Search

ZusammenfassungVaskulopathien und Vaskulitiden stellen diagnostisch und therapeutisch eine interdisziplinäre Herausforderung dar. Zugrunde liegen unterschiedliche pathophysiologische Mechanismen, die zu vielfältigen klinischen Krankheitsbildern führen können und therapeutisch unterschiedliche Ansätze erlauben. Sowohl Vaskulitiden als auch Vaskulopathien müssen nicht zwangsläufig mit einer Systembeteiligung einhergehen, sondern können auch als rein kutane Varianten auftreten. Aufgrund mangelnder pathognomonischer Laborparameter ist die Diagnose häufig klinisch zu stellen. Dieser Artikel soll den differentialdiagnostischen Blick, insbesondere auf die kutanen Manifestationsformen bei Vaskulopathien und Vaskulitiden, schärfen.

Objectives Gastroesophageal reflux disease (GERD) occurs frequently in patients with SSc. We investigated whether the presence of GERD and/or the use of anti-acid therapy, specifically proton-pump inhibitors (PPIs), are associated with long-term outcomes, especially in SSc-associated interstitial lung disease (SSc-ILD). Methods We retrospectively analysed patients with SSc and SSc-ILD from the German Network for Systemic Sclerosis (DNSS) database (2003 onwards). Kaplan–Meier analysis compared overall survival (OS) and progression-free survival (PFS) in patients with GERD vs without GERD (SSc and SSc-ILD), and PPI vs no PPI use (SSc-ILD only). Progression was defined as a decrease in either percentage predicted forced vital capacity of ≥10% or single-breath diffusing capacity for carbon monoxide of ≥15%, or death. Results It was found that 2693/4306 (63%) registered patients with SSc and 1204/1931 (62%) with SSc-ILD had GERD. GERD was not associated with decreased OS or decreased PFS in patients in either cohort. In SSc-ILD, PPI use was associated with improved OS vs no PPI use after 1 year [98.4% (95% CI: 97.6, 99.3); n = 760 vs 90.8% (87.9–93.8); n = 290] and after 5 years [91.4% (89.2–93.8); n = 357 vs 70.9% (65.2–77.1); n = 106; P Conclusion GERD had no effect on survival in SSc or SSc-ILD. PPIs improved survival in patients with SSc-ILD. Controlled, prospective trials are needed to confirm this finding.

Das Schleimhautpemphigoid (SHP) ist eine Pemphigoid-Erkrankung, die sich überwie-gend an der Schleimhaut manifestiert. Betroffen sind vor allem die Schleimhäute von Mund, Augen, Nase und Pharynx, aber auch von Larynx, Trachea, Ösophagus sowie die Genital- und Perianal-Region. Die Ausprägung der Erkrankung ist variabel und reicht von gingivalem Erythem und einzelnen oralen Läsionen bis zu schwerwiegen-den trachealen Strikturen, die die Atmung behindern sowie konjunktivaler Vernarbung mit deutlichen Visuseinschränkungen und, nicht selten, Erblindung. Die Diagnose beruht neben dem klinisch vorherrschenden Schleimhautbefall auf der direkten Im-munfluoreszenz eines nichtläsionalen Biopsats und der Serologie. Das hauptsächliche Zielantigen ist BP180 (Kollagen XVII) und Reaktivität mit Laminin 332 ist in circa 25 % der SHP-Patienten mit einem Malignom assoziiert. Die Behandlung des SHP ist eine Herausforderung. Einerseits ist durch den Befall verschiedener Schleimhäute eine gute interdisziplinäre Zusammenarbeit der verschiedenen Fachdisziplinen gefordert, ande-rerseits stehen auf Grund der Seltenheit der Erkrankung keine randomisierten kont-rollierten klinischen Studien zur Verfügung. Ziel der Leitlinie ist es, das klinische Bild einschließlich Schweregrade und Scoring-Systeme darzustellen sowie Anleitung zu geben für die Diagnosestellung und Therapie dieser komplexen Erkrankung. Beim SHP spielt die interdisziplinäre Zusammenarbeit eine wesentliche Rolle sowie die möglichst zeitnahe Diagnosestellung und Einleitung einer adäquaten Therapie, um irreversible Schäden der Schleimhäute mit schwerwiegenden Komplikationen zu vermeiden.

