Delayed antiretroviral therapy in HIV-infected individuals leads to irreversible depletion of skin- and mucosa-resident memory T cells.

People living with HIV (PLWH) are at increased risk for developing skin and mucosal malignancies despite systemic reconstitution of CD4+ T cells upon antiretroviral therapy (ART). The underlying mechanism of chronic tissue-related immunodeficiency in HIV is unclear. We found that skin CD4+ tissue-resident memory T (Trm) cells were depleted after HIV infection and replenished only upon early ART initiation. TCR clonal analysis following early ART suggested a systemic origin for reconstituting CD4+ Trm cells. Single-cell RNA sequencing in PLWH that received late ART treatment revealed a loss of CXCR3+ Trm cells and a tolerogenic skin immune environment. Human papilloma virus-induced precancerous lesion biopsies showed reduced CXCR3+ Trm cell frequencies in the mucosa in PLWH versus HIV- individuals. These results reveal an irreversible loss of CXCR3+ Trm cells confined to skin and mucosa in PLWH who received late ART treatment, which may be a precipitating factor in the development of HPV-related cancer.

Single-cell analysis reveals innate lymphoid cell lineage infidelity in atopic dermatitis.

BACKGROUND: Although ample knowledge exists about phenotype and function of cutaneous T lymphocytes, much less is known about the lymphocytic components of the skin's innate immune system. OBJECTIVE: To better understand the biologic role of cutaneous innate lymphoid cells (ILCs), we investigated their phenotypic and molecular features under physiologic (normal human skin [NHS]) and pathologic (lesional skin of patients with atopic dermatitis [AD]) conditions. METHODS: Skin punch biopsies and reduction sheets as well as blood specimens were obtained from either patients with AD or healthy individuals. Cell and/or tissue samples were analyzed by flow cytometry, immunohistochemistry, and single-cell RNA sequencing or subjected to in vitro/ex vivo culture. RESULTS: Notwithstanding substantial quantitative differences between NHS and AD skin, we found that the vast majority of cutaneous ILCs belong to the CRTH2+ subset and reside in the upper skin layers. Single-cell RNA sequencing of cutaneous ILC-enriched cell samples confirmed the predominance of biologically heterogeneous group 2 ILCs and, for the first time, demonstrated considerable ILC lineage infidelity (coexpression of genes typical of either type 2 [GATA3 and IL13] or type 3/17 [RORC, IL22, and IL26] immunity within individual cells) in lesional AD skin, and to a much lesser extent, in NHS. Similar events were demonstrated in ILCs from skin explant cultures and in vitro expanded ILCs from the peripheral blood. CONCLUSION: These findings support the concept that instead of being a stable entity with well-defined components, the skin immune system consists of a network of highly flexible cellular players that are capable of adjusting their function to the needs and challenges of the environment.

Safety of Brodalumab in Plaque Psoriasis: Integrated Pooled Data from Five Clinical Trials.

Brodalumab is approved for treatment of moderate-to-severe plaque psoriasis. Here, we assess the safety profile of brodalumab using pooled safety data from 5 phase II/III trials of brodalumab 140 mg or 210 mg. In total, 4,464 patients received brodalumab, representing 8,891.6 patient-years of exposure. During the placebo-controlled 12-week induction period, rates of serious adverse events per 100 patient-years were 10.8 and 9.6 (brodalumab 140 mg and 210 mg, respectively) vs 4.3 and 6.5 (ustekinumab and placebo, respectively); infections were the most frequent serious adverse event. Rates of serious adverse events during the comparator-controlled 52-week period were 14.4, 10.2 and 8.3 per 100 patient-years for brodalumab 210 mg, brodalumab 140 mg, and ustekinumab, respectively. Brodalumab was not associated with increased risks of malignancy, major adverse cardiac events, suicidal ideation and behaviour, or fatal events. Overall, brodalumab demonstrated an acceptable safety profile in short- and long-term treatment.

Single-cell RNA sequencing reveals markers of disease progression in primary cutaneous T-cell lymphoma.

