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Editors’ Picks
EDITORS’ PICKS Disrupted inflammasome sensor Zhong and colleagues recently discovered germline gain-offunction mutations in the inflammasome complex ligandsensing nucleotide-binding domain, leucine-rich repeat containing pyrin domain-containing protein 1 (NLPR1) underlying the phenotype in two skin disorders, multiple self-healing palmoplantar carcinoma (MSPC) and familial keratosis lichenoides chronica (FKLC). Specifically, MSPC arises due to heterozygous missense mutations in the pyrin domain (PYD) of NLPR1, while FKLC arises from bi-allelic inheritance of a deletion within the LRR domain. Aberrant activation of this inflammasome sensor results in spontaneous inflammasome activation and paracrine signaling via interleukin (IL)-1 in keratinocytes, resulting in skin inflammation and epidermal hyperplasia. Mechanistically, these mutations disrupt the PYD and LRR domain interactions, which maintain NLRP1 in an inactive state, and thus, these alterations abrogate the auto-inhibitory mechanism, leading to increased oligomerization and inflammasome activation. This link between inflammasome activation and inherited inflammatory and proliferative skin disorders offers a new avenue for clinical modulation. (Cell http://dx.doi.org/10.1016/cell.2 016.09.001, 2016) Selected by B.A. Gilchrest
CAR technology Treatment of the life-threatening autoimmune blistering disease pemphigus vulgaris is aimed at dampening the causative IgG autoantibodies against the desmoglein 3 (Dsg3) adhesion molecule. While corticosteroids and an anti-CD20 monoclonal antibody rituximab have shown efficacy, these methods are not specific, rendering the patient susceptible to infection. Ellebrecht and colleagues utilized chimeric antigen receptor (CAR) technology, which has proved effective in cancer therapy, to target the autoimmune B cells in pemphigus by exchanging the extracellular domain of CAR with that of Dsg3 to yield a chimeric autoantibody receptor (CAAR). This molecule killed Dsg3-specific B cells even in the presence of circulating Dsg3 autoantibodies without significant off-target toxicity. In a summary describing the clinical implications of this basic research, Dr. Amagai highlights these exciting findings and describes the potential for development of antigen-specific immunosuppression CAAR therapies for pemphigus as well as for other B cell-mediated tissue-specific autoimmune diseases. (Science http://dx.doi.org/10.1126/ science.aaf6756, 2016; N Engl J Med http://dx.doi.org/10.1056 NEJMcibr1608900, 2016) Selected by B.A. Gilchrest
Tale of two trials Moderate-to-severe atopic dermatitis (AD) induces intense persistent pruritus that often impacts the patient’s quality of life. Topical therapies often have minimal efficacy; however, systemic treatments such as glucocorticoids often have toxic effects. On the heels of early-phase trials of the fully human monoclonal antibody dupilumab, which specifically binds a shared subunit of type 2 inflammatory cytokines IL-4 and IL-13 that drive atopic diseases, Journal of Investigative j.jid.2016.11.008
Dermatology
(2017)
ª 2016 The Society for Investigative Dermatology.
137,
5.
doi:10.1016/
Simpson and colleagues conducted two phase 3 trials of monotherapy with dupilumab in patients with inadequately controlled moderate-to-severe AD. Dupilumab, in both regimens (weekly and every other week), yielded better results than placebo over a 16-week period. Patients in the treatment groups reported decreased pruritus and improvements in anxiety, depression, and quality of life. The two trials (SOLO1 and SOLO2) were designed to provide replication, and indeed, the outcomes were quite consistent between the two trials. Thus, although trials of longer duration are required, these results support the effectiveness and safety of dupilumab for the treatment of moderate-tosevere AD. (N Engl J Med http://dx.doi.org/10.1056/NEJMoa161 0020, 2016) Selected by T. Nijsten
PIONEERing studies of adalimumab The chronic inflammatory skin disease hidradenitis suppurativa is characterized by increased levels of IL-1b, tumor necrosis factor (TNF)-a, and IL-10. While adalimumab, a fully human IgG1 monoclonal antibody specific for TNF-a, has been approved for treatment of several inflammatory diseases, including plaque psoriasis, few options for treatment for hidradenitis suppurativa are available. Thus, positive results of adalimumab efficacy in a phase 2 trial of hidradenitis suppurativa were promising. Kimball and colleagues recently reported that in two phase 3 multicenter trials (PIONEER I and PIONEER II) of 633 total patients with two double-blind placebo-controlled periods, weekly administration of adalimumab was efficacious for treating moderate-to-severe hidradenitis suppurativa at week 12. No increased risk of severe adverse effects was noted in the treatment groups. Although the patients rarely experienced complete remission of symptoms, a significant improvement in secondary outcomes of lesion count, pain score, and disease severity was also observed specifically in PIONEER II. (N Engl J Med http://dx.doi.org/10.1056/ NEJMoa1504370, 2016) Selected by T. Nijsten
