Barbara Meier

Cytotoxic Cutaneous Adverse Drug Reactions during Anti-PD-1 Therapy

Purpose: Immunotherapy has experienced impressive progress in cancer treatment. Antibodies against PD-1 improved survival in different types of cancer including melanoma. They are generally well tolerated. However, skin toxicities including pruritus, rashes, and vitiligo are reported. Although frequent, they have not been characterized further yet. In this analysis, we aimed to systematically assess and characterize the adverse cutaneous reactions observed in patients with melanoma treated with anti-PD-1 antibodies. Experimental Design: Patients with melanoma were treated with anti-PD-1 antibodies within clinical trials and an early-access program. Adverse cutaneous eruptions that emerged in our melanoma patient cohort were systematically investigated and classified using histology and gene expression profiling in comparison with maculopapular drug rash, cutaneous GVHD, and the severe drug eruption toxic epidermal necrolysis (TEN). Results: Between February 2013 and September 2015, 68 patients with stage IV melanoma were treated at the University Hospital Zurich (Zurich, Switzerland); 15 patients (22%) developed cutaneous reactions and 10 (15%) vitiligo. The cutaneous reactions ranged from small erythematous papules with mild pruritus to disseminated erythematous maculopapular rashes (MPR) without signs of epidermal involvement to severe MPRs, including epidermal detachment and mucosal involvement. Although skin involvement varied from mild rash to bullous drug eruptions, gene expression profiling pathogenically classified all investigated cases as TEN-like reactions. Conclusions: As predicted by the PD-1 knockout mouse, anti-PD-1 antibodies frequently cause adverse cutaneous reactions. Gene expression profiling reminds in all cases of a TEN-like pattern, suggesting that PD-1/PD-L1 interaction is required to preserve epidermal integrity during inflammatory skin reactions. Clin Cancer Res; 22(16); 4023–9. ©2016 AACR.

Canakinumab in adults with steroid-refractory pyoderma gangrenosum.

Pyoderma gangrenosum (PG) is a rare, neutrophilic, ulcerative skin disease that is difficult to treat, especially when unresponsive to steroids.

Propionibacterium acnes promotes Th17 and Th17/Th1 responses in acne patients

Propionibacterium acnes is a Gram-positive commensal bacterium thought to be involved in the pathogenesis of acne vulgaris. Although the ability of P. acnes in the initiation of pro-inflammatory responses is well documented, little is known about adaptive immune responses to this bacterium. The observation that infiltrating immune cells consist mainly of CD4(+) T cells in the perifollicular space of early acne lesions suggests that helper T cells may be involved in immune responses caused by the intra-follicular colonization of P. acnes. A recent report showing that P. acnes can induce IL-17 production by T cells suggests that acne might be a T helper type 17 (Th17)-mediated disease. In line with this, we show in this work that, in addition to IL-17A, both Th1 and Th17 effector cytokines, transcription factors, and chemokine receptors are strongly upregulated in acne lesions. Furthermore, we found that, in addition to Th17, P. acnes can promote mixed Th17/Th1 responses by inducing the concomitant secretion of IL-17A and IFN-γ from specific CD4(+) T cells in vitro. Finally, we show that both P. acnes-specific Th17 and Th17/Th1 cells can be found in the peripheral blood of patients suffering from acne and, at lower frequencies, in healthy individuals. We therefore identified P. acnes-responding Th17/Th1 cells as, to our knowledge, a previously unreported CD4(+) subpopulation involved in inflammatory acne.

Severe Sweet's Syndrome with Elevated Cutaneous Interleukin-1β after Azathioprine Exposure: Case Report and Review of the Literature.

Sweets syndrome (SS) is a dermatosis with systemic symptoms characterized by tender, red nodules or papules, occasionally covered with vesicles, pustules or bullae, usually affecting the upper limbs, face and neck. SS is frequently observed in patients with leukemia or connective tissue diseases, while it is rather seldom in patients with inflammatory bowel disease. The exact pathogenesis of SS is only partially understood. We report the case of a 50-year-old patient with indeterminate colitis, presenting with a febrile diffuse papulopustular and necrotizing skin eruption that healed with significant scarring and appeared 14 days after onset of treatment with azathioprine. Histological examination revealed the presence of features typical of SS, gene expression analysis very high levels of interleukin-1β (IL-1β) mRNA in lesional skin, and immunohistochemistry high levels of IL-1β at the protein level. SS associated with azathioprine is being increasingly reported and is reviewed herein.