BACKGROUND: In early-stage mycosis fungoides (MF), the most common primary cutaneous T-cell lymphoma, limited skin involvement with patches and plaques is associated with a favorable prognosis. Nevertheless, approximately 20-30% of cases progress to tumors or erythroderma, resulting in poor outcome. At present, factors contributing to this switch from indolent to aggressive disease are only insufficiently understood. METHODS: In patients with advanced-stage MF, we compared patches with longstanding history to newly developed plaques and tumors by using single-cell RNA sequencing, and compared results with early-stage MF as well as nonlesional MF and healthy control skin. RESULTS: Despite considerable inter-individual variability, lesion progression was uniformly associated with downregulation of the tissue residency markers CXCR4 and CD69, the heat shock protein HSPA1A, the tumor suppressors and immunoregulatory mediators ZFP36 and TXNIP, and the interleukin 7 receptor (IL7R) within the malignant clone, but not in benign T cells. This phenomenon was not only found in conventional TCR-αß MF, but also in a case of TCR-γδ MF, suggesting a common mechanism across MF subtypes. Conversely, malignant cells in clinically unaffected skin from MF patients showed upregulation of these markers. CONCLUSIONS: Our data reveal a specific panel of biomarkers that might be used for monitoring MF disease progression. Altered expression of these genes may underlie the switch in clinical phenotype observed in advanced-stage MF.

The Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD): The development and reliability testing of a novel clinical outcome measurement instrument for the severity of atopic dermatitis.

BACKGROUND: An Investigator Global Assessment (IGA) is recommended by health agencies for drug registration in atopic dermatitis (AD). Current IGA scales lack standardization. OBJECTIVES: To develop an IGA scale, training module, and clinical certification examination for use in AD trials; establish content validity; and assess reliability. METHODS: Expert dermatologists participated in the development of the validated IGA for AD (vIGA-ADTM). Reliability (interrater and intrarater) was assessed by 2 web-based surveys. Clinical certification for investigators consisted of a training module and examination. RESULTS: Expert consensus was achieved around a 5-point IGA scale including morphologic descriptions, and content validity was established. Survey 1 showed strong interrater reliability (Kendall's coefficient of concordance W [Kendall's W], 0.809; intraclass correlation [ICC], 0.817) and excellent agreement (weighted kappa, 0.857). Survey 2, completed 5 months after training of dermatologists, showed improvements in scale reliability (Kendall's W, 0.819; ICC, 0.852; weighted kappa, 0.889). In this study, 627 investigators completed vIGA-AD training and certification. LIMITATIONS: Ratings were assessed on photographs. CONCLUSION: A validated IGA scale and training module were developed with the intent of harmonizing assessment of disease severity in AD trials. Strong reliability and excellent agreement between assessments were observed.

[European Guidelines (S1) on the use of high-dose intravenous immunoglobulin in dermatology]. / Europäische Leitlinien (S1) für die Verwendung von hoch dosierten intravenösen Immunglobulinen in der Dermatologie.

BACKGROUND AND OBJECTIVES: Treatment of severe dermatological autoimmune diseases and toxic epidermal necrolysis (TEN) with high-dose intravenous immunoglobulin (IVIg) is a well-established procedure in dermatology. As treatment with IVIg is usually considered for rare clinical entities or severe cases, the use of immunoglobulin is not generally based on data from randomized controlled trials usually required for evidence-based medicine. Since the indications for the use of IVIg are rare, it is unlikely that such studies will be available in the foreseeable future. Because first-line use is limited by the high costs of IVIg, the first clinical guidelines on the use of IVIg in dermatological conditions were established in 2008 and renewed in 2011. METHODS: The European guidelines presented here were prepared by a panel of experts nominated by the European Dermatology Forum (EDF) and European Academy of Dermatology and Venereology (EADV). The guidelines were developed to update the indications for treatment currently considered effective and to summarize the evidence for the use of IVIg in dermatological autoimmune diseases and TEN. RESULTS AND CONCLUSION: The current guidelines represent consensual expert opinions and definitions on the use of IVIg reflecting current published evidence and are intended to serve as a decision-making tool for the use of IVIg in dermatological diseases.

