review the efficacy/adverse effects of thalidomide and lenalidomide for SLE and CLE. In addition, we provide a specialist approach for clinical practice based on the available evidence. Efficacy of thalidomide for refractory cutaneous lupus treatment was demonstrated by several studies, mostly retrospective with small sample size(≤20). The frequency of peripheral polyneuropathy is controversial varying from 15-80% with no consistent data regarding cumulative dose and length of use. Drug withdrawn results in clinical partial/complete reversibility for most cases (70%). For lenalidomide, seven studies (small sample sizes) reported its efficacy for SLE/CLE with complete/partial response in all patients with a mean time to response of 3 months. Flare rate varied from 25-75% occurring 0.5-10 months after drug withdrawn. There were no reports of polyneuropathy/worsening of previous thalidomide-induced neuropathy, but most of them did not perform nerve conduction studies. Teratogenicity risk exist for both drugs and strict precautions are required. Thalidomide is very efficacious as an induction therapy for patients with severe/refractory cutaneous lupus with high risk of scarring, but its longstanding use should be avoided due to neurotoxicity. Lenalidomide is a promising drug for skin lupus treatment, particularly regarding the apparent lower frequency of nerve side effects.

Investigating the presence of neutrophil extracellular traps in cutaneous lesions of different subtypes of lupus erythematosus

Neutrophil extracellular traps (NETs) are implicated in the pathogenesis of systemic lupus erythematosus (SLE). However, little is known about the implication of NETs in cutaneous lupus. In this case series of 30 patients, we compared the amounts of neutrophils producing NETs in cutaneous lesions of different subtypes of lupus (5 with discoid lupus or DLE, 5 with subacute cutaneous lupus or SCLE, 11 with acute cutaneous SLE, 7 with lupus panniculitis and 2 with chilblains). Immunofluorescence was performed on formalin-fixed paraffin-embedded skin biopsies using antibodies against neutrophilic granules (elastase, myeloperoxidase, PR-3 proteins and citrullinated histone 3). Dihydroethidium staining was performed to detect reactive oxygen species (ROS), known inducers of NETs. NETs were detected in the different subtypes of cutaneous lupus as well as in cutaneous lesions of SLE. The amounts of neutrophils producing NETs were significantly higher in lupus panniculitis (49%), acute cutaneous SLE (41%) and DLE (32%), in comparison with SCLE (5%) and chilblains (0%). This suggests that NETs might be associated with more tissue damage and scarring. ROS were observed in the different cutaneous subtypes of lupus independent of NETs.

Renal pathology and clinical associations in systemic sclerosis: a historical cohort study.

BackgroundThe information guiding the treatment decision(s) for renal diseases in systemic sclerosis (SSc) is the renal pathological finding. This study aimed to evaluate the renal pathological diagnosis and its clinical feature among SSc.MethodA historical cohort study was performed on adult Thai SSc patients who underwent renal biopsy during January 2005–December 2016. The renal pathologic findings and patient clinical characteristics were reviewed. Chi-square or Fisher’s exact test was applied to analyze the association between clinical manifestation and renal pathology.ResultsOf the 26 SSc patients identified (77% female), 46% had the diffuse cutaneous SSc subtype. The mean age at the time of biopsy was 53.2±14.4 years and median duration of disease was 2.4 years (IQR 0.5–7.0). Rapidly progressive glomerulonephritis (RPGN) was the most common renal manifestation (53.9%) followed by nephrotic syndrome (19.2%) and nephritis (11.5%). The pathological diagnosis included lupus nephritis (LN) class IV (26.9%), LN class V (19.2%), scleroderma renal crisis (SRC; 19.3%), progressive renal disease in scleroderma (7.7%), and IgA nephropathy (7.7%). The nephrotic syndrome was the most common renal feature among LN class V patients, whereas RPGN was the commonest renal presentation among LN class IV and SRC patients (p=0.001). Dialysis treatment at the time of kidney biopsy was significantly higher in SRC patients than in the other groups (p<0.001). The SRC tended to have more frequent cardiac involvement, pulmonary fibrosis, and shorter disease duration than the other groups.ConclusionThis is the first report of renal pathologic findings in Thai SSc patients. RPGN is the commonest renal manifestation among SSc who underwent kidney biopsy; for whom LN was the most common pathological finding. Nephrotic syndrome is a clinical feature of glomerular diseases other than renal involvement in SSc.

Molecular Profiling of Cutaneous Lupus Lesions Identifies Subgroups Distinct from Clinical Phenotypes.

Cutaneous lupus erythematosus (CLE) is a common manifestation of systemic lupus erythematosus (SLE), and CLE can also develop without systemic involvement. CLE can be difficult to treat and negatively contributes to quality of life. Despite the importance of CLE, our knowledge of what differentiates cutaneous lupus subtypes is limited. Here, we utilized a large cohort of 90 CLE lesional biopsies to compare discoid lupus erythematosus (DLE) and subacute cutaneous lupus (SCLE) in patients with and without associated SLE in order to discern the drivers of disease activity and possibly uncover better treatment targets. Overall, we found that DLE and SCLE share many differentially expressed genes (DEG) reflecting type I interferon (IFN) signaling and repression of EGFR pathways. No differences between CLE only and SLE-associated CLE lesions were found. Of note, DLE uniquely expresses an IFN-γ node. Unbiased cluster analysis of the DEGs identified two groups separated by neutrophilic vs. monocytic signatures that did not sort the patients based on clinical phenotype or disease activity. This suggests that unbiased analysis of the pathobiology of CLE lesions may be important for personalized medicine and targeted therapeutic decision making.