Eosinophilic dermatoses.

Eosinophilic dermatoses are a heterogeneous group of diseases, characterized by an eosinophil-rich infiltrate and/or degranulation of eosinophils. Blood eosinophilia may be an associated feature. Typical, albeit not specific histological findings include 'flame figures', which are caused by the accumulation of cationic proteins released by eosinophils and subsequent collagen denaturation. "Classic" eosinophilic dermatoses include eosinophilic cellulitis (Wells syndrome), granuloma faciale, eosinophilic fasciitis (Shulman syndrome) and eosinophilic folliculitis (Ofuji disease). In addition, there is a multitude of skin diseases that present with varying degrees of eosinophilic infiltration. These include atopic dermatitis, bullous pemphigoid, urticaria, allergic contact dermatitis, prurigo nodularis, arthropod bite reaction, parasitic infections, and drug hypersensitivity. Even though these disorders share a common characteristic (tissue eosinophilia), they differ greatly in their clinical presentation.

Clinicopathologic and immunophenotypic features of eosinophilic fasciitis and morphea profunda: A comparative study of 27 cases.

BACKGROUND: Eosinophilic fasciitis (EF) and morphea profunda (MP) are inflammatory and sclerosing disorders of the subcutis that can exhibit clinical and pathologic presentations that overlap. OBJECTIVE: To identify clinicopathologic features that can be used to distinguish EF from MP. METHODS: We performed a retrospective review of 16 patients with EF and 11 patients with MP. Hematoxylin-eosin, CD123, CD34, and Verhoeff-Van Gieson stains were evaluated on skin biopsies that included the fascia. RESULTS: EF patients were more likely than MP patients to be men (P = .047), have forearm involvement (P = .003), and have peripheral eosinophilia (P < .01). Compared with MP patients, patients with EF were more likely to have fascia that contained eosinophils (P = .003), although eosinophils were absent in 3 (19%) patients with EF. Focal absence of CD34 staining was more prominent in the fascia of EF patients (P = .04). The extent of Verhoeff-Van Gieson staining did not differ between the 2 groups. Dermal sclerosis was not detected in many cases of EF and MP (56% and 36%, respectively). LIMITATIONS: This was a retrospective study at a single institution. CONCLUSION: Although EF and MP share clinical and pathologic features, our results indicate that the presence of eosinophils in the blood and fascia and focal loss of CD34 staining might be more suggestive of EF than MP.

Th1- and Th17-polarized immune infiltrates in eosinophilic fasciitis-A potential marker for histopathologic distinction from morphea.

BACKGROUND: Morphea (localized scleroderma) and eosinophilic fasciitis (EF) are rare fibrosing disorders which may present a diagnostic challenge. While histopathologic features are often distinct, in some cases there may be overlap. T-cells contribute to etiopathogenesis of both autoimmune conditions. We sought to determine whether T-cell immune polarization enables histopathologic distinction. MATERIALS & METHODS: We retrospectively examined clinicopathologically confirmed cases of morphea (n = 12) and EF (n = 8) using immunohistochemistry for CD3, CD8, and dual staining for CD4 with T-bet, GATA-3, STAT-3 or BNC-2 (transcription factors reported to be specific and mutually exclusive for Th1, Th2, Th17 and Th22 cells, respectively) to characterize the T-cell infiltrate. RESULTS: No significant difference in CD3+ cells was identified (P = .195), however, the CD4/CD8+ T-cell ratio was significantly greater in morphea compared to EF (1.2 and 0.6, respectively; P = .034). Th1/Th2 was significantly lower in morphea compared to EF (1.7 and 2.7, respectively; P = .027). The percent of Th17+ cells was significantly higher in EF (P = 0.041). No significant difference in percent of Th22+ cells was identified. CONCLUSION: Morphea and EF may be histopathologically distinguished based on helper T-cell subtype polarization. These findings offer novel insight into our understanding of disease pathogenesis and support a role for Th1/Th2 immune regulation and Th17 inhibition in anti-fibrotic therapeutic strategy.

Imatinib mesylate for the treatment of steroid-refractory sclerotic-type cutaneous chronic graft-versus-host disease.