Tumour hypoxia promotes melanoma growth and metastasis via High Mobility Group Box-1 and M2-like macrophages.

Hypoxia is a hallmark of cancer that is strongly associated with invasion, metastasis, resistance to therapy and poor clinical outcome. Tumour hypoxia affects immune responses and promotes the accumulation of macrophages in the tumour microenvironment. However, the signals linking tumour hypoxia to tumour-associated macrophage recruitment and tumour promotion are incompletely understood. Here we show that the damage-associated molecular pattern High-Mobility Group Box 1 protein (HMGB1) is released by melanoma tumour cells as a consequence of hypoxia and promotes M2-like tumour-associated macrophage accumulation and an IL-10 rich milieu within the tumour. Furthermore, we demonstrate that HMGB1 drives IL-10 production in M2-like macrophages by selectively signalling through the Receptor for Advanced Glycation End products (RAGE). Finally, we show that HMGB1 has an important role in murine B16 melanoma growth and metastasis, whereas in humans its serum concentration is significantly increased in metastatic melanoma. Collectively, our findings identify a mechanism by which hypoxia affects tumour growth and metastasis in melanoma and depict HMGB1 as a potential therapeutic target.

Metastatic melanoma cell lines do not secrete IL-1β but promote IL-1β production from macrophages

We are grateful to the patients and their family members for participation in the study. The study was conducted by grant received from Higher Education Commission (HEC) of Pakistan. SH is supported by HEC’s indigenous PhD fellowship. [5] Alperin ES, Shapiro LJ. Characterization of point mutations in patients with Xlinked ichthyosis. Effects on the structure and function of the steroid sulfatase protein. J Biol Chem 1997;272:20756–63. [6] Oyama N, Satoh M, Iwatsuki K, Kaneko F. Novel point mutations in the steroid sulfatase gene in patients with X-linked ichthyosis: transfection analysis using the mutated genes. J Invest Dermatol 2000;114:1195–9. [7] Ramesh R, Chen H, Kukula A, Wakeling EL, Rustin MHA, Irwin McLean WH. Exacerbation of X-linked ichthyosis phenotype in a female by inheritance of filaggrin and steroid sulfatase mutations. J Dermatol Sci 2011;64:159–62. [8] Nagtzaam IF, Stegmann APA, Steijlen PM, Herbergs J, Van Lent-Albrechts JA, Van Geel M, et al. Clinically manifest X-linked recessive ichthyosis in a female due to a homozygous interstitial 1.6-Mb deletion of Xp22.31. Br J Dermatol 2012;166: 905–7.

Efficacy and Survival of Systemic Psoriasis Treatments: An Analysis of the Swiss Registry SDNTT.

Background: The Swiss psoriasis registry SDNTT (Swiss Dermatology Network for Targeted Therapies) records the long-term safety and effectiveness of systemic treatment regimens for psoriasis. Patients and Methods: Patients with moderate to severe psoriasis are included in the SDNTT when treatment with a conventional systemic agent or biologic is initiated that was not previously used by the respective patient. Patients are followed over a 5-year period. Clinical data are obtained every 3-6 months using standardized case report forms. Here, baseline data and follow-up data for 1 year of patients included from October 2011 until December 2014 were analyzed. Results: Within 39 months, 323 patients from 7 tertiary dermatology centers in Switzerland were recruited in the SDNTT; 165 patients received biologics and 158 conventional systemic therapies. Patients treated with biologics had a significantly higher severity (PASI 11.3 vs. 9.2, BSA 15.6 vs.11.9, psoriatic arthritis 36.4 vs. 10.8%; p ≤ 0.005, p ≤ 0.013, p ≤ 0.001) and a longer duration of illness (19.2 vs. 14.4 years, p ≤ 0.003) compared to patients starting a conventional systemic treatment. PASI reduction was satisfying in both treatment groups, with 60.6% of patients treated with biologics achieving PASI75 after 1 year compared to 54.2% of patients receiving conventional systemic drugs (nonsignificant). On average, the drug survival in patients receiving a biologic therapy was significantly longer than those receiving conventional systemic treatments (30.5 vs. 19.2 months, p ≤ 0.001). Conclusions: In the real-world setting of a prospective national therapy registry, the application of current therapeutic guidelines for patients with moderate to severe psoriasis resulted in a PASI reduction of approximately 70% within the first year of treatment, but current therapeutic targets of PASI75 and PASI90 were reached in only 58 and 36% of patients, respectively, at 1 year, highlighting a gap in efficacy between selective clinical trials and the real-world setting.

