Hepatitis B Virus--Specific and Global T-Cell Dysfunction in Chronic Hepatitis B.

BACKGROUND & AIMS: T cells play a critical role in viral infection. We examined whether T-cell effector and regulatory responses can define clinical stages of chronic hepatitis B (CHB). METHODS: We enrolled 200 adults with CHB who participated in the National Institutes of Health-supported Hepatitis B Research Network from 2011 through 2013 and 20 uninfected individuals (controls). Peripheral blood lymphocytes from these subjects were analyzed for T-cell responses (proliferation and production of interferon gamma and interleukin 10) to overlapping hepatitis B virus (HBV) peptides (preS, S, preC, core, and reverse transcriptase), influenza matrix peptides, and lipopolysaccharide. T-cell expression of regulatory markers FOXP3, programmed death-1, and cytotoxic T lymphocyte-associated antigen-4 was examined by flow cytometry. Immune measures were compared with clinical parameters, including physician-defined immune-active, immune-tolerant, or inactive CHB phenotypes, in a blinded fashion. RESULTS: Compared with controls, patients with CHB had weak T-cell proliferative, interferon gamma, and interleukin 10 responses to HBV, with increased frequency of circulating FOXP3(+)CD127(-) regulatory T cells and CD4(+) T-cell expression of programmed death-1 and cytotoxic T lymphocyte-associated antigen-4. T-cell measures did not clearly distinguish between clinical CHB phenotypes, although the HBV core-specific T-cell response was weaker in hepatitis B e antigen (HBeAg)(+) than HBeAg(-) patients (percent responders: 3% vs 23%; P = .00008). Although in vitro blockade of programmed death-1 or cytotoxic T lymphocyte-associated antigen-4 increased T-cell responses to HBV, the effect was weaker in HBeAg(+) than HBeAg(-) patients. Furthermore, T-cell responses to influenza and lipopolysaccharide were weaker in CHB patients than controls. CONCLUSIONS: HBV persists with virus-specific and global T-cell dysfunction mediated by multiple regulatory mechanisms, including circulating HBeAg, but without distinct T-cell-based immune signatures for clinical phenotypes. These findings suggest additional T-cell-independent or regulatory mechanisms of CHB pathogenesis that warrant further investigation.

Outcomes of Patients With Multiple Cutaneous Squamous Cell Carcinomas: A 10-Year Single-Institution Cohort Study.

IMPORTANCE: Patients with multiple cutaneous squamous cell carcinomas (CSCCs) pose a management challenge for physicians, but their prognosis is unknown because outcomes have not been compared between patients who form single vs multiple CSCCs. OBJECTIVE: To compare outcomes in patients with 1 vs multiple CSCCs. DESIGN, SETTING, AND PARTICIPANTS: A 10-year retrospective single-institution cohort study at an academic tertiary care center of patients with dermally invasive (non-in situ) primary CSCC diagnosed from January 1, 2000, through December 31, 2009. MAIN OUTCOMES AND MEASURES: Electronic medical records were reviewed to determine the tumor stage (Brigham and Women's Hospital tumor stage) and outcomes (local recurrence [LR], nodal metastases [NM], and death due to CSCC). Outcomes were compared between patients with 1 vs more than 1 CSCC via multivariable competing-risk regression adjusted for other significant cofactors. RESULTS: Of 985 patients with CSCC, 727 had 1 CSCC, 239 had 2 to 9 CSCCs, and 19 had 10 or more CSCCs. Most patients with 10 or more CSCCs were immunosuppressed (15 of 19 [78.9%]). The median follow-up time was 50 months (range, 2-142 months). Patients with more than 1 CSCC had a higher risk of LR (subhazard ratio for 2-9 CSCCs, 1.8; 95% CI, 1.1-4.3; and for ≥10 CSCCs, 3.8; 95% CI, 1.4-10.0) and NM (subhazard ratio for 2-9 CSCCs, 3.0; 95% CI, 1.4-6.5; and for ≥10 CSCCs, 4.2; 95% CI, 1.4-10.4) compared with patients with 1 CSCC, adjusted for Brigham and Women's Hospital tumor stage. The 10-year cumulative incidence of LR and NM was higher in patients with 2 to 9 CSCCs and markedly higher in those with 10 or more CSCCs compared with patients who had 1 CSCC (10-year cumulative incidence for 1 CSCC: LR, 3.0%; 95% CI, 2.0%-4.5%; and NM, 2.3%; 95% CI, 1.5%-3.8%; for 2-9 CSCCs: LR, 6.7%; 95% CI, 4.2%-10.6%; and NM, 5.9%; 95% CI, 3.5%-9.6%; and for ≥10 CSCCs: LR, 36.8%; 95% CI, 19.2%-59.0%; and NM, 26.3%; 95% CI, 11.8%-48.8%). CONCLUSIONS AND RELEVANCE: Patients with multiple CSCCs warrant frequent follow-up because they have an elevated risk of LR and NM. In particular, patients with 10 or more CSCCs have markedly elevated risks of recurrence and metastasis.