Summary Mucous membrane pemphigoid (MMP) is a pemphigoid disease with predominant mucous membrane involvement. It mainly affects the mucous membranes of the mouth, eyes, nose and pharynx, but also the larynx, trachea, esophagus, genital and perianal regions. The manifestation of the disease covers a wide spectrum from gingival erythema and single oral lesions to severe tracheal strictures that obstruct breathing and conjunctival scarring with marked visual impairment and, not infrequently, blindness. In addition to a clinical picture of predominant mucosal involvement, diagnosis is based on direct immunofluorescence of a peri‐lesional biopsy and serology. The main target antigen is BP180 (collagen XVII), and reactivity with laminin 332 is associated with malignancy in approximately 25 % of MMP patients. The treatment of MMP is challenging. On the one hand, due to the involvement of different mucous membranes, good interdisciplinary cooperation is required; on the other hand, due to the rarity of the disease, no randomized controlled clinical trials are available. The aim of this guideline is to present the clinical picture, including severity and scoring systems, and to give guidance for diagnosing and treating this complex disease. In MMP, interdisciplinary cooperation plays an essential role as well as the prompt diagnosis and initiation of adequate therapy in order to avoid irreversible damage to the mucous membranes with serious complications.

Antinuclear antibodies (ANA) are a common diagnostic finding in patients with systemic autoimmune diseases. In patients with typical clinical symptoms, the determination of ANA is of both diagnostic and prognostic importance. However, if ANA were determined due to unspecific symptoms, the interpretation of ANA findings can be problematic. In these cases, misjudgements with severe consequences for the patients are possible. Many systemic autoimmune diseases have prominent early skin involvement and the dermatologist can be the first physician that such a patient sees. Therefore, knowledge of ANA diagnostics is important for dermatologists. Basic principles of autoantibody diagnostics, guidance for the interpretation of laboratory results and new developments are discussed in this overview.

Hintergrund und ziele Das Erysipel, hervorgerufen durch beta-hamolysierende Streptokokken, und die begrenzte Phlegmone, haufig ausgelost durch Staphylococcus aureus oder andere Bakterien, sind Infektionen der Haut und des Weichteilgewebes mit typischen klinischen Symptomen. Allerdings wird oft (etwa in klinischen Studien) nicht zwischen den beiden Krankheitsbildern differenziert, obwohl dies therapeutisch relevant sein konnte. Das Erysipel lasst sich mit Penicillin effektiv behandeln, wahrend man fur die begrenzte Phlegmone Antibiotika mit breiterem Spektrum benotigt. Diese Studie untersucht, inwieweit Parameter wie CRP, Blutbild oder neuere Parameter wie unreife Granulozyten als Biomarker dienen konnen, um zwischen den beiden Entitaten zu unterscheiden. Patienten und methoden In diese retrospektive Analyse wurden 163 Patienten einbezogen. Wir verglichen Laborparameter von Patienten mit Erysipel (n = 68) mit denen von Patienten mit begrenzter Phlegmone (n = 41). In allen Fallen handelte es sich um Infektionen am Bein. Die Diagnose „Erysipel“ beziehungsweise „begrenzte Phlegmone“ wurde klinisch gestellt, mit dem zusatzlichen Aspekt, dass ein schnelles Ansprechen auf Penicillin fur die Diagnose „Erysipel“ sprach. Ergebnisse Beim Erysipel war die Entzundungsreaktion starker ausgepragt. Als die besten Parameter zur Unterscheidung zwischen den beiden Formen der Infektion erwiesen sich CRP und Leukozytenzahl. Ein CRP-Wert von ≥ 3,27 mg/dl sprach mit 75 % Sensitivitat und 73,2 % Spezifitat fur die Diagnose „Erysipel“. Schlussfolgerungen Unsere Ergebnisse stutzen die in den deutschen Leitlinien vertretene These, dass das Erysipel und die begrenzte Phlegmone unterschiedliche Formen der Entzundung sind. Die Bestimmung von CRP und Leukozyten hilft bei der Differenzialdiagnose.

Background: Pemphigus encompasses a group of life-threatening autoimmune bullous diseases characterized by blisters and erosions of the mucous membranes and skin. Before the era of immunosuppressive treatment, the prognosis of pemphigus was almost always fatal. Due to its rarity, only few randomized controlled therapeutic trials are available. Recently, rituximab has been approved as first-line treatment for moderate and severe pemphigus vulgaris in Europe and the USA.Objectives: The Autoimmune blistering diseases Task Force of the European Academy of Dermatology and Venereology (EADV) has initiated a throughout update of the guideline for the management of patients with pemphigus. Results: The guidelines for the management of pemphigus were updated and the degree of consent among all task force members was included. The final version of the guideline was consented by the European Dermatology Forum (EDF) and several patient organisations.