Das subkutane weiße Fettgewebe: die unterste Etage der immunologischen Hautbarriere.

Die äußere Begrenzung des Körpers von Säugetieren, die Haut, besteht aus drei Schichten, Epidermis, Dermis und subkutanem weissem Fettgewebe (subcutaneous white adipose tissue, SWAT). Während die Epidermis und Dermis hinsichtlich ihrer Funktion als «Immunbarriere¼ eingehend charakterisiert sind, ist über das SWAT nur wenig bekannt. SWAT des Menschen setzt sich aus Läppchen zusammen, die vor allem aus Adipozyten bestehen und durch vaskularisierte Bindegewebssepten unterteilt und voneinander getrennt werden. Eine immun-phänotypische Untersuchung von durch Fettabsaugung gewonnenem SWAT zeigte, dass gesundes SWAT keine Entzündungszeichen aufweist, jedoch Immunzellen beherbergt.  Im Unterschied zur restlichen Haut handelt es sich dabei hauptsächlich um Makrophagen und, in geringerem Maße, T- Lymphozyten, deren Phänotyp darauf hinweist, dass ihnen primär anti-inflammatorische und regulierende Funktionen zukommen. SWAT besitzt also nicht nur eine mechanische, sondern möglicherweise auch immunologische Schutzfunktion, die darin besteht, überschießende Immun- sowie Entzündungsreaktionen zu verhindern oder zumindest abzumildern.

Subcutaneous white adipose tissue: The deepest layer of the cutaneous immune barrier.

Mammalian skin, the outer covering of the body, is composed of three layers, i.e. the epidermis, the dermis and the subcutaneous white adipose tissue (SWAT). While the contribution of epidermis and dermis to the skin's immune function is well established, the role, if any, of SWAT in this regard has yet to be determined. Human SWAT is made up of lobules which consist mainly of adipocytes and are subdivided and separated from each other by vascularized septae of connective tissue. An immunophenotypic analysis of liposuction-derived SWAT demonstrated that healthy subcutaneous fat tissue, although showing no overt signs of inflammation, harbors an indigenous system of immunocytes. As opposed to epidermis and dermis, they belong mainly to the mononuclear phagocyte lineage and, to a lesser extent, represent T-lymphocytes. Their phenotype indicates that these two major subsets of SWAT leukocytes are primarily concerned with ant-inflammatory and/or regulatory functions. It thus appears that SWAT is more than a cushion protecting against mechanical trauma, and may subserve immunomodulatory functions aimed at preventing or, at least, mitigating exaggerated immune and/or inflammatory reactions..

Prevalence of Skin-specific Autoantibodies in HIV-infected Patients and Uninfected Controls.

Various autoantibodies are detected more frequently in HIV-infected individuals than in HIV-negative controls; however, limited data exist regarding autoimmune blistering skin diseases. Using enzyme-linked immunoassay (ELISA) and indirect immunofluore-scence, no difference in the frequency and magnitude of autoantibodies against BP180, BP230, desmoglein 1 and 3 was found between 594 HIV-infected patients and 248 uninfected controls in this cross-sectional study (16.0% vs. 11.7%, respectively, for at least one positive ELISA, p = 0.11). Interestingly, reactive syphilis serology in both HIV-infected individuals and uninfected controls was associated with positive anti-BP180 ELISA results (adjusted odds ratio (OR) 2.14, 95% confidence interval (CI) 1.07-4.29, p = 0.03 and OR 4.70, CI 1.3-16.86; p = 0.0180). Our study shows a comparably low prevalence of cutaneous autoantibodies in both HIV-infected patients and uninfected controls lacking signs of autoimmune blistering skin disease. Positive BP180 ELISA in the absence of clinical signs of bullous pemphigoid should prompt further evaluation for syphilis antibodies.

Mycobacterium tuberculosis-Infected Hematopoietic Stem and Progenitor Cells Unable to Express Inducible Nitric Oxide Synthase Propagate Tuberculosis in Mice.