Pseudoherpetic grover disease: report of 2 cases and review of the literature.

Two cases of a pseudoherpetic variant of Grover disease are presented. The first patient was a 60-year-old woman who had high fevers in combination with right lower lobe pneumonia. She developed an itchy papulovesicular rash on her back and upper abdomen. The second patient was a 68-year-old woman who while bedridden developed an itchy papulovesicular rash on her back. Vesiculobullous forms of dermatitis were clinically suspected in both cases, and herpetic vesicles were the lead diagnosis in one case. Pathologically, lesions from both patients revealed intraepidermal fluid-filled vesicles that at scanning magnification raised the suspicion of herpetic lesions. At higher magnification, acantholytic cells, some seemingly multinucleated, could be ppreciated. However, immunohistochemistry for herpes simplex virus and varicella zoster virus antigens proved negative. Moreover, some of the lesional cells revealed dyskeratosis more typical of the spongiotic/vesicular variant of Grover disease, and accordingly, this diagnosis was eventually established in both patients. Recognition of the pseudoherpetic variant of spongiotic/vesicular Grover disease is important in determining correct treatment, and therefore, subtle clues to its diagnosis should be sought in evaluation of such lesions.

Current status of diagnostic and prognostic markers in melanoma.

Melanoma is the most life-threatening common form of skin cancer. While most cutaneous melanomas are cured by surgical resection, a minority will relapse locally, regionally, or distantly. Biomarkers have represented a focal point for research aimed at improving diagnostic accuracy as well as providing prognostic information that may help to guide therapeutic decisions. While systemic melanoma therapies were of extremely limited utility for patients with advanced disease in the past, two drugs have been approved the FDA within the past several years, and it is possible that they may provide even greater impact if employed earlier in the disease process. To optimally employ these therapies, prognostic biomarkers may offer significant value. This article reviews methodologies for both discovery and routine testing of melanoma biomarkers. It also focuses on specific commonly used markers, as well as approaches to studying their applications to specific clinical settings. As the armamentarium of melanoma drugs grows, it is hoped that specific biomarkers will aid in guiding the use of these agents for patients in the clinic.

Prevalence of the metabolic syndrome in children with psoriatic disease.

Adults with psoriasis have a greater risk of developing metabolic syndrome (MetS) and cardiovascular disease (CVD), but few studies have investigated the prevalence of MetS and other risk factors for CVD in children with psoriasis. In an assessor-blinded study, 20 children ages 9-17 years with a current or previously documented history of psoriasis involving 5% or more of their body surface area or psoriatic arthritis were compared with a cohort of age- and sex-matched controls with benign nevi, warts, or acne. MetS, our primary endpoint, was defined by the presence of abnormal values in at least three of the following measures: triglycerides, high-density lipoprotein cholesterol (HDL-C), fasting blood glucose (FBG), waist circumference, and blood pressure. Secondary endpoints included high-sensitivity C-reactive protein (hs-CRP), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C). Thirty percent (6/20) of children with psoriasis met the criteria for MetS, compared with 5% (1/20) of the control group (p < 0.05). Subjects with psoriasis had higher mean FBG (91.1 mg/dL) than the control group (82.9 mg/dL) (p = 0.01). There were no statistically significant differences in the other four components of MetS, BMI, BMI percentile, hs-CRP, TC, or LDL-C. The results of this trial demonstrate that children with psoriasis have higher rates of MetS than age- and sex-matched controls. It may therefore be important to evaluate children with psoriasis for components of MetS to prevent future CVD morbidity and mortality.