ObjectivesSystemic sclerosis is a heterogeneous, multisystem disease. It can occur at any age, but most patients develop the disease between the age of 40 to 50 years. There is controversial evidence on whether/how the age at disease onset affects their clinical phenotype. We here investigate the relationship between age at disease onset and symptoms in a large cohort of SSc patients (lcSSc, dcSSc and SSc-overlap syndromes).MethodsClinical data of the registry of the German Network for Systemic Scleroderma including 3281 patients were evaluated and subdivided into three age groups at disease onset (60 years).ResultsAmong all SSc patients, 24.5% developed their first non-Raynaud phenomenon symptoms at the age 60 years), except for gastrointestinal and musculoskeletal involvement. No significant difference was found for the use of corticosteroids. However, significantly, fewer patients older than 60 years received immunosuppressive treatment.ConclusionIn this large registry, ∼25% of patients developed SSc at an age above 60 years with an increased frequency of lcSSc. In this age group, an onset of internal organ involvement was significantly accelerated across all three subsets. These findings suggest that, in the elderly cohort, more frequent follow-up examinations are required for an earlier detection of organ complications.

Background Cold-induced urticaria is triggered by exposure to local or environmental cold and manifests as localized or systemic pruritic papules, sometimes accompanied by angio-oedema and anaphylaxis representing a life-threatening condition. Therapy options of atrial fibrillation (AF) include catheter ablation with different energy sources, of which cryoenergy may be superior to other energy sources regarding safety and efficacy. Case summary We report the case of a 60-year-old man suffering from symptomatic paroxysmal AF. The patient had a history of cold-induced urticaria without occurrence of systemic reactions to date. After successful pulmonary vein isolation (PVI) using cryoenergy, post-interventional oesophagogastroduodenoscopy and endosonography revealed newly occurred oedema in the middle oesophagus with inclusion of all oesophageal wall layers. Due to missing peri-atrial lesions, activation of cold urticaria during cryoablation rather than procedure-associated alterations was diagnosed. The patient reported no systemic or gastrointestinal symptoms after PVI. Discussion We could demonstrate that cold urticaria can manifest as oesophageal angio-oedema in AF patients undergoing cryoablation. Therefore, these patients should be carefully considered for an alternative energy source for PVI or premedication with antihistamines when using cryoenergy.

Background IgA vasculitis (IgAV) encompasses a systemic form involving kidneys, gut, skin, or joints, and a skin-limited form. One characteristic feature of systemic IgAV is deposition of galactose-deficient IgA1 (GD-IgA1) in kidneys (as in IgA nephropathy). The relevance of GD-IgA1 for cutaneous vasculitis is unknown. Objective We investigated whether GD-IgA1 is deposited perivascularly in systemic and also skin-limited IgAV and whether its serum levels differ between both forms. Methods In a case-control study, deposition of GD-IgA1 was analyzed immunohistochemically by KM55 antibody in skin biopsy specimens from 12 patients with skin-limited IgAV and 4 with systemic IgAV. GD-IgA1 levels were compared by enzyme-linked immunosorbent assay in sera from 15 patients each with skin-limited and systemic IgAV and from 11 healthy individuals. Results All biopsy samples from systemic IgAV, and also from skin-limited IgAV, revealed perivascular GD-IgA1 deposition. The average GD-IgA1 concentration in serum was significantly higher in systemic IgAV than in skin-limited IgAV, despite overlap between the groups. Limitations Although high GD-IgA1 levels may be predictive of systemic IgAV, patient numbers were too low to determine cutoff values for systemic versus skin-limited IgAV. Conclusion Perivascular GD-IgA1 deposition is a prerequisite for systemic and skin-limited IgAV; however, high GD-IgA1 levels in some patients with systemic IgAV suggest a dose-dependent effect of GD-IgA1 in IgAV.

Bullous pemphigoid (BP) is the most common autoimmune skin blistering disease characterized by autoimmunity against the hemidesmosomal proteins BP180, type XVII collagen, and BP230. To elucidate the genetic basis of susceptibility to BP, we performed the first genome-wide association study (GWAS) in Germans. This GWAS was combined with HLA locus targeted sequencing in an additional independent BP cohort. The strongest association with BP in Germans tested in this study was observed in the two HLA loci, HLA-DQA1*05:05 and HLA-DRB1*07:01. Further studies with increased sample sizes and complex studies integrating multiple pathogenic drivers will be conducted. Supplementary Information The online version contains supplementary material available at 10.1186/s13023-021-01863-9.