Sclerotic skin manifestations of chronic graft-versus-host disease (ScGVHD) lead to significant morbidity, including functional disability from joint range of motion (ROM) restriction. No superior second-line therapy has been established for steroid-refractory disease. Imatinib mesylate is a multikinase inhibitor of several signaling pathways implicated in skin fibrosis with in vitro antifibrotic activity. We performed an open-label pilot phase II trial of imatinib in children and adults with corticosteroid-refractory ScGVHD. Twenty patients were enrolled in a 6-month trial. Eight received a standard dose (adult, 400 mg daily; children, 260 mg/m(2) daily). Because of poor tolerability, 12 additional patients underwent a dose escalation regimen (adult, 100 mg daily initial dose up to 200 mg daily maximum; children, initial dose 65 mg/m(2) daily up to 130 mg/m(2) daily). Fourteen patients were assessable for primary response, improvement in joint ROM deficit, at 6 months. Primary outcome criteria for partial response was met in 5 of 14 (36%), stable disease in 7 of 14 (50%), and progressive disease in 2 of 14 (14%) patients. Eleven patients (79%), including 5 with partial response and 6 with stable disease, demonstrated a positive gain in ROM (range of 3% to 94% improvement in deficit). Of 13 patients with measurable changes at 6 months, the average improvement in ROM deficit was 24.2% (interquartile range, 15.5% to 30.5%; P = .011). This trial is registered at http://clinicaltrials.gov as NCT007020689.

Th2-M2 immunity in lesions of muscular sarcoidosis and macrophagic myofasciitis.

OBJECTIVE: To analyse the paradox of a lack of giant cell formation and fibrosis in chronic lesions of macrophagic myofasciitis (MMF) in comparison with muscular sarcoidosis (MuS). METHODS: Inflammatory lesions and contiguous muscle regions from biopsy samples of 10 patients with MuS and 10 patients with MMF were cut out by laser microdissection. Mediators of the T helper cell (Th)1 inducing classical macrophage activation (e.g. STAT1, IFNγ and CXCR3), and Th2 inducing alternative activation of macrophages (e.g. CD206/MRC1, STAT6, SOCS1), molecules involved in development of fibrosis (e.g. TGFß) and giant cells (e.g. TYROBP), were assessed by immunohistochemistry and real-time polymerase chain reaction (PCR). RESULTS: STAT6-induced Th2 immunity was associated with up-regulated gene expression of MRC1, SOCS1 and TGFB in inflammatory foci, in comparison with adjacent tissue. TYROBP and TREM2, genes regulating giant cell formation, were more strongly expressed in lesions of MuS patients than in those of MMF. TGFß co-localized with CD206(+) macrophages in MuS but not in MMF. Conversely, Th1 immunity was illustrated by STAT1 staining both in macrophages and myofibres in MuS, but not in MMF. Also, STAT1-induced IFNG and CXCR3 expression in lesions and the surrounding tissue was elevated compared with normal controls, but without statistically significant differences. CONCLUSION: Giant cell and typical granuloma formations, including fibrogenesis, is dependent on two main mechanisms, both involving specific macrophage activation: a strong Th2-M2 polarization and a significant expression of TYROBP and TGFß in macrophages. The low-grade alternative activation of macrophages in MMF lesions and poor TYROBP and TGFßco-expression are obviously insufficient to produce giant cells.

[Eosinophilic fasciitis]. / Eozynofilowe zapalenie powiezi.

Eosinophilic fasciitis is a rare connective tissue disease with unclear etiology and pathogenesis. It is classified as a scleroderma-like syndrome. The disease is characterized by fibrosis of the skin and subcutaneous tissues with significant thickening of fascia. Visceral involvement is rare. Characteristic feature in laboratory tests is peripheral blood eosinophilia. Differential diagnosis should be performed, including ruling out systemic sclerosis, nephrogenic systemic fibrosis, eosinophilia-myalgia syndrome, scleromyxedema, hypereosinophilic syndrome or Churg-Strauss syndrome. Final diagnosis is confirmed by histopathological examination. In treatment of the disease corticosteroids and/or immunosuppressive drugs are used. Some other drugs showed activity in this disease e.g. dapsone, infiximab or rituximab. Prognosis is rather good but sometimes a long-term treatment is necessary. In this paper we summarized the current knowledge on eosinophilic fasciitis.

Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) 2013: Unveiling the pathogenic, clinical and diagnostic aspects.

In 2011 a new syndrome termed 'ASIA Autoimmune/Inflammatory Syndrome Induced by Adjuvants' was defined pointing to summarize for the first time the spectrum of immune-mediated diseases triggered by an adjuvant stimulus such as chronic exposure to silicone, tetramethylpentadecane, pristane, aluminum and other adjuvants, as well as infectious components, that also may have an adjuvant effect. All these environmental factors have been found to induce autoimmunity by themselves both in animal models and in humans: for instance, silicone was associated with siliconosis, aluminum hydroxide with post-vaccination phenomena and macrophagic myofasciitis syndrome. Several mechanisms have been hypothesized to be involved in the onset of adjuvant-induced autoimmunity; a genetic favorable background plays a key role in the appearance on such vaccine-related diseases and also justifies the rarity of these phenomena. This paper will focus on protean facets which are part of ASIA, focusing on the roles and mechanisms of action of different adjuvants which lead to the autoimmune/inflammatory response. The data herein illustrate the critical role of environmental factors in the induction of autoimmunity. Indeed, it is the interplay of genetic susceptibility and environment that is the major player for the initiation of breach of tolerance.

Eosinophilic fasciitis as a manifestation of a cutaneous T-cell lymphoma not otherwise specified.

Eosinophilic fasciitis (EF) is a rare entity characterized by symmetrical and painful thickness and induration of the skin, especially localized on forearms and thorax and generally accompanied by eosinophilia. Although several reports indicate the relationship between EF and hematological disorders such as aplastic anemia, polycythemia vera, or myelomonocytic leukemia, the association with lymphomas is extremely rare. Only a few cases of EF have been previously described preceding or concomitant to the Hodgkin disease, peripheral T-cell lymphoma, B-cell lymphoma, and mycosis fungoides. We report for the first time a 76-year-old man with an EF associated with a peripheral T-cell lymphoma not otherwise specified. We review the relationship between both conditions. In conclusion, we present a unique case of EF as a manifestation of a T-cell lymphoma not otherwise specified. The present case demonstrates the importance of clinical and radiological studies in those cases of EF to rule out a visceral, lymph node, or cutaneous lymphoma.

Autoimmune syndrome induced by adjuvants (ASIA) in the Middle East: morphea following silicone implantation.

Morphea and other scleroderma-like skin conditions are occasionally linked with exposure to chemical compounds such as silicone. We treated a 56-year-old woman with generalized severe skin induration accompanied with systemic symptoms and peripheral eosinophilia, which appeared 2.5 years after breast silicone implantation and abdominal liposuction. Blood test results and histopathological examination of her skin suggested the diagnosis of morphea overlapping with eosinophilic fasciitis. Her skin disease was presumed to be an autoimmune reaction to silicone implantation. While the removal of the implants did not improve her illness, treatment with 1 mg/kg prednisone and PUVA bath was initiated, with some improvement. This patient illustrates an example of ASIA (Autoimmune Syndrome Induced by Adjuvants), as her disease appeared following exposure to an adjuvant stimulus, with 'typical', although not well-defined, autoimmune manifestations.

Macrophagic myofasciitis: characterization and pathophysiology.

Aluminium oxyhydroxide (alum), a nanocrystalline compound forming agglomerates, has been used in vaccines for its immunological adjuvant effect since 1927. Alum is the most commonly used adjuvant in human and veterinary vaccines, but the mechanisms by which it stimulates immune responses remain incompletely understood. Although generally well tolerated, alum may occasionally cause disabling health problems in presumably susceptible individuals. A small proportion of vaccinated people present with delayed onset of diffuse myalgia, chronic fatigue and cognitive dysfunction, and exhibit very long-term persistence of alum-loaded macrophages at the site of previous intramuscular (i.m.) immunization, forming a granulomatous lesion called macrophagic myofasciitis (MMF). Clinical symptoms associated with MMF are paradigmatic of the recently delineated 'autoimmune/inflammatory syndrome induced by adjuvants' (ASIA). The stereotyped cognitive dysfunction is reminiscent of cognitive deficits described in foundry workers exposed to inhaled Al particles. Alum safety concerns will largely depend on whether the compound remains localized at the site of injection or diffuses and accumulates in distant organs. Animal experiments indicate that biopersistent nanomaterials taken up by monocyte-lineage cells in tissues, such as fluorescent alum surrogates, can first translocate to draining lymph nodes, and thereafter circulate in blood within phagocytes and reach the spleen, and, eventually, slowly accumulate in the brain.