Persistence of Mycobacterium tuberculosis within human bone marrow stem cells has been identified as a potential bacterial niche during latent tuberculosis. Using a murine model of tuberculosis, we show here that bone marrow stem and progenitor cells containing M. tuberculosis propagated tuberculosis when transferred to naive mice, given that both transferred cells and recipient mice were unable to express inducible nitric oxide synthase, which mediates killing of intracellular bacteria via nitric oxide. Our findings suggest that bone marrow stem and progenitor cells containing M. tuberculosis propagate hallmarks of disease if nitric oxide-mediated killing of bacteria is defective.

Phase 3 Studies Comparing Brodalumab with Ustekinumab in Psoriasis.

BACKGROUND: Early clinical studies suggested that the anti-interleukin-17 receptor A monoclonal antibody brodalumab has efficacy in the treatment of psoriasis. METHODS: In two phase 3 studies (AMAGINE-2 and AMAGINE-3), patients with moderate-to-severe psoriasis were randomly assigned to receive brodalumab (210 mg or 140 mg every 2 weeks), ustekinumab (45 mg for patients with a body weight ≤100 kg and 90 mg for patients >100 kg), or placebo. At week 12, patients receiving brodalumab were randomly assigned again to receive a brodalumab maintenance dose of 210 mg every 2 weeks or 140 mg every 2 weeks, every 4 weeks, or every 8 weeks; patients receiving ustekinumab continued to receive ustekinumab every 12 weeks, and patients receiving placebo received 210 mg of brodalumab every 2 weeks. The primary aims were to evaluate the superiority of brodalumab over placebo at week 12 with respect to at least a 75% reduction in the psoriasis area-and-severity index score (PASI 75) and a static physician's global assessment (sPGA) score of 0 or 1 (clear or almost clear skin), as well as the superiority of brodalumab over ustekinumab at week 12 with respect to a 100% reduction in PASI score (PASI 100). RESULTS: At week 12, the PASI 75 response rates were higher with brodalumab at the 210-mg and 140-mg doses than with placebo (86% and 67%, respectively, vs. 8% [AMAGINE-2] and 85% and 69%, respectively, vs. 6% [AMAGINE-3]; P<0.001); the rates of sPGA scores of 0 or 1 were also higher with brodalumab (P<0.001). The week 12 PASI 100 response rates were significantly higher with 210 mg of brodalumab than with ustekinumab (44% vs. 22% [AMAGINE-2] and 37% vs. 19% [AMAGINE-3], P<0.001). The PASI 100 response rates with 140 mg of brodalumab were 26% in AMAGINE-2 (P=0.08 for the comparison with ustekinumab) and 27% in AMAGINE-3 (P=0.007). Rates of neutropenia were higher with brodalumab and with ustekinumab than with placebo. Mild or moderate candida infections were more frequent with brodalumab than with ustekinumab or placebo. Through week 52, the rates of serious infectious episodes were 1.0 (AMAGINE-2) and 1.3 (AMAGINE-3) per 100 patient-years of exposure to brodalumab. CONCLUSIONS: Brodalumab treatment resulted in significant clinical improvements in patients with moderate-to-severe psoriasis. (Funded by Amgen; AMAGINE-2 and AMAGINE-3 ClinicalTrials.gov numbers, NCT01708603 and NCT01708629.).

Human skin dendritic cell fate is differentially regulated by the monocyte identity factor Kruppel-like factor 4 during steady state and inflammation.