Although it is unquestionable that monoclonal gammopathy causes occlusive nonvasculitic vasculopathy,1 it is not clear yet, if it can cause immunoglobulin-mediated leukocytoclastic vasculitis (LcV) and how vigorously both conditions should be treated in monoclonal gammopathy of unclear significance (MGUS). In the recent nomenclature of cutaneous vasculitides (addendum to the CHCC2012),2 vasculitis in MGUS is mentioned as a possible, so-far unproven entity. Previous case reports did not sufficiently or explicitly distinguish it from occlusive vasculopathy. Adding to this dilemma is a lack of consensus with oncologists if or when chemotherapies are justified in MGUS with a paraprotein-associated disease. We provide evidence by means of 2 cases of MGUS that monoclonal gammopathy can cause primary immunoglobulin-mediated LcV and that its oncologic treatment abolishes it.

Raynaud's phenomenon (RP) is a painful vasospasm of small arteries, localised in fingers and toes. Typically these body parts turn white (ischemia), then blue (deoxygenation) and then red (reperfusion). Two different types of RP exist: the common primary RP without underlying disease and the rare secondary RP, mostly associated with rheumatoid diseases such as systemic sclerosis. Thus, the dermatologist has to be aware of this condition. In this article the clinical criteria, differential diagnoses, diagnostic considerations and treatment options are discussed.

Antinuclear antibodies (ANA) are a common diagnostic finding in patients with systemic autoimmune diseases. In patients with typical clinical symptoms, the determination of ANA is of both diagnostic and prognostic importance. However, if ANA were determined due to unspecific symptoms, the interpretation of ANA findings can be problematic. In these cases, misjudgements with severe consequences for the patients are possible. Many systemic autoimmune diseases have prominent early skin involvement and the dermatologist can be the first physician that such a patient sees. Therefore, knowledge of ANA diagnostics is important for dermatologists. Basic principles of autoantibody diagnostics, guidance for the interpretation of laboratory results and new developments are discussed in this overview.Antinukleäre Antikörper (ANA) sind ein typischer Laborbefund bei systemischen Autoimmunerkrankungen. Bei konkretem Verdacht auf diese Erkrankungen ist die Bestimmung der ANA sowohl diagnostisch als auch prognostisch wichtig. In der Praxis werden ANA allerdings oft aufgrund unspezifischer Symptome bestimmt, sodass die Interpretation eines positiven ANA-Nachweises häufig zu Problemen führt. Hier kann es zu Fehleinschätzungen mit schwerwiegenden Folgen für die Patienten kommen. Viele Kollagenosen manifestieren sich früh an der Haut. Entsprechende Patienten wenden sich daher entweder direkt an den Hautarzt oder werden von hausärztlichen oder rheumatologischen Kollegen zur dermatologischen Mitbeurteilung vorgestellt. Kenntnisse der ANA-Labordiagnostik sind aus diesem Grund für den Dermatologen wichtig. Daher werden in diesem Überblick grundlegende Prinzipien der Autoantikörperdiagnostik, Interpretationshilfen und aktuelle Neuerungen in der Diagnostik aus dermatologischer Perspektive zusammengefasst.

Background and objectives Erysipelas, caused by beta-hemolytic streptococci, and limited cellulitis, frequently caused by Staphylococcus aureus or other bacteria, are skin and soft tissue infections characterized by typical clinical signs. However, despite the therapeutical relevance they are often not differentiated (e.g in clinical trials). Erysipelas are efficiently treated with penicillin, while limited cellulitis is treated with more wide-spectrum antibiotics. This study investigates whether parameters such as CRP, blood counts or novel parameters like immature granulocytes could serve as biomarkers to distinguish between these entities. Patients and methods For this retrospective analysis 163 patients were included. We compared laboratory markers in patients with erysipelas (n = 68) to those with limited cellulitis (n = 41) of the leg. Both erysipelas and limited cellulitis were defined clinically, with an additional aspect for erysipelas being a prompt response to penicillin. Results Erysipelas were characterized by higher levels of inflammation. CRP and leukocyte counts are the best parameters to discriminate between both infections. A CRP value ≥ 3.27 mg/dl indicated the diagnosis of erysipelas with 75 % sensitivity and 73.2 % specificity. Conclusions Our results support the thesis that erysipelas and limited cellulitis are distinct infections as defined in the German guidelines and that an assessment of CRP and leukocytes is useful for differential diagnosis.