Eosinophilic fasciitis induced by a game of drumming probably via type 2 innate immunity.

We report a case of eosinophilic fasciitis triggered by strenuous physical activity, which did not relapse during the follow-up period. We ascertained that interleukin-33 (IL-33) was released from the vascular endothelial cells after intense exercise, inducing type 2 innate lymphocytes (ILC2) and causing fasciitis. A healthy woman experienced itching on both limbs a few hours after a game of drumming. Her hand, knee joints, and legs gradually swelled up with groove signs along the superficial veins. White blood cell and eosinophil counts were significantly elevated. Magnetic resonance imaging revealed a high signal at the fascia on both lower limbs. Histopathological findings of the left lower limb tissue specimen showed edematous fascia with eosinophils. No relapse of eosinophilic fasciitis was observed after finishing treatment with prednisolone. Immunological staining for IL-4, IL-5, IL-33, tumor necrosis factor-α, and interferon-γ was performed on the fascial tissue. Both IL-4 and IL-5 were stained on the lymphocytes at the muscle and fascia levels; however, CD3 and CD4 were unstained in these cells, suggesting that those cells were ILC2. Tumor necrosis factor-α and interferon-γ were unstained. Vascular endothelial cells in the fascia strongly expressed IL-33. Eosinophilic fasciitis may be associated with type 2 immunity triggered by IL-33 in the current case.

'ASIA' - autoimmune/inflammatory syndrome induced by adjuvants.

The role of various environmental factors in the pathogenesis of immune mediated diseases is well established. Of which, factors entailing an immune adjuvant activity such as infectious agents, silicone, aluminium salts and others were associated with defined and non-defined immune mediated diseases both in animal models and in humans. In recent years, four conditions: siliconosis, the Gulf war syndrome (GWS), the macrophagic myofasciitis syndrome (MMF) and post-vaccination phenomena were linked with previous exposure to an adjuvant. Furthermore, these four diseases share a similar complex of signs and symptoms which further support a common denominator.Thus, we review herein the current data regarding the role of adjuvants in the pathogenesis of immune mediated diseases as well as the amassed data regarding each of these four conditions. Relating to the current knowledge we would like to suggest to include these comparable conditions under a common syndrome entitled ASIA, "Autoimmune (Auto-inflammatory) Syndrome Induced by Adjuvants".

['ASIA' - Autoimmune/inflammatory syndrome induced by adjuvants: even and odd]. / 'SAIA' - Sindrome autoimmune/infiammatoria indotta da adiuvanti: presente e futuro.

Recently, Shoenfeld and Agmon-Levin described a potential new syndrome, namely ASIA - autoimmune/inflammatory syndrome induced by adjuvants, that comprises four medical conditions: siliconosis, the Gulf war syndrome, the macrophagic myofasciitis syndrome and post-vaccination phenomena, characterized by hyperactive immune responses accompanied by a similar complex of signs and symptoms. Most relevantly, these conditions share a linkage represented by adjuvants. This common soil may possibly induce autoimmune or auto-inflammatory diseases in humans as it was demonstrated in different animal models. Reconsidering under a unified umbrella this apparently detached condition is not only intriguing, but also provocative, and may help in unraveling novel pathogenetic mechanisms, preventive measures, and therapeutic targets.

Clinical experience with biologic treatment in resistant eosinophilic fasciitis: Case reports and review of the literature.