BACKGROUND: Langerhans cell (LC) networks play key roles in immunity and tolerance at body surfaces. LCs are established prenatally and can be replenished from blood monocytes. Unlike skin-resident dermal DCs (dDCs)/interstitial-type DCs and inflammatory dendritic epidermal cells appearing in dermatitis/eczema lesions, LCs lack key monocyte-affiliated markers. Inversely, LCs express various epithelial genes critical for their long-term peripheral tissue residency. OBJECTIVE: Dendritic cells (DCs) are functionally involved in inflammatory diseases; however, the mechanisms remained poorly understood. METHODS: In vitro differentiation models of human DCs, gene profiling, gene transduction, and immunohistology were used to identify molecules involved in DC subset specification. RESULTS: Here we identified the monocyte/macrophage lineage identity transcription factor Kruppel-like factor 4 (KLF4) to be inhibited during LC differentiation from human blood monocytes. Conversely, KLF4 is maintained or induced during dermal DC and monocyte-derived dendritic cell/inflammatory dendritic epidermal cell differentiation. We showed that in monocytic cells KLF4 has to be repressed to allow their differentiation into LCs. Moreover, respective KLF4 levels in DC subsets positively correlate with proinflammatory characteristics. We identified epithelial Notch signaling to repress KLF4 in monocytes undergoing LC commitment. Loss of KLF4 in monocytes transcriptionally derepresses Runt-related transcription factor 3 in response to TGF-ß1, thereby allowing LC differentiation marked by a low cytokine expression profile. CONCLUSION: Monocyte differentiation into LCs depends on activation of Notch signaling and the concomitant loss of KLF4.

Human embryonic epidermis contains a diverse Langerhans cell precursor pool.

Despite intense efforts, the exact phenotype of the epidermal Langerhans cell (LC) precursors during human ontogeny has not been determined yet. These elusive precursors are believed to migrate into the embryonic skin and to express primitive surface markers, including CD36, but not typical LC markers such as CD1a, CD1c and CD207. The aim of this study was to further characterize the phenotype of LC precursors in human embryonic epidermis and to compare it with that of LCs in healthy adult skin. We found that epidermal leukocytes in first trimester human skin are negative for CD34 and heterogeneous with regard to the expression of CD1c, CD14 and CD36, thus contrasting the phenotypic uniformity of epidermal LCs in adult skin. These data indicate that LC precursors colonize the developing epidermis in an undifferentiated state, where they acquire the definitive LC marker profile with time. Using a human three-dimensional full-thickness skin model to mimic in vivo LC development, we found that FACS-sorted, CD207(-) cord blood-derived haematopoietic precursor cells resembling foetal LC precursors but not CD14(+)CD16(-) blood monocytes integrate into skin equivalents, and without additional exogenous cytokines give rise to cells that morphologically and phenotypically resemble LCs. Overall, it appears that CD14(-) haematopoietic precursors possess a much higher differentiation potential than CD14(+) precursor cells.

Ustekinumab treatment in severe atopic dermatitis: Down-regulation of T-helper 2/22 expression.

BACKGROUND: It has recently been suggested that patients with moderate to severe atopic dermatitis (AD) may profit from anti-interleukin (IL)-12/-23 p40 therapy. OBJECTIVE: We sought to assess the immunologic effects of ustekinumab treatment on AD skin and to correlate them with the clinical efficacy of this drug. METHODS: We investigated the course of 3 patients with severe AD who were administered 45 mg of subcutaneous ustekinumab over a period of 16 weeks. Clinical scores and skin biopsy specimens, taken at baseline and at week 8, were used to assess changes in disease severity. RESULTS: All patients showed a gradual improvement of the disease, achieving a 50% reduction in the Eczema Area and Severity Index score by week 16. Immunohistology of skin biopsy specimens revealed a significant decrease in the degree of epidermal hyperplasia/proliferation and the number of infiltrating dermal T cells, dendritic cells, and mast cells after treatment. Using quantitative real-time polymerase chain reaction of lesional skin, we found a clear reduction of T-helper 2-/22-associated molecules after therapy. LIMITATIONS: The small number of patients (n = 3) limits efficacy analysis and warrants prospective placebo-controlled studies in larger patient cohorts. CONCLUSION: Blocking IL-12/-23 p40 could be beneficial for a subgroup of patients with severely infiltrated AD.

Kombinierte Hoch-/Niedrig-Dosis-Therapie mit systemischen Glukokor-tikoiden bei schweren Verlaufsformen der Alopecia areata im Kindesalter.