Imatinib mesylate (Glivec; Novartis AG, Basel, Switzerland) is a tyrosine kinase inhibitor which is used in the treatment of oncologic diseases like chronic myeloid leukemia and gastrointestinal stroma tumor (GIST). Among cutaneous side effects, bullous reactions are rare. The authors describe the case of a 66-year-old woman developing blistering and skin fragility on her hands, foot, lower legs, and back after intake of imatinib for treatment of GIST. Biopsy showed vacuolar alteration at the dermoepidermal junction (DEJ) associated with a few lymphocytes and a subepidermal blister. The upper papillary dermis below the vacuolar alteration and below the blister showed hyalinization and loss of elastic microfibrils. Direct immunofluorescence was negative for deposits of immunoglobulins. Immunofluorescence on cryosections revealed loss of laminin and collagen IV in vacuoles at the DEJ. Electron microscopy showed dissolution of lamina lucida and lamina densa of the basement membrane below as well as next to the vacuoles and blister. In conclusion, the authors present the first patient with GIST with blistering and skin fragility due to imatinib therapy. As a pathophysiological explanation the authors propose loss of laminin and collagen IV at the DEJ leading to basement membrane instability and blistering. This case also suggests additional features reminiscent of lichen sclerosus induced by imatinib, a drug which is actually known for its antifibrotic effects.

Clinical differentiation between herpes zoster and bacterial superficial skin and soft tissue infections of the face can be difficult. In addition, diagnosis can be complicated by bacterial superinfection of lesional herpes zoster. The aim of this study was to determine whether inflammatory parameters, such as C-reactive protein (CRP) and blood counts, might be reliable biomarkers to distinguish between skin and soft tissue infections and herpes zoster when the face is infected. The study data (multivariate analysis and area under the curve) identified CRP (0.880) and leukocytes (0.730) together as the parameters that best discriminate between skin and soft tissue infections and herpes zoster. A CRP threshold ≥ 2.05 mg/dl indicated a diagnosis of skin and soft tissue infection with a sensitivity of 80% and specificity of 83.8%. For leukocytes ≥ 7.3×109/l, diagnosis of skin and soft tissue infection had a sensitivity of 75% and specificity of 67.6%. Thus, when differential diagnosis is difficult, CRP and leukocytes should be determined, while parameters such as neutrophils or immature granulocytes do not add diagnostic value.

Uncontrolled inflammation is a leading cause of many clinically relevant diseases. Current therapeutic strategies focus mainly on immunosuppression rather than on the mechanisms of inflammatory resolution. Glucocorticoids (GCs) are still the most widely used anti-inflammatory drugs. GCs affect most immune cells but there is growing evidence for cell type specific mechanisms. Different subtypes of monocytes and macrophages play a pivotal role both in generation as well as resolution of inflammation. Activation of these cells by microbial products or endogenous danger signals results in production of pro-inflammatory mediators and initiation of an inflammatory response. GCs efficiently inhibit these processes by down-regulating pro-inflammatory mediators from macrophages and monocytes. On the other hand, GCs act on “naïve” monocytes and macrophages and induce anti-inflammatory mediators and differentiation of anti-inflammatory phenotypes. GC-induced anti-inflammatory monocytes have an increased ability to migrate toward inflammatory stimuli. They remove endo- and exogenous danger signals by an increased phagocytic capacity, produce anti-inflammatory mediators and limit T-cell activation. Thus, GCs limit amplification of inflammation by repressing pro-inflammatory macrophage activation and additionally induce anti-inflammatory monocyte and macrophage populations actively promoting resolution of inflammation. Further investigation of these mechanisms should lead to the development of novel therapeutic strategies to modulate undesirable inflammation with fewer side effects via induction of inflammatory resolution rather than non-specific immunosuppression.

International audience; Many pathogens, ranging from viruses to multicellular parasites, promote expansion of MDSCs, which are myeloid cells that exhibit immunosuppressive features. The roles of MDSCs in infection depend on the class and virulence mechanisms of the pathogen, the stage of the disease, and the pathology associated with the infection. This work compiles evidence supported by functional assays on the roles of different subsets of MDSCs in acute and chronic infections, including pathogen-associated malignancies, and discusses strategies to modulate MDSC dynamics to benefit the host.

