IgE blockade with omalizumab reduces pruritus related to immune checkpoint inhibitors and anti-HER2 therapies.

BACKGROUND: Immunoglobulin E (IgE) blockade with omalizumab has demonstrated clinical benefit in pruritus-associated dermatoses (e.g. atopic dermatitis, bullous pemphigoid, urticaria). In oncology, pruritus-associated cutaneous adverse events (paCAEs) are frequent with immune checkpoint inhibitors (CPIs) and targeted anti-human epidermal growth factor receptor 2 (HER2) therapies. Thus, we sought to evaluate the efficacy and safety of IgE blockade with omalizumab in cancer patients with refractory paCAEs related to CPIs and anti-HER2 agents. PATIENTS AND METHODS: Patients included in this multicenter retrospective analysis received monthly subcutaneous injections of omalizumab for CPI or anti-HER2 therapy-related grade 2/3 pruritus that was refractory to topical corticosteroids plus at least one additional systemic intervention. To assess clinical response to omalizumab, we used the Common Terminology Criteria for Adverse Events version 5.0. The primary endpoint was defined as reduction in the severity of paCAEs to grade 1/0. RESULTS: A total of 34 patients (50% female, median age 67.5 years) received omalizumab for cancer therapy-related paCAEs (71% CPIs; 29% anti-HER2). All had solid tumors (29% breast, 29% genitourinary, 15% lung, 26% other), and most (n = 18, 64%) presented with an urticarial phenotype. In total 28 of 34 (82%) patients responded to omalizumab. The proportion of patients receiving oral corticosteroids as supportive treatment for management of paCAEs decreased with IgE blockade, from 50% to 9% (P < 0.001). Ten of 32 (31%) patients had interruption of oncologic therapy due to skin toxicity; four of six (67%) were successfully rechallenged following omalizumab. There were no reports of anaphylaxis or hypersensitivity reactions related to omalizumab. CONCLUSIONS: IgE blockade with omalizumab demonstrated clinical efficacy and was well tolerated in cancer patients with pruritus related to CPIs and anti-HER2 therapies.

T-helper immune phenotype may underlie 'paradoxical' tumour necrosis factor-α inhibitor therapy-related psoriasiform dermatitis.

BACKGROUND: Therapeutics targeting tumour necrosis factor (TNF)-α are effective for psoriasis; however, in patients treated for other disorders, psoriasis may worsen and psoriasiform dermatitis (PsoD) may arise. T helper (Th) cytokines in psoriasis upregulate keratin (K)17, which modulates TNF-α transduction, leading to vascular adhesion molecule upregulation and lymphocytic extravasation. AIM: We investigated Th phenotype and expression of K17, intercellular adhesion molecule (ICAM)-1 and vascular adhesion molecule (VCAM)-1 in psoriasis and anti-TNF-α-related PsoD. METHODS: Skin biopsies from patients with psoriasis unresponsive to TNF-α inhibitor therapy (n = 11), PsoD-related to TNF-α inhibition (n = 9), untreated psoriasis (n = 9) or atopic dermatitis (AD; n = 9) were immunohistochemically analysed for Th1, Th2, Th17 and Th22. Expression of K17, ICAM-1 and VCAM-1 was also examined. RESULTS: Anti-TNF-α-unresponsive psoriasis and anti-TNF-α-related PsoD showed decreased Th1 : Th2 raio and increased Th17 : Th1 ratio compared with untreated psoriasis. Anti-TNF-α-unresponsive psoriasis had significantly fewer Th1 (4% vs. 12%) and more Th17 (51% vs. 20%) cells than untreated psoriasis. No difference in Th22 cells was identified. K17 was present in all cases of untreated psoriasis and anti-TNF-α-related PsoD, 91% of anti-TNF-α-unresponsive psoriasis, and only 22% of AD. VCAM-1 and ICAM-1 in anti-TNF-α-related PsoD was akin to untreated psoriasis, but decreased in anti-TNF-α-unresponsive psoriasis. CONCLUSIONS: These findings further the current understanding of the anti-TNF-α-related psoriasiform phenotype and support a rationale for therapeutic targeting of interleukin-17 and TNF-α in combination.

Determinants of oxygen uptake kinetics in older humans following single-limb endurance exercise training.

We hypothesised that the observed acceleration in the kinetics of exercise on-transient oxygen uptake (VO2) of five older humans (77 +/- 7 years (mean +/- S.D.) following 9 weeks of single-leg endurance exercise training was due to adaptations at the level of the muscle cell. Prior to, and following training, subjects performed constant-load single-limb knee extension exercise. Following training VO2 kinetics (phase 2, tau) were accelerated in the trained leg (week 0, 92 +/- 44 s; week 9, 48 +/- 22 s) and unchanged in the untrained leg (week 0, 104 +/- 43 s; week 9, 126 +/- 35 s). The kinetics of mean blood velocity in the femoral artery were faster than the kinetics of VO2, but were unchanged in both the trained (week 0, 19 +/- 10 s; week 9, 26 +/- 11 s) and untrained leg (week 0, 20 +/- 18 s; week 9, 18 +/- 10 s). Maximal citrate synthase activity, measured from biopsies of the vastus lateralis muscle, increased (P < 0.05) in the trained leg (week 0, 6.7 +/- 2.0 micromol x (g wet wt)(-1) x min(-1); week 9, 11.4 +/- 3.6 micromol x (g wet wt)(-1) x min(-1)) but was unchanged in the untrained leg (week 0, 5.9 +/- 0.5 micromol x (g wet wt)(-1) x min(-1); week 9, 7.9 +/- 1.9 micromol x (g wet wt)(-1) x min(-1)). These data suggest that the acceleration of VO2 kinetics was due to an improved rate of O2 utilisation by the muscle, but was not a result of increased O2 delivery.