Assessor-blinded study of the metabolic syndrome and surrogate markers of increased cardiovascular risk in children with moderate-to-severe psoriasis compared with age-matched population of children with warts.

Adult patients with psoriasis have an increased prevalence of the metabolic syndrome (MetS) and cardiovascular disease (CVD) risk factors due to elevations of Tumor Necrosis Factor and other inflammatory cytokines.1,2 Recently, higher rates of hyperlipidemia, obesity, hypertension, and diabetes mellitus were seen in patients with juvenile psoriasis.3 Here, we report the interim results of an ongoing study of MetS and CVD risk factors in pediatric psoriasis patients.

Cutaneous lupus erythematosus and anti-TNF-alpha therapy: a case report with review of the literature.

Anti-tumor necrosis factor-alpha (TNF-alpha) immunotherapy is revolutionizing the treatment of immune disease, particularly Crohn's disease, rheumatoid arthritis, psoriatic arthritis and psoriasis. The role of anti-TNF-alpha agents in the management of cutaneous lupus erythematosus (LE), however, is not as clear. While experimental reports have suggested a potential benefit of anti-TNF-alpha therapy in severe cutaneous LE, newer reports have identified these medications as instigators or exacerbators of the disease. In this review, the authors present a case of a patient whose persistent discoid LE (DLE) was exacerbated by a trial of adalimumab, one of the currently available TNF-alpha-blocking agents. The authors review 128 cases in the literature in which anti-TNF-alpha therapy was implicated in cutaneous LE pathogenesis, with emphasis on DLE, and consider a number of mechanisms whereby this arguably paradoxical effect may occur. The authors then propose possible approaches to the management of anti-TNF-alpha therapy-induced cutaneous LE.

Paraneoplastic dermatoses associated with gynecologic and breast malignancies.

UNLABELLED: Paraneoplastic dermatoses are a heterogeneous group of skin disorders that manifest an underlying internal malignancy. Early recognition of these cutaneous hallmarks offers an opportunity for early diagnosis, treatment of the internal malignancy and monitoring for tumor recurrence. The 9 most common paraneoplastic and metastatic cutaneous manifestations of malignancies found in women with gynecologic or breast disease are reviewed including a review of multicentric reticulohistiocytosis, dermatomyositis, malignant acanthosis nigricans, erythema gyratum repens, hypertrichosis lanuginosa acquisita, Sweet syndrome, Paget disease, extramammary Paget disease, and Sister Mary Joseph nodule. TARGET AUDIENCE: General obstetricians & gynecologists, reproductive endocrinology & infertility specialists, radiologists. LEARNING OBJECTIVES: After completion of this educational activity, the participant should be better able to identify cutaneous manifestations of gynecologic malignancies, evaluate patients with a thorough workup to screen those who have dermatoses suggestive of malignancy and assess patients with malignancy for the opportunity of early diagnosis and appropriate treatment.

Inhibition of melanoma angiogenesis by telomere homolog oligonucleotides.

Telomere homolog oligonucleotides (T-oligos) activate an innate telomere-based program that leads to multiple anticancer effects. T-oligos act at telomeres to initiate signaling through the Werner protein and ATM kinase. We wanted to determine if T-oligos have antiangiogenic effects. We found that T-oligo-treated human melanoma (MM-AN) cells had decreased expression of vascular endothelial growth factor (VEGF), VEGF receptor 2, angiopoeitin-1 and -2 and decreased VEGF secretion. T-oligos activated the transcription factor E2F1 and inhibited the activity of the angiogenic transcription factor, HIF-1alpha. T-oligos inhibited EC tubulogenesis and total tumor microvascular density matrix invasion by MM-AN cells and ECs in vitro. In melanoma SCID xenografts, two systemic T-oligo injections decreased by 60% (P < .004) total tumor microvascular density and the functional vessels density by 80% (P < .002). These findings suggest that restriction of tumor angiogenesis is among the host's innate telomere-based anticancer responses and provide further evidence that T-oligos may offer a powerful new approach for melanoma treatment.