Raynaud's phenomenon (RP) is a painful vasospasm of small arteries, localised in fingers and toes. Typically these body parts turn white (ischemia), then blue (deoxygenation) and then red (reperfusion). Two different types of RP exist: the common primary RP without underlying disease and the rare secondary RP, mostly associated with rheumatoid diseases such as systemic sclerosis. Thus, the dermatologist has to be aware of this condition. In this article the clinical criteria, differential diagnoses, diagnostic considerations and treatment options are discussed.

In patients with juvenile idiopathic arthritis (JIA), increased release of IFN-γ and GM-CSF in cells infiltrating synovial tissue can be a potent driver of monocyte activation. Given the fundamental role of monocyte activation in remodeling the early phases of inflammatory responses, here we analyze the GM-CSF/IFN-γ induced activity of human monocytes in such a situation in vitro and in vivo. Monocytes from healthy donors were isolated and stimulated with GM-CSF ± IFN-γ. Monocyte activation and death were analyzed by flow cytometry, immunofluorescence microscopy, ELISA, and qPCR. T-cell GM-CSF/IFN-γ expression and monocyte function were determined in synovial fluid and peripheral blood from 15 patients with active JIA and 21 healthy controls. Simultaneous treatment with GM-CSF and IFN-γ induces cell death of monocytes. This cell death is partly cathepsin B-associated and has morphological characteristics of necrosis. Monocytes responding to costimulation with strong proinflammatory activities are consequently eliminated. Monocytes surviving this form of hyperactivation retain normal cytokine production. Cathepsin B activity is increased in monocytes isolated from synovial fluid from patients with active arthritis. Our data suggest GM-CSF/IFN-γ induced cell death of monocytes as a novel mechanism to eliminate overactivated monocytes, thereby potentially balancing inflammation and autoimmunity in JIA.

Objective.Vasculopathy is a key factor in the pathophysiology of systemic sclerosis (SSc) and the main cause for Raynaud phenomenon (RP), digital ulcers (DU), and/or pulmonary arterial hypertension (PAH). It is so far unknown how patients with SSc are treated with vasoactive agents in daily practice. To determine to which extent patients with SSc were treated with different vasoactive agents, we used data from the German Network for Systemic Scleroderma registry.Methods.The data of 3248 patients with SSc were analyzed.Results.Patients were treated with vasoactive drugs in 61.1% of cases (1984/3248). Of these, 47.6% received calcium channel inhibitors, followed by 34.2% treated with angiotensin-converting enzyme (ACE) inhibitors, 21.1% treated with intravenous (IV) prostanoids, 10.1% with pentoxifylline, 8.8% with angiotensin 1 receptor antagonists (AT1RA), 8.7% with endothelin 1 receptor antagonists (ET1RA), 4.1% with phosphodiesterase type 5 (PDE5) inhibitors, and 5.3% with others. Patients with RP received vasoactive therapy in 63.3% of cases, with DU in 70.1%, and with PAH in 78.2% of cases. Logistic regression analysis revealed that patients with PAH were significantly more often treated with PDE5 inhibitors and ET1RA, and those with DU with ET1RA and IV prostanoids. In addition, 41.8% of patients were treated with ACE inhibitors and/or AT1RA. Patients registered after 2009 received significantly more often ET1RA, AT1RA, and IV prostanoids compared with patients registered prior to 2005.Conclusion.These data clearly indicate that many patients with SSc do not yet receive sufficient vasoactive therapy. Further, in recent years, a marked change of treatment regimens can be observed.

ObjectiveTo report 3 patients with relapsing-remitting multiple sclerosis (RRMS) showing vitiligo after treatment with alemtuzumab.MethodsRetrospective case series including flow cytometric analyses and T-cell receptor (TCR) sequencing of peripheral blood mononuclear cells.ResultsWe describe 3 cases of alemtuzumab-treated patients with RRMS developing vitiligo 52, 18, and 14 months after alemtuzumab initiation. Histopathology shows loss of epidermal pigmentation with absence of melanocytes and interface dermatitis with CD8+ T-cell infiltration. Also compatible with pathophysiologic concepts of vitiligo, peripheral blood mononuclear cells of one patient showed high proportions of CD8+ T cells with an activated (human leukocyte antigen–DR+), memory (CD45RO+), and type 1 cytokine (interferon-γ + tumor necrosis factor–α) phenotype at vitiligo onset compared to a control cohort of alemtuzumab-treated patients with RRMS (n = 30). Of note, analysis of CD8 TCR repertoire in this patient revealed a highly increased clonality and reduced repertoire diversity compared to healthy controls and treatment-naive patients with RRMS. We observed a predominance of single clones at baseline in this patient and alemtuzumab treatment did not substantially affect the proportions of most abundant clones over time.ConclusionThe 3 cases represent a detailed description of vitiligo as a T-cell-mediated secondary autoimmune disease following alemtuzumab treatment. The prevailing concept of unleashed B-cell responses might therefore not cover all facets of alemtuzumab-related secondary autoimmunity. Mechanistic studies, especially on TCR repertoire, might help clarify the underlying mechanisms.

