Takafumi Kadono

Atopic dermatitis: immune deviation, barrier dysfunction, IgE autoreactivity and new therapies

Atopic dermatitis (AD) is a chronic or chronically relapsing, eczematous, severely pruritic skin disorder mostly associated with IgE elevation and skin barrier dysfunction due to decreased filaggrin expression. The lesional skin of AD exhibits Th2- and Th22-deviated immune reactions that are progressive during disease chronicity. Th2 and Th22 cytokines further deteriorate the skin barrier by inhibiting filaggrin expression. Some IgEs are reactive to self-antigens. The IgE autoreactivity may precipitate the chronicity of AD. Upon activation of the ORAI1 calcium channel, atopic epidermis releases large amounts of thymic stromal lymphopoietin (TSLP), which initiates the Th2 and Th22 immune response. Th2-derived interleukin-31 and TSLP induce an itch sensation. Taken together, TSLP/Th2/Th22 pathway is a promising target for developing new therapeutics for AD. Enhancing filaggrin expression using ligands for the aryl hydrocarbon receptor may also be an adjunctive measure to restore the disrupted barrier function specifically for AD.

New therapies for controlling atopic itch.

Chronic itch in atopic dermatitis markedly diminishes the quality of life of affected individuals. Sleep disturbance and impaired productivity in work due to chronic itch impose a socioeconomic burden. Conventional therapies for atopic dermatitis are capable of reducing atopic itch. However, the majority of patients are not satisfied with the antipruritic capacity of conventional treatments. In this review, we summarize recent progress in itch signaling in the skin, dorsal root ganglion and spinal cord. New therapies for controlling atopic itch are also discussed.

Pathogenesis of systemic sclerosis—current concept and emerging treatments

Systemic sclerosis (SSc) is an intractable multifaceted disease with high mortality. Although its pathogenesis is not fully understood, recent studies have advanced our knowledge on SSc. The cardinal pathological features of SSc are autoimmunity, vasculopathy, and fibrosis. The B cells in SSc are constitutively activated and lead to the production of a plethora of autoantibodies, such as anti-topoisomerase I and anti-centromere antibodies. In addition to these autoantibodies, which are valuable for diagnostic criteria or biomarkers, many other autoantibodies targeting endothelial cells, including endothelin type A receptor and angiotensin II type I receptor, are known to be functional and induce activation or apoptosis of endothelial cells. The autoantibody-mediated endothelial cell perturbation facilitates inflammatory cell infiltration, cytokine production, and myofibroblastic transformation of fibroblasts and endothelial cells. Profibrotic cytokines, such as transforming growth factor β, connective tissue growth factor, interleukin 4/interleukin 13, and interleukin 6, play a pivotal role in collagen production from myofibroblasts. Specific treatments targeting these causative molecules may improve the clinical outcomes of patients with SSc. In this review, we summarize recent topics on the pathogenesis (autoantibodies, vasculopathy, and fibrosis), animal models, and emerging treatments for SSc.

“Inflammatory skin march” in atopic dermatitis and psoriasis

BackgroundComorbidities of cardiovascular diseases (CVDs), metabolic syndrome and autoimmune diseases with systemic inflammation are recent topics in medicine. Inflammatory skin diseases such as atopic dermatitis and psoriasis are an active source of diverse proinflammatory cytokines and chemokines, which are readily detectable in the circulation and are likely to be involved in developing comorbidities.EvidenceBoth atopic dermatitis and psoriasis are frequently comorbid with CVD, metabolic syndrome and autoimmune diseases, the consequence of which is called “inflammatory skin march”, “psoriatic march” or “march of psoriasis”.ConclusionIn this review, we summarize the epidemiological evidence and pathogenetic concepts regarding inflammatory skin march in atopic dermatitis and psoriasis.

Psoriasis: Behind the scenes.

Psoriasis is a chronic inflammatory skin disease characterized by a significant deterioration in the quality of life of affected individuals. Notably, psoriasis is significantly associated with cardiovascular and metabolic syndrome and other autoimmune disorders. Recent progress in biologic therapies has revealed the fundamental role of tumor necrosis factor‐α, interleukin (IL)‐23 and the IL‐17A axis together with aberrant overproduction of epidermal IL‐36γ in the pathogenesis of psoriasis. This review provides an update on the clinical, pathological and therapeutic advancements involving psoriasis.

Cardiovascular and metabolic diseases comorbid with psoriasis: Beyond the skin

A close association of systemic inflammation with cardiovascular diseases and metabolic syndrome is recently a popular topic in medicine. Psoriasis is a chronic inflammatory skin disease with a prevalence of approximately 0.1-0.5% in Asians. It is characterized by widespread scaly erythematous macules that cause significant physical and psychological burdens for the affected individuals. The accelerated inflammation driven by the TNF-α/IL-23/IL-17A axis is now known to be the major mechanism in the development of psoriasis. Psoriasis is not a mere skin disease; it is significantly associated with cardiovascular diseases and metabolic syndrome, which suggests that the chronic skin inflammation extends the systemic inflammation beyond the skin. In this article, we review the epidemiological and pathological aspects of psoriasis and its comorbidities.