Pilot, multicenter, double-blind, randomized placebo-controlled bilateral comparative study of a combination of calcipotriene and nicotinamide for the treatment of psoriasis.

BACKGROUND: Calcipotriene has limited efficacy in treating psoriasis. By inhibiting proinflammatory cytokines such as interleukin-12, interleukin-23, and tumor necrosis factor-alfa, nicotinamide may enhance the efficacy of calcipotriene therapy when used in combination. OBJECTIVE: We sought to determine if the combination of nicotinamide with calcipotriene is more effective than either component alone. METHODS: In this randomized, double-blinded, multicenter 7-arm bilateral comparison-controlled trial, patients were randomized to two of 7 treatments--placebo, calcipotriene 0.005% alone, nicotinamide 1.4% alone, calcipotriene plus nicotinamide 0.05%, calcipotriene plus nicotinamide 0.1%, calcipotriene plus nicotinamide 0.7%, or calcipotriene plus nicotinamide 1.4%--each administered to lesions on one side of the body or to one of two lesions at least 5 cm apart, for 12 weeks. Efficacy was measured using a clear to almost clear outcome. RESULTS: In all, 50.0% of patients in the calcipotriene and nicotinamide 1.4% combination group achieved a clear to almost clear outcome at week 12, compared with only 18.8% of patients treated with placebo (P = .002), 25% of patients treated with nicotinamide 1.4% alone (P = .02), and 31.5% of patients treated with calcipotriene alone (P = .096). A dose-response trend existed for increasing concentrations of nicotinamide, but it was not significant. LIMITATIONS: The relatively small patient numbers, relatively high placebo effect, and maximum in-life portion of only 12 weeks of dosing are weaknesses of the study. CONCLUSION: This study provides evidence that using the combination nicotinamide and calcipotriene may provide additional benefit in the topical treatment for patients with psoriasis and may be an adequate steroid-sparing substitute treatment.

The treatment of moderate-to-severe psoriasis: prescreening and monitoring psoriatic patients on biologics.

The development of biologics has dramatically altered the treatment of moderate-to-severe psoriasis while also introducing new standards of care for therapeutic monitoring. Currently, the biologics approved by the US Food and Drug Administration are divided into 3 classes: T-cell modulators, tumor necrosis factor-alpha inhibitors, and interleukin-12/23 inhibitors. Although the US Food and Drug Administration has established recommendations for pre- and peri-treatment screening evaluations, much of the evidence comes from clinical trials evaluating the short-term safety and efficacy of each medication, rather than long-term data, or studies that summarize either the appropriateness or feasibility of screening. Instead of following a blanket algorithm, providers must understand the evidence as it relates to each medication to determine which tests are appropriate for any specific patient. This chapter summarizes the current body of evidence and recommends a practical approach for monitoring psoriasis patients who are receiving biologic therapies.

Evaluation and management of psoriasis: an internist's guide.

Psoriasis is a debilitating chronic skin condition that afflicts millions of patients worldwide. Patients experiencing psoriasis report a magnitude of impaired quality of life that is often similar to that of patients who have heart failure and cancer. Many patients who have psoriasis are even themselves at risk for developing heart disease, metabolic syndrome, certain cancers, and psychiatric illness. Therefore, primary care physicians must appreciate the current psoriatic disease model and share a basic understanding of psoriasis management. This article reviews the epidemiology, clinical features, pathogenesis, comorbidities, and treatment of psoriasis, with special emphasis placed on the new class of medications, biologics, which are revolutionizing the management of the disease.

Pemphigus vulgaris in pregnancy: analysis of current data on the management and outcomes.