HINTERGRUND: Schwere Verlaufsformen der Alopecia areata (AA) im Kindesalter sind aufgrund limitierter Optionen therapeutisch herausfordernd. Systemische, hochdosierte Glukokortikoide weisen die schnellste Ansprechrate auf, nach dem Absetzen kommt es allerdings zu Rezidiven. Eine längerfristige Hochdosis-Anwendung ist aufgrund der zu erwartenden Nebenwirkungen nicht empfehlenswert. Eine dauerhafte Steroiderhaltungstherapie unterhalb der Cushing-Schwellen-Dosis nach Bolustherapie könnte die Krankheitsaktivität ohne Nebenwirkungen längerfristig unterdrücken. PATIENTEN UND METHODIK: Im Rahmen einer offenen Anwendungsbeobachtung wurden 13 Kinder mit schweren Formen der AA in diese Studie eingeschlossen. Bei sieben Kindern lag eine AA totalis/universalis vor, bei sechs eine multifokale AA mit Befall von mehr als 50 % der Kopfhaut. Das Therapieregime sah eine initiale Prednisolon-Dosierung von 2 mg/kg Körpergeweicht (KG) vor und wurde innerhalb von neun Wochen auf eine Erhaltungsdosierung unter der individuellen Cushing-Schwelle reduziert. Der Nachbeobachtungszeitraum betrug ein bis drei Jahre. ERGEBNISSE: Wir beobachteten in 62 % aller Fälle ein komplettes Nachwachsen der Haare. Die mittlere Dauer bis zum Ansprechen lag bei 6,6 Wochen und konnte mit der Erhaltungstherapie über den gesamten Beobachtungszeitraum aufrechterhalten werden. An Nebenwirkungen wurden ausschließlich eine Gewichtszunahme (1-3 kg) bei allen Behandelten sowie eine milde Steroidakne in 23 % der Fälle beobachtet. SCHLUSSFOLGERUNGEN: Die kombinierte Hoch-/Niedrig-Dosis-Therapie mit systemischen Glukokortikoiden mittels Prednisolon zeigte eine hohe, dauerhafte Ansprechrate ohne signifikante Nebenwirkungen.

Sequential high- and low-dose systemic corticosteroid therapy for severe childhood alopecia areata.

BACKGROUND: Given the limited number of therapeutic options, severe childhood alopecia areata (AA) poses a clinical challenge. The best and most rapid response rates can be achieved with high-dose systemic corticosteroids, however, relapse following treatment discontinuation is inevitable. Due to systemic side effects, long-term high-dose corticosteroid regimens are not feasible. Following initial pulse therapy, continuation of corticosteroid therapy at a dose below the Cushing threshold might be able to suppress disease activity without causing severe side effects. PATIENTS AND METHODS: Thirteen children with severe AA were enrolled in our open observational study. Seven had alopecia totalis or universalis; the remaining six children had multifocal alopecia affecting more than 50 % of the scalp. The treatment regimen consisted of initial pulse therapy with prednisolone 2 mg/kg PO, which was subsequently tapered to a maintenance dose below the individual Cushing threshold within nine weeks. Children were followed-up for one to three years. RESULTS: Sixty-two percent of individuals showed complete hair regrowth. The mean time to response was 6.6 weeks. Said response was sustained with maintenance therapy for the entire follow-up period. Noticeable side effects included weight gain (1-3 kg), which was observed in all children, and mild steroid acne in 23 % of cases. CONCLUSIONS: Sequential high- and low-dose prednisolone therapy is an effective and safe therapeutic option for childhood AA.

Europäische Leitlinien (S1) für die Anwendung von hochdosierten intravenösen Immunglobulinen in der Dermatologie.