Highlighting interleukin-36 signalling in plaque psoriasis and pustular psoriasis

Plaque psoriasis and pustular psoriasis are overlapping, but distinct, disorders. The therapeutic response to biologics supports the pivotal role of the tumour necrosis alpha (TNF-?)/ interleukin (IL)-23/IL-17/IL-22 axis in the pathogenesis of these disorders. Recently, functional activation of the IL-36 receptor (IL-36R) was discovered to be another driving force in the pathogenesis of psoriasis. This was first highlighted by the discovery that a loss-of-function mutation of the IL-36R antagonist (IL-36Ra) causes pustular psoriasis. Although the TNF-?/IL-23/IL-17/IL-22 axis and the functional activation of IL-36R are fundamentally involved in plaque psoriasis and pustular psoriasis, respectively, the 2 pathways are closely related and mutually reinforced, resulting in full-blown clinical manifestations. This review summarizes current topics on how IL-36 agonists (IL-36?, IL-36?, IL-36?) signal IL-36R, the pathological expression of IL-36 agonists and IL-36Ra in plaque and pustular psoriatic lesions, and the cross-talk between the TNF-?/IL-23/IL-17/IL-22 axis and the functional activation of IL-36R in the epidermal milieu.

Pemphigus, a pathomechanism of acantholysis

Autoantibodies to the desmosomal proteins desmoglein 1 and 3 cause pemphigus foliaceus and pemphigus vulgaris, which are characterised by keratinocyte dissociation (acantholysis) and intraepidermal blister formation. The passive transfer of pathogenic anti‐desmoglein antibodies induces blisters in mice in vivo and the loss of keratinocyte adhesion in vitro. The pathogenetic mechanisms of acantholysis due to anti‐desmoglein autoantibodies are not fully understood. However, recent studies have revealed that signalling‐dependent and signalling‐independent pathways are operative in the loss of cell adhesion. In this review, we focus on the pathomechanism of acantholysis due to autoantibodies to desmogleins and recent therapeutic approaches.

Melanoma therapy: Check the checkpoints.

Recent mutational and translational studies have revealed that the Ras/Raf/mitogen‐activated protein kinase kinase (MEK)/extracellular signal‐regulated kinase (ERK) pathway plays a key role in melanomagenesis. Mutations in NRAS and BRAF are found in the majority of melanomas resulting in the formation of constitutively active NRAS and BRAF molecules, which leads to the proliferation and survival of melanoma cells through the activation of MEK/ERK signals. Inhibitors of BRAF or MEK significantly extend the progression‐free survival and overall survival of melanoma patients compared with conventional chemotherapies. Combining BRAF and MEK inhibitors further enhances the clinical effectiveness. Cytotoxic T‐lymphocyte‐associated antigen 4 (CTLA‐4) is an immune checkpoint molecule that downregulates T‐cell activation by binding to B7 (CD80/CD86) molecules on antigen‐presenting cells. Programmed death receptor ligand 1 on melanoma cells negatively regulates T‐cell function by binding to the programmed death‐1 (PD‐1) receptor on T cells. Antibodies against CTLA‐4 and PD‐1 also enhance the survival of melanoma patients. In this review, we summarize the clinical effectiveness and adverse events of the BRAF inhibitors, MEK inhibitors and anti‐immune checkpoint antibodies in melanoma treatment.

Pazopanib induced a partial response in a patient with metastatic fibrosarcomatous dermatofibrosarcoma protuberans without genetic translocations resistant to mesna, doxorubicin, ifosfamide and dacarbazine chemotherapy and gemcitabine-docetaxel chemotherapy.

Dear Editor, Fibrosarcomatous dermatofibrosarcoma protuberans (FSDFSP) is a variant of DFSP with increased risk of recurrence and metastasis (~30% and 15%, respectively). There are only limited choices of treatment once metastasis occurs. Metastatic DFSP is resistant to conventional chemotherapy. Imatinib is effective for metastatic DFSP with genetic translocations involving the platelet-derived growth factor (PDGF) locus. However, it is known that imatinib is not efficacious without the fusion genes, and in such cases there has been almost no promising systemic treatment. We first describe a case of metastatic FS-DFSP without genetic translocations which was resistant to conventional chemotherapy but was sensitive to pazopanib. A 47-year-old man was referred to our department with an abdominal mass (Fig. 1a). Wide local excision was performed. Histopathology revealed that spindle cells were arranged in irregular interwoven fascicles in most parts, while in some parts these cells were lined in diagonal fascicles (Fig. 1b). The tumor cells forming a storiform pattern stained positively for