OBJECTIVES: The occurrence of pemphigus vulgaris (PV) during pregnancy is rare. The purpose of this review was to describe management of PV in the mother, and report maternal and perinatal outcomes associated with the disease. DATA SOURCES: A search of PubMed was conducted using the phrases "pemphigus and pregnancy" and "neonatal pemphigus." The bibliographies of retrieved articles were also searched for relevant reports. Only articles in English and in which the diagnosis of pemphigus had been made on the basis of histology or immunopathology were included. TABULATION, INTEGRATION, AND RESULTS: In 38 reports, pregnancies from 49 women with PV were described. Among the 40 patients in whom clinical profiles were provided, 33 had active disease and 7 were disease free. Prednisone was used in 37 of 49 (75%) patients with doses ranging from 5 to 300 mg/day (mean 152.5 mg). Concomitant therapies included plasmapheresis, plasma exchange, and dapsone in 1 patient each, and azathioprine in 5. Of the 44 live births, 20 (45%) neonates had PV lesions at birth and 24 (55%) were lesion-free. Five stillbirths were reported. In all neonates, PV lesions resolved within 1 to 4 weeks, either spontaneously or with mild topical corticosteroids treatment. Of the 5 intrauterine deaths, 1 was due to umbilical cord prolapse, 1 attributed to placental dysfunction, and 1 to cytomegalovirus pneumonitis. In the remaining 2, the cause was unknown. One neonate died 2 days after delivery due to meconium aspiration syndrome. Thus the aggregate perinatal mortality rate was 12% (6/49). CONCLUSIONS: The outcome of pregnancies complicated by pemphigus is generally good, but achieving good outcomes likely depends on the collaborative efforts of the dermatologist and obstetrician. The available data suggest that the rate of perinatal mortality is increased, but these data may be subject to publication bias. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this educational activity, the participant should be better able to describe appropriate medical therapies for pemphigus vulgaris complicating pregnancy, and plan the management of pregnancies complicated by pemphigus vulgaris.

Polypodium leucotomos extract decreases UV-induced Cox-2 expression and inflammation, enhances DNA repair, and decreases mutagenesis in hairless mice.

UV-irradiated skin and UV-induced tumors overexpress the inducible isoform of cyclooxygenase-2 (Cox-2), and Cox-2 inhibition reduces photocarcinogenesis. To evaluate photoprotective effects of Polypodium leucotomos extract (PL), hairless Xpc(+/-) mice were fed for 10 days with PL (300 mg/kg) or vehicle then UV-irradiated, once. By 24 hours, UV-induced Cox-2 levels were increased in vehicle-fed and PL-fed mice, whereas by 48 and 72 hours, Cox-2 levels were four- to fivefold lower in PL-fed mice (P < 0.05). p53 expression/activity was increased in PL-fed versus vehicle-fed then UV-irradiated mice. UV-induced inflammation was decreased in PL-fed mice, as shown by approximately 60% decrease (P < 0.001) in neutrophil infiltration at 24 hours, and macrophages by approximately 50% (<0.02) at 24 and 48 hours. By 72 hours, 54 +/- 5% cyclobutane pyrimidine dimers remained in vehicle-fed versus 31 +/- 5% in PL-fed skin (P < 0.003). The number of 8-hydroxy-2'-deoxyguanosine-positive cells were decreased before UV irradiation by approximately 36% (P < 0.01), suggesting that PL reduces constitutive oxidative DNA damage. By 6 and 24 hours, the number of 8-hydroxy-2'-deoxyguanosine-positive cells were approximately 59% (P < 0.01) and approximately 79% (P < 0.03) lower in PL-fed versus vehicle-fed mice. Finally, UV-induced mutations in PL-fed-mice were decreased by approximately 25% when assessed 2 weeks after the single UV exposure. These data demonstrate that PL extract supplementation affords the following photoprotective effects: p53 activation and reduction of acute inflammation via Cox-2 enzyme inhibition, increased cyclobutane pyrimidine dimer removal, and reduction of oxidative DNA damage.