RATIONALE: Eosinophilic fasciitis (EF) is an uncommon connective tissue disorder characterized by limb and trunk erythema, with symmetrical thickening of the skin. Its pathogenesis is poorly understood. Treatment consists mainly of glucocorticoids. Yet, no randomized trials have evaluated therapies for this rare disease and the optimal treatment modality remains unclear. Although most patients show partial or complete response to glucocorticoids, many relapse upon drug tapering, while others either do not respond at all or fail to sustain prolonged remission. Second-line therapy for this rare disorder includes mainly methotrexate (MTX), azathioprine, cyclosporine and hydroxychloroquine. Recently, several attempts using rituximab and intravenous immunoglobulins (IVIG) have shown good clinical results. PATIENT CONCERNS: The three patients had good clinical response to glucocorticoid treatment, followed by disease flare when the drug dose was tapered. Adding methotrexate in all patients and azathioprine to patient 3 did not lead to remission. DIAGNOSES: EF was diagnosed in all patients based on clinical presentation accompanied by fascia biopsy that demonstrated eosinophilic fasciitis. INTERVENTIONS: The patients were successfully treated with rituximab or IVIG, achieving sustained remission. OUTCOMES: The three cases had good clinical response to glucocorticoid treatment, followed by disease flare when the drug dose was tapered. The patients were then successfully treated with rituximab or IVIG, achieving sustained remission. LESSONS: This review of three cases of EF supports the results of previous reports, suggesting addition of rituximab and IVIG is an effective treatment for patients with refractory disease.

Macrophage-derived exosomes in cancers: Biogenesis, functions and therapeutic applications.

Macrophages are fundamental to promote tumorigenesis, tumor development and metastasis, and chemotherapy resistance through modulating tumor microenvironment and cancer cells. Recently, increasing studies have shown that exosomes could play a crucial role in orchestrating the crosstalk between macrophages and cancer cells. Exosomes, as one of the extracellular vehicles, deliver a diverse cast of molecules including lipids, proteins, and nucleic acids, etc. to the targeted cells to exert pleiotropic effects. The macrophage-derived exosomes have heterogeneity in different cancers and play paradoxical roles in suppressing and promoting tumors mainly via post-transcriptional control and regulating the phosphorylation of proteins in the recipient cells. Meanwhile, exosomes secreted by different phenotypes of macrophages provide diverse therapeutic options. Thus, in this review, we summarized the latest progress in outlining the current understanding of macrophage-derived exosomal biogenesis and mechanisms in mediating cancer progression, as well as their potential clinical applications.

Macrophagic myofasciitis and subcutaneous pseudolymphoma caused by aluminium adjuvants.

Aluminium hydroxide is a well-known adjuvant used in vaccines. Although it can enhance an adaptive immune response to a co-administered antigen, it causes adverse effects, including macrophagic myofasciitis (MMF), subcutaneous pseudolymphoma, and drug hypersensitivity. The object of this study is to demonstrate pediatric cases of aluminium hydroxide-induced diseases focusing on its rarity, under-recognition, and distinctive pathology. Seven child patients with biopsy-proven MMF were retrieved from the Seoul National University Hospital (SNUH) pathology archives from 2015 to 2019. The medical records and immunisation history were reviewed, and a full pathological muscle examination was carried out. The mean age was 1.7 years (8.9-40 months), who had records of vaccination against hepatitis B, hepatitis A, and tetanus toxoid on the quadriceps muscle. The chief complaints were muscle weakness (n = 6), delayed motor milestones (n = 6), instability, dysarthria, and involuntary movement (n = 1), swallowing difficulty (n = 1), high myopia (n = 1), and palpable subcutaneous nodules with skin papules (n = 1). Muscle biopsy showed MMF (n = 6) and pseudolymphoma (n = 1) with pathognomic basophilic large macrophage infiltration, which had distinctive spiculated inclusions on electron microscopy. The intracytoplasmic aluminium was positive for PAS and Morin stains. Distinctive pathology and ultrastructure suggested an association with aluminium hydroxide-containing vaccines. To avoid misdiagnosis and mistreatment, we must further investigate this uncommon condition, and pharmaceutical companies should attempt to formulate better adjuvants that do not cause such adverse effects.

Polyglandular autoimmunity with macrophagic myofasciitis.

We report a man with chronic fatigue, multiple autoimmune disorders, and a muscle biopsy consistent with macrophagic myofasciitis. This rare and recently described muscle disorder is seen in patients exposed to vaccinations with aluminum hydroxide adjuvant. This case highlights the relationship between macrophagic myofasciitis and autoimmunity.