HINTERGRUND UND ZIELE: Die Behandlung schwerer dermatologischer Autoimmunerkrankungen und der toxischen epidermalen Nekrolyse (TEN) mit hochdosierten intravenösen Immunglobulinen (IVIg) ist ein bewährtes therapeutisches Verfahren in der Dermatologie. Da eine IVIg-Therapie in der Regel nur bei seltenen Erkrankungen oder bei schweren Fällen in Betracht gezogen wird, stützt sich die Anwendung von Immunglobulinen zumeist nicht auf Daten aus randomisierten kontrollierten Studien, wie sie in der evidenzbasierten Medizin erforderlich sind. Da Indikationen für die Anwendung von IVIg selten sind, ist es unwahrscheinlich, dass solche Studien in absehbarer Zeit durchgeführt werden. Wegen der hohen Kosten für IVIg im First-Line-Einsatz wurden die ersten klinischen Leitlinien für die Anwendung von IVIg bei dermatologischen Erkrankungen im Jahr 2008 herausgegeben und im Jahr 2011 überarbeitet. METHODEN: Diese europäischen Leitlinien wurden von einer Gruppe durch das EDF und die EADV benannter Experten erarbeitet. Die Leitlinien wurden erstellt, um die derzeit als wirksam erachteten Behandlungsindikationen zu aktualisieren und die für die Anwendung von IVIg bei dermatologischen Autoimmunerkrankungen und TEN vorliegenden Daten zusammenzufassen. ERGEBNISSE UND SCHLUSSFOLGERUNG: Die vorliegenden Leitlinien repräsentieren die einvernehmlichen Meinungen und Definitionen von Experten zur Anwendung von IVIg, die die aktuell publizierten Daten widerspiegeln, und sollen als Entscheidungshilfe für den Einsatz von IVIg bei dermatologischen Erkrankungen dienen.

European Guidelines (S1) on the use of high-dose intravenous immunoglobulin in dermatology.

BACKGROUND AND OBJECTIVES: Treatment of severe dermatological autoimmune diseases and toxic epidermal necrolysis (TEN) with high-dose intravenous immunoglobulin (IVIg) is a well-established procedure in dermatology. As treatment with IVIg is usually considered for rare clinical entities or severe cases, the use of immunoglobulin is not generally based on data from randomized controlled trials usually required for evidence-based medicine. Since the indications for the use of IVIg are rare, it is unlikely that such studies will be available in the foreseeable future. Because first-line use is limited by the high costs of IVIg, the first clinical guidelines on the use of IVIg in dermatological conditions were established in 2008 and renewed in 2011. METHODS: The European guidelines presented here were prepared by a panel of experts nominated by the EDF and EADV. The guidelines were developed to update the indications for treatment currently considered effective and to summarize the evidence for the use of IVIg in dermatological autoimmune diseases and TEN. RESULTS AND CONCLUSION: The current guidelines represent consensual expert opinions and definitions on the use of IVIg reflecting current published evidence and are intended to serve as a decision-making tool for the use of IVIg in dermatological diseases.

Diverse T-cell responses characterize the different manifestations of cutaneous graft-versus-host disease.

Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HCT) and can present in an acute (aGVHD), a chronic lichenoid (clGVHD), and a chronic sclerotic form (csGVHD). It is unclear whether similar or different pathomechanisms lead to these distinct clinical presentations. To address this issue, we collected lesional skin biopsies from aGVHD (n = 25), clGVHD (n = 17), and csGVHD (n = 7) patients as well as serial nonlesional biopsies from HCT recipients (prior to or post-HCT) (n = 14) and subjected them to phenotypic and functional analyses. Our results revealed striking differences between aGVHD and clGVHD. In aGVHD, we found a clear predominance of T helper (Th)2 cytokines/chemokines and, surprisingly, of interleukin (IL)-22 messenger RNA as well as an increase of IL-22-producing CD4(+) T cells. Thymic stromal lymphopoietin, a cytokine skewing the immune response toward a Th2 direction, was elevated at day 20 to 30 post-HCT in the skin of patients who later developed aGVHD. In sharp contrast to aGVHD, the immune response occurring in clGVHD showed a mixed Th1/Th17 signature with upregulated Th1/Th17 cytokine/chemokine transcripts and elevated numbers of interferon-γ- and IL-17-producing CD8(+) T cells. Our findings shed new light on the T-cell responses involved in the different manifestations of cutaneous GVHD and identify molecular signatures indicating the development of the disease.