Benjamin H. Kaffenberger

Ibrutinib treatment ameliorates murine chronic graft-versus-host disease

Chronic graft-versus-host disease (cGVHD) is a life-threatening impediment to allogeneic hematopoietic stem cell transplantation, and current therapies do not completely prevent and/or treat cGVHD. CD4+ T cells and B cells mediate cGVHD; therefore, targeting these populations may inhibit cGVHD pathogenesis. Ibrutinib is an FDA-approved irreversible inhibitor of Brutons tyrosine kinase (BTK) and IL-2 inducible T cell kinase (ITK) that targets Th2 cells and B cells and produces durable remissions in B cell malignancies with minimal toxicity. Here, we evaluated whether ibrutinib could reverse established cGVHD in 2 complementary murine models, a model interrogating T cell-driven sclerodermatous cGVHD and an alloantibody-driven multiorgan system cGVHD model that induces bronchiolar obliterans (BO). In the T cell-mediated sclerodermatous cGVHD model, ibrutinib treatment delayed progression, improved survival, and ameliorated clinical and pathological manifestations. In the alloantibody-driven cGVHD model, ibrutinib treatment restored pulmonary function and reduced germinal center reactions and tissue immunoglobulin deposition. Animals lacking BTK and ITK did not develop cGVHD, indicating that these molecules are critical to cGVHD development. Furthermore, ibrutinib treatment reduced activation of T and B cells from patients with active cGVHD. Our data demonstrate that B cells and T cells drive cGVHD and suggest that ibrutinib has potential as a therapeutic agent, warranting consideration for cGVHD clinical trials.

Estrogen modulation of endosome-associated toll-like receptor 8: an IFNα-independent mechanism of sex-bias in systemic lupus erythematosus.

Females of child-bearing age are more resistant to infectious disease and have an increased risk of systemic lupus erythematosus (SLE). We hypothesized that estrogen-induced gene expression could establish an immunoactivated state which would render enhanced defense against infection, but may be deleterious in autoimmune development. Using peripheral blood mononuclear cells (PBMCs), we demonstrate enhanced responses with immunogen stimulation in the presence of 17β-estradiol (E2) and gene array analyses reveal toll-like receptor 8 (TLR8) as an E2-responsive candidate gene. TLR8 expression levels are up-regulated in SLE and PBMCs stimulated with TLR8 agonist display a female sex-biased, E2-sensitive response. Moreover, we identify a putative ERα-binding region near the TLR8 locus and blocking ERα expression significantly decreases E2-mediated TLR8 induction. Our findings characterize TLR8 as a novel estrogen target gene that can lower the inflammatory threshold and implicate an IFNα-independent inflammatory mechanism that could contribute to higher SLE incidence in women.

The use of high resolution optical coherence tomography to evaluate robotic radical prostatectomy specimens.

OBJECTIVE Optical coherence tomography (OCT) is a unique technology, developed to provide high resolution, cross sectional images of human tissue. The objective of this study was to explore the feasibility of OCT for the evaluation of positive surgical margins and extra capsular extension in robotic prostatectomy specimens and compare it to histopathology. MATERIALS AND METHODS Radical prostatectomy was performed in 100 patients. Twenty OCT images of each specimen were taken from the base of the seminal vesicles (SV), apical and vesicle margins, peripheral and posterolateral area and any palpable nodule. Predictions were made regarding positive surgical margin, SV involvement, capsular invasion and compared with the final histopathology. RESULTS A total of 2000 OCT images were taken and analyzed. Out of 100 specimens, 85 had T2 disease, 15 had T3 disease with a median Gleasons score of 7 (range 6 to 9) and 10 had positive surgical margins. We predicted 21 specimens to have positive margins based on OCT images out of which 7 were truly positive and 14 were falsely positive. Based on OCT images, 79 specimens were predicted to have negative margins out of which 76 were truly negative and 3 were falsely negative. We found the sensitivity, specificity, positive predictive value and negative predictive value to be 70%, 84%, 33% and 96% respectively. CONCLUSION Our initial feasibility study established the template for the visual OCT characteristics of the prostate, SV and cancerous tissue. The negative predictive value of evaluating surgical margins was high.