Therapy response was not altered by HLA-Cw6 status in psoriasis patients treated with secukinumab: a retrospective case series

Physicians can treat psoriasis patients with several effective treatments, however the response is individual and even the most effective therapies do sometimes not lead to a success of treatment. Currently, possible genetic markers that can predict individual therapy response are investigated. Up to now 45 genes have been identified to be associated with psoriasis [1].

Clinical disease patterns in a regional Swiss cohort of 34 pyoderma gangrenosum patients

Background/Aim: Pyoderma gangrenosum (PG) is a rare, neutrophilic dermatosis often associated with an underlying disease, and clinical data or larger studies are rare. Methods: In this retrospective study, disease characteristics, clinical manifestations, and treatment response were evaluated in a Swiss cohort of PG patients. Results: In participating centers, 34 cases (21 females) of PG were analyzed based on clinical and histological presentation between 2002 and 2012. The mean age at diagnosis was 61.2 years; 50% of the patients experienced only 1 episode of PG. In 13 cases (out of 20), recurrences occurred during PG therapy; 64.1% showed only 1 lesion simultaneously. The predominant localization was the lower limb (67%). The lesions were disseminated in 26.6%. At the time of diagnosis or recurrence, the mean diameter was 37.6 mm and the mean ulcer size was 10.3 cm2. C-reactive protein (CRP) was elevated in 73.2%; leukocytosis was present in 58.9% and neutrophilia in 50.9%. At least 1 associated comorbidity was present in 85% (the most prominent being cardiovascular disease). The most often used systemic treatments were steroids (68.3%), cyclosporine A (31.7%), dapsone (31.7%), and infliximab (13.3%), and the most often used topicals were tacrolimus 0.1% (48.3%) and corticosteroids (35%). PG healed completely at discharge in 50.8%. The average time to diagnosis was 8 months, and the mean duration to healing was 7.1 months. Conclusion: PG is a difficult-to-diagnose skin disease. Here, markers for inflammation such as CRP, leukocytosis, and neutrophilia were elevated in 50-73% of the PG patients.

Rapid Involution of Pustules during Topical Steroid Treatment of Acute Generalized Exanthematous Pustulosis

Acute generalized exanthematous pustulosis (AGEP) is a dramatic generalized pustular rash of severe onset, which is considered a serious cutaneous adverse reaction to drugs. However, even though the clinical features are impressive and are often accompanied by systemic inflammation, it can be controlled quickly and safely by topical steroids subsequent to interruption of the offending drug. Here, we describe the management of a case and the evolution of the pustular rash. An elderly woman consulted with a generalized crop of 2–3 mm, nonfollicular pustules on erythematous background. In the 4 preceding weeks, she had been using amoxicillin/clavulanic acid for a bacterial implant infection and rivaroxaban. The clinical EuroSCAR criteria including the histology confirmed AGEP. Her medication was stopped and topical clobetasol propionate was used. Within 24 h, the development of new pustules ceased and the patient was discharged after 7 days of hospitalization with only a faint, diffuse erythema and focal desquamation remaining. This and many other cases in the literature suggest that topical steroids should be considered as a first-line treatment option, especially as systemic steroids themselves can sometimes induce generalized pustulosis.