The skin is one of the organs most frequently involved in vasculitides. Cutaneous vasculitis may present (1) part of a systemic vasculitis (e.g., IgA vasculitis), (2) a skin-restricted or skin-dominant variant of the corresponding systemic vasculitis without clinically apparent visceral involvement (e.g., cutaneous IgA vasculitis), or (3) a vasculitis occurring exclusively in the skin (e.g., erythema elevatun diutinum). The clinical symptoms of vasculitides are markedly determined by the size of the predominantly affected blood vessels. Systemic polyarteritis nodosa is regarded as a medium vessel vasculitis and is associated with multiple skin symptoms: (1) vasculitis of digital arteries with ensuing digital infarction, (2) livedo racemosa and subcutaneous nodules, and (3) in some patients even purpura and hemorrhagic macules due to additional small vessel vasculitis. In contrast, in its skin-restricted entity (i.e., cutaneous polyarteritis nodosa), the predominant symptoms are subcutaneous nodules surrounded by livedo racemosa, often on the lower legs. Among small-vessel vasculitides palpable purpura with predilection for the legs is a nearly pathognomonic feature of immune complex vasculitis. Variations in clinical symptoms indicate additional pathophysiological mechanisms or different vascultides: (1) ANCA-associated vasculitides often also entail nodules or sometimes livedo, (2) cryoglobulinemic vasculitis additionally may present with necrosis at cold exposed areas and involvement of vessels of various size, (3) small vessel vasculitis associated with systemic lupus erythematosus or rheumatoid arthritis shows predilection for additional sites (e.g., nailfolds) and also involvement of vessels beyond postcapillary venules, (4) recurrent macular vasculitis in hypergammaglobulinemia also occurs on dependent parts, but shows numerous small hemorrhagic macules instead of palpable purpura, (5) erythema elevatum diutinum begins with brightly red to violaceous plaques at extensor sites, followed by fibrotic nodules. Consequently, cutaneous symptoms provide pivotal clues for further diagnosis and ensuing management of vasculitides.

Human and murine studies showed that GM-CSF exerts beneficial effects in intestinal inflammation. To explore whether GM-CSF mediates its effects via monocytes, we analyzed effects of GM-CSF on monocytes in vitro and assessed the immunomodulatory potential of GM-CSF–activated monocytes (GMaMs) in vivo. We used microarray technology and functional assays to characterize GMaMs in vitro and used a mouse model of colitis to study GMaM functions in vivo. GM-CSF activates monocytes to increase adherence, migration, chemotaxis, and oxidative burst in vitro, and primes monocyte response to secondary microbial stimuli. In addition, GMaMs accelerate epithelial healing in vitro. Most important, in a mouse model of experimental T cell–induced colitis, GMaMs show therapeutic activity and protect mice from colitis. This is accompanied by increased production of IL-4, IL-10, and IL-13, and decreased production of IFN-γ in lamina propria mononuclear cells in vivo. Confirming this finding, GMaMs attract T cells and shape their differentiation toward Th2 by upregulating IL-4, IL-10, and IL-13 in T cells in vitro. Beneficial effects of GM-CSF in Crohn’s disease may possibly be mediated through reprogramming of monocytes to simultaneously improved bacterial clearance and induction of wound healing, as well as regulation of adaptive immunity to limit excessive inflammation.

Antiphospholipid antibody syndrome (APS) is a systemic autoimmune disease characterized by arterial and/or venous thrombosis, recurrent abortions and detection of antiphospholipid antibodies. In fulminant cases, involvement of multiple organs can lead to significant morbidity and even fatal outcomes, so that a rapid, interdisciplinary treatment is needed. Here, we describe the case of a 39-year-old woman with a severe hard-to-treat APS with arterial occlusion and progressive skin necrosis, who was successfully treated with a combination therapy with plasmapheresis and rituximab. The treatment led to complete remission of the skin lesions for over a year. Clinical response correlated with a long-lasting reduction of antiphospholipid antibodies and B-cell depletion. This case demonstrates the use of antiphospholipid antibodies for monitoring APS-activity and shows that this severe vascular disease requires rigorous therapeutic approaches.