Local recurrence rate of fine‐needle aspiration biopsy in primary high‐grade sarcomas

Fine‐needle aspiration biopsy (FNAB) is an emerging technique for diagnosis of bone and soft tissue lesions. While multiple studies have demonstrated efficacy, cost‐effectiveness, and convenience, none have attempted to determine if the modality leads to an increased rate of local recurrence. Our objective was to determine whether FNAB could be linked to an increased rate of local recurrence.

A retrospective descriptive study of oral azole antifungal agents in patients with patch test–negative head and neck predominant atopic dermatitis

BACKGROUND Head and neck dermatitis is a subtype of atopic dermatitis driven by Malassezia yeast. OBJECTIVE We sought to evaluate the response of these patients to systemic azole antifungals. METHODS We queried the electronic medical records from our institution for patients that were referred for allergy patch testing, were ultimately given the diagnosis of head and neck dermatitis, and were treated with oral azole antifungals over a 2-year period. RESULTS Twenty-four patients met inclusion criteria and were analyzed. Most patients noted their characteristic flare beginning during their teenage, young adult, or adult years. All were noted to have some involvement of the head and neck, and 17 responded to treatment. The mean time taking an azole antifungal medication was 8 months, with a mean overall follow-up of 10 months. LIMITATIONS This was a retrospective descriptive study, from a single institution, of a limited number of patients, and did not use a validated scoring system. CONCLUSION Itraconazole and other azole antifungals were an effective treatment for more than two-thirds of adult patients with head and neck predominant atopic dermatitis.

Remission of psoriasis after allogeneic, but not autologous, hematopoietic stem-cell transplantation

Hematopoietic stem-cell transplantation (HSCT) has emerged as an effective immunotherapy for several severe autoimmune diseases. A comprehensive search of the existing literature was performed for patients with psoriasis and HSCT. Nineteen patients have been reported to have psoriasis resolution after allogeneic or autologous HSCT. In the allogeneic setting, 10 of 13 were noted to have durable remission of their psoriasis with a mean follow-up of 49 months. Two cases that did reoccur were only transient. Six patients underwent autologous transplantation. Of these, 5 of 6 developed a recurrence of their psoriasis within 2 years. Based on a limited number of patients, psoriasis is likely to remit after allogeneic HSCT, but it is likely to recur after autologous HSCT.

Novel estrogen target gene ZAS3 is overexpressed in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a prototypic, inflammatory autoimmune disease characterized by significant gender bias. Previous studies have established a role for hormones in SLE pathogenesis, including the sex hormone estrogen. Estrogen regulates gene expression by translocating estrogen receptors (ER) α and β into the nucleus where they induce transcription by binding to estrogen response elements (EREs) of target genes. The ZAS3 locus encodes a signaling and transcriptional molecule involved in regulating inflammatory responses. We show that ZAS3 is significantly up-regulated in SLE patients at both the protein and mRNA levels in peripheral blood mononuclear cells (PBMCs). Furthermore, estrogen stimulates the expression of ZAS3 in vitro in several leukocyte and breast cancer cell lines of both human and murine origin. In vivo estrogen treatment mediates induction of tissue specific ZAS3 expression in several lymphoid organs in mice. Estrogen stimulation also significantly up-regulates ZAS3 expression in primary PBMCs, while treatment with testosterone has no effect. Mechanistically, estrogen induces differential ERα binding to putative EREs within the ZAS3 gene and ERα knockdown with siRNA prevents estrogen induced ZAS3 up-regulation. In contrast, siRNA targeting IFNα has no effect. These data demonstrate that ZAS3 expression is directly regulated by estrogen and that ZAS3 is overexpressed in lupus. Since ZAS3 has been shown to regulate inflammatory pathways, its up-regulation by estrogen could play a critical role in female-biased autoimmune disorders.