Poison ivy and psoriasis Langerhans cells (LCs) reside in the epidermis and express CD1a, which displays a broad spectrum of exogenous and self lipid antigens to T lymphocytes. Thus, Kim and colleagues explored the notion that LCs and CD1a-restricted T cells are important for regulating skin immunity. Using mice with transgenic expression of CD1a, as mice do not express this molecule, these investigators demonstrated that CD1a promoted skin inflammation in response to poison ivyderived urushiol. In structural studies, urushiol (C15:2) was found to be a true antigen for CD1a-restricted T cells, and CD1a-expressing LCs were required for TH17 cell generation and resultant skin inflammation. Furthermore, CD1a was found to drive TH17 cell-powered skin inflammation in psoriasis in mice and human patients in accord with the substantial IL-17 production by CD1a-autoreactive T cells and the critical role of IL-17 in psoriasis. As blockade of CD1a in vivo using specific antibody treatment significantly decreased skin inflammation in CD1a-transgenic mice, targeting of CD1a offers therapeutic possibilities aimed at inflammatory skin diseases. (Nat Immunol http://dx.doi.org/ 10.1038/ni.3523, 2016) Selected by M. Amagai www.jidonline.org
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CAR technology Treatment of the life-threatening autoimmune blistering disease pemphigus vulgaris is aimed at dampening the causative IgG autoantibodies against the desmoglein 3 (Dsg3) adhesion molecule. While corticosteroids and an anti-CD20 monoclonal antibody rituximab have shown efficacy, these methods are not specific, rendering the patient susceptible to infection. Ellebrecht and colleagues utilized chimeric antigen receptor (CAR) technology, which has proved effective in cancer therapy, to target the autoimmune B cells in pemphigus by exchanging the extracellular domain of CAR with that of Dsg3 to yield a chimeric autoantibody receptor (CAAR). This molecule killed Dsg3-specific B cells even in the presence of circulating Dsg3 autoantibodies without significant off-target toxicity. In a summary describing the clinical implications of this basic research, Dr. Amagai highlights these exciting findings and describes the potential for development of antigen-specific immunosuppression CAAR therapies for pemphigus as well as for other B cell-mediated tissue-specific autoimmune diseases. (Science http://dx.doi.org/10.1126/ science.aaf6756, 2016; N Engl J Med http://dx.doi.org/10.1056 NEJMcibr1608900, 2016) Selected by B.A. Gilchrest
Tale of two trials Moderate-to-severe atopic dermatitis (AD) induces intense persistent pruritus that often impacts the patient’s quality of life. Topical therapies often have minimal efficacy; however, systemic treatments such as glucocorticoids often have toxic effects. On the heels of early-phase trials of the fully human monoclonal antibody dupilumab, which specifically binds a shared subunit of type 2 inflammatory cytokines IL-4 and IL-13 that drive atopic diseases, Journal of Investigative j.jid.2016.11.008
Dermatology
(2017)
ª 2016 The Society for Investigative Dermatology.
137,
5.
doi:10.1016/
Simpson and colleagues conducted two phase 3 trials of monotherapy with dupilumab in patients with inadequately controlled moderate-to-severe AD. Dupilumab, in both regimens (weekly and every other week), yielded better results than placebo over a 16-week period. Patients in the treatment groups reported decreased pruritus and improvements in anxiety, depression, and quality of life. The two trials (SOLO1 and SOLO2) were designed to provide replication, and indeed, the outcomes were quite consistent between the two trials. Thus, although trials of longer duration are required, these results support the effectiveness and safety of dupilumab for the treatment of moderate-tosevere AD. (N Engl J Med http://dx.doi.org/10.1056/NEJMoa161 0020, 2016) Selected by T. Nijsten
PIONEERing studies of adalimumab The chronic inflammatory skin disease hidradenitis suppurativa is characterized by increased levels of IL-1b, tumor necrosis factor (TNF)-a, and IL-10. While adalimumab, a fully human IgG1 monoclonal antibody specific for TNF-a, has been approved for treatment of several inflammatory diseases, including plaque psoriasis, few options for treatment for hidradenitis suppurativa are available. Thus, positive results of adalimumab efficacy in a phase 2 trial of hidradenitis suppurativa were promising. Kimball and colleagues recently reported that in two phase 3 multicenter trials (PIONEER I and PIONEER II) of 633 total patients with two double-blind placebo-controlled periods, weekly administration of adalimumab was efficacious for treating moderate-to-severe hidradenitis suppurativa at week 12. No increased risk of severe adverse effects was noted in the treatment groups. Although the patients rarely experienced complete remission of symptoms, a significant improvement in secondary outcomes of lesion count, pain score, and disease severity was also observed specifically in PIONEER II. (N Engl J Med http://dx.doi.org/10.1056/ NEJMoa1504370, 2016) Selected by T. Nijsten
Poison ivy and psoriasis Langerhans cells (LCs) reside in the epidermis and express CD1a, which displays a broad spectrum of exogenous and self lipid antigens to T lymphocytes. Thus, Kim and colleagues explored the notion that LCs and CD1a-restricted T cells are important for regulating skin immunity. Using mice with transgenic expression of CD1a, as mice do not express this molecule, these investigators demonstrated that CD1a promoted skin inflammation in response to poison ivyderived urushiol. In structural studies, urushiol (C15:2) was found to be a true antigen for CD1a-restricted T cells, and CD1a-expressing LCs were required for TH17 cell generation and resultant skin inflammation. Furthermore, CD1a was found to drive TH17 cell-powered skin inflammation in psoriasis in mice and human patients in accord with the substantial IL-17 production by CD1a-autoreactive T cells and the critical role of IL-17 in psoriasis. As blockade of CD1a in vivo using specific antibody treatment significantly decreased skin inflammation in CD1a-transgenic mice, targeting of CD1a offers therapeutic possibilities aimed at inflammatory skin diseases. (Nat Immunol http://dx.doi.org/ 10.1038/ni.3523, 2016) Selected by M. Amagai www.jidonline.org
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