To decipher early promoters of the local microenvironment for Th2-type immunity, we wanted to identify gene patterns that were induced by Leishmania major in the infected skin of susceptible, Th2-prone BALB/c, but not of resistant, Th1-prone C57BL/6 mice. We found a marked up-regulation of the chemokine I-TAC (Cxcl11) during the first 2 d of infection in the epidermis of susceptible but not of resistant mice. Accordingly, local injection of I-TAC (2×1 μg) in resistant mice on the first day of infection resulted in a Th2-driven, sustained deterioration of disease and dramatically enhanced parasite levels. On the cellular level, I-TAC decreased IL-12 production by dendritic cells (DCs) in skin-draining lymph nodes and by DCs in vitro. Thus, we demonstrate for the first time that epidermis-derived I-TAC triggers a sustained Th2-response that determines the outcome of a complex immunological process.—Roebrock, K., Sunderkotter, C., Munck, N-A., Wolf, M., Nippe, N., Barczyk, K., Varga, G., Vogl, T., Roth, J., ...

CCL2, also referred to as MCP-1, is critically involved in directing the migration of blood monocytes to sites of inflammation. Consequently, excessive CCL2 secretion has been linked to many inflammatory diseases, whereas a lack of expression severely impairs immune responsiveness. We demonstrate that IκBζ, an atypical IκB family member and transcriptional coactivator required for the selective expression of a subset of NF-κB target genes, is a key activator of the Ccl2 gene. IκBζ-deficient macrophages exhibited impaired secretion of CCL2 when challenged with diverse inflammatory stimuli, such as LPS or peptidoglycan. These findings were reflected at the level of Ccl2 gene expression, which was tightly coupled to the presence of IκBζ. Moreover, mechanistic insights acquired by chromatin immunoprecipitation demonstrate that IκBζ is directly recruited to the proximal promoter region of the Ccl2 gene and is required for transcription-enhancing histone H3 at lysine-4 trimethylation. Finally, IκBζ-deficient mice showed significantly impaired CCL2 secretion and monocyte infiltration in an experimental model of peritonitis. Together, these findings suggest a distinguished role of IκBζ in mediating the targeted recruitment of monocytes in response to local inflammatory events.

The protozoan parasite Leishmania (Viannia) braziliensis is one of the main causes of cutaneous and mucocutaneous leishmaniasis in South America. Here, we describe three cases of L. (V.) braziliensis infection which were acquired during travelling in Bolivia, Peru or Paraguay and illustrate the phenotypic heterogeneity and therapeutic complexity of the disease. Two patients presented with unusual clinical manifestations, i.e. with prominent regional lymphadenopathy ("bubonic leishmaniasis") and with simultaneously emerged skin and mucosal lesions, respectively. Both patients insufficiently responded to oral treatment with miltefosine; resolution of the lesions was only achieved after a course of intravenous liposomal amphotericin B.

Background α-Melanocyte-stimulating hormone (α-MSH) is a melanocortin peptide that increases skin pigmentation during ultraviolet light-mediated tanning. As α-MSH has been shown to possess anti-inflammatory effects, we assessed the clinical potential of a superpotent α-MSH analogue, afamelanotide (Nle4-d-Phe7-α-MSH), in patients with acne vulgaris, the most common inflammatory skin disorder. Methods Afamelanotide (16 mg) was given in a phase II open-label pilot study subcutaneously as a sustained-release resorbable implant formulation to 3 patients with mild-to-moderate facial acne vulgaris. Evaluation included lesion count, adverse effects and patient-reported outcome. Monitoring of laboratory parameters included differential blood counts, electrolytes, urine analysis, and liver and kidney function tests. Skin melanin density was measured by reflectance spectrophotometry. Results The total number as well as the number of inflammatory acne lesions declined in all patients 56 days after the first injection of afamelanotide. Life quality as measured by Dermatology Life Quality Index likewise improved in all 3 patients 56 days after the first injection of afamelanotide. There were no adverse effects except mild and short-term fatigue in one patient. All patients experienced increased pigmentation especially on the face. Clinically relevant changes in laboratory parameters were not detected. Conclusions Afamelanotide appears to have anti-inflammatory effects in patients with mild-to-moderate acne vulgaris. Future trials are needed to confirm the anti-inflammatory action of this melanocortin analogue in patients with acne vulgaris.