Aberrant Muscle Antigen Exposure in Mice Is Sufficient to Cause Myositis in a Treg Cell–Deficient Milieu

Objective Myositis is associated with muscle-targeted inflammation and is observed in some Treg cell–deficient mouse models. Because an autoimmune pathogenesis has been strongly implicated, the aim of this study was to investigate the hypothesis that abnormal exposure to muscle antigens, as observed in muscle injury, can induce autoimmune-mediated myositis in susceptible hosts. Methods FoxP3 mutant (scurfy) mice were mated to synaptotagmin VII (Syt VII) mutant mice, which resulted in a new mouse strain that combines impaired membrane resealing with Treg cell deficiency. Lymphocyte preparations from double-mutant mice were adoptively transferred intraperitoneally, with or without purified Treg cells, into recombination-activating gene 1 (RAG-1)–null recipients. Lymph node cells from mice with the FoxP3 mutation were transferred into RAG-1–null mice either 1) intraperitoneally in conjunction with muscle homogenate or purified myosin protein or 2) intramuscularly with or without cotransfer of purified Treg cells. Results FoxP3-deficient mouse lymph node cells transferred in conjunction with myosin protein or muscle homogenate induced robust skeletal muscle inflammation. The infiltrates consisted predominantly of CD4+ and CD8+ T cells, a limited number of macrophages, and no B cells. Significant inflammation was also seen in similar experiments using lymph node cells from FoxP3/Syt VII double-mutant mice but was absent in experiments using adoptive transfer of FoxP3 mutant mouse cells alone. The cotransfer of Treg cells completely suppressed myositis. Conclusion These data, derived from a new, reproducible model, demonstrate the critical roles of Treg cell deficiency and aberrant muscle antigen exposure in the priming of autoreactive cells to induce myositis. This mouse system has multifaceted potential for examining the interplay in vivo between tissue injury and autoimmunity.

The effect of climate change on skin disease in North America

&NA; Global temperatures continue to rise, reaching new records almost every year this decade. Although the causes are debated, climate change is a reality. Consequences of climate change include melting of the arctic ice cap, rising of sea levels, changes in precipitation patterns, and increased severe weather events. This article updates dermatologists about the effects of climate change on the epidemiology and geographic ranges of selected skin diseases in North America. Although globalization, travel, and trade are also important to changing disease and vector patterns, climate change creates favorable habitats and expanded access to immunologically naïve hosts. Endemic North American illnesses such as Lyme disease, leishmaniasis, and dimorphic fungal infections have recently expanded the geographic areas of risk. As temperatures increase, epidemic viral diseases such as hand‐foot‐and‐mouth disease may develop transmission seasons that are longer and more intense. Chikungunya and dengue are now reported within the southern United States, with Zika on the horizon. Cutaneous injuries from aquatic and marine organisms that have expanding habitats and longer durations of peak activity include jellyfish envenomation, cercarial dermatitis, and seabather eruption, among others. Skin cancer rates may also be affected indirectly by changes in temperature and associated behaviors.

Association of Dermatology Consultations With Patient Care Outcomes in Hospitalized Patients With Inflammatory Skin Diseases

Importance The value of inpatient dermatology consultations has traditionally been demonstrated with frequency in changes of diagnosis and management; however, the impact of dermatology consultations on metrics such as hospital length of stay and readmission rates remains unknown. Objective To determine the association of dermatology consultations with patient care in hospitalized patients using objective values. Design, Setting, and Participants We retrospectively queried the deidentified database of patients hospitalized between January 1, 2012, and December 31, 2014, at a single university medical center. A total of 413 patients with a primary inflammatory skin condition discharge diagnosis and 647 patients with primary inflammatory skin condition admission diagnosis were selected. Main Outcomes and Measures Hospital length of stay and 1-year readmission with inflammatory skin conditions. Results The 413 patients with a primary inflammatory skin condition discharge diagnosis were 61.0% female and had a mean (SD) age of 55.1 (16.4) years. The 647 patients with primary inflammatory skin condition admission diagnosis were 50.8% female and had a mean (SD) age of 57.8 (15.9) years. Multivariable modeling showed that dermatology consultations were associated with a reduction of 1-year inflammatory skin condition readmissions among patients who were discharged primarily with an inflammatory skin condition (readmission probability, 0.0025; 95% CI, 0.00020-0.030 with dermatology consult vs 0.026; 95% CI, 0.0065-0.10 without; odds ratio, 0.093; 95% CI, 0.010-0.840; P = .03). No other confounding variable was associated with reduction in readmissions. Multivariable modeling also showed that dermatology consultations were associated with a reduction in the adjusted hospital length of stay by 2.64 days (95% CI, 1.75-3.53 days; P < .001). Conclusions and Relevance Dermatology consultations were associated with improvements of outcomes among hospitalized patients. The expansion of the role of dermatology consultation services may improve patient care in a cost-effective manner.