Page 643 - Clinical Immunology_ Principles and Practice ( PDFDrive )

618 Part five Allergic Diseases

Rituximab Recombinant Human Interferon-γ
Rituximab, a chimeric monoclonal anti-CD20 antibody has been Interferon-γ suppresses IgE synthesis and inhibits Th2 cell func-
given to patients with severe AD, with skin biopsies showing tion. In patients with AD, treatment with subcutaneous recom-
significant improvement in spongiosis and acanthosis and dermal binant human interferon-γ (rhIFN-γ) resulted in reduced clinical
13
13
T-cell and B-cell infiltrates decreased as well. Although total severity and decreased total circulating eosinophil counts.
serum IgE levels were reduced, allergen-specific IgE levels were rhIFN-γ may act primarily on the allergic inflammatory response
not affected. Treatment combining omalizumab and rituximab as opposed to IgE synthesis, and a subset of patients treated with
in patients with severe refractory AD was found to be effective, rhIFN-γ could respond to individualized titration of their treat-
suggesting that optimal therapy may require use of several ment dose. In a case series of pediatric patients with ADEH,
biologics. IFN-γ and IVIG were thought to be less likely to enhance the
cutaneous viral susceptibility of these patients compared with
Dupilumab systemic immunosuppressive therapies. 21
Dupilumab is a fully human mAb directed against the IL-4
receptor α subunit that blocks signaling of both IL-4 and IL-13. Phosphodiesterase-4 Inhibitors
Results from several randomized, double-blind, placebo-controlled Apremilast, an oral phosphodiesterase-4 inhibitor approved for the
trials involving adults with moderate-to-severe AD showed that treatment of psoriasis, was shown in a pilot study in adults with
treatment with dupilumab resulted in rapid and dose-dependent AD to reduce pruritus and improve the Dermatology Quality of
29
improvements in clinical indexes, biomarker levels, and disease Life Index (DLQI) and EASI scores. Gene ontological analyses
transcriptome. 22a,26 Of the patients in the dupilumab group, 85% comparing baseline samples with samples obtained during
had a 50% reduction in the Eczema Area and Severity Index treatment revealed alterations in immune response pathways,
(EASI) score compared with 35% in the placebo group (P <0.001); especially those related to cyclic adenosine monophosphate
40% of patients in the dupilumab group had an investigator’s (cAMP)–mediated signaling.
global assessment score of 0–1 (clear or almost clear) compared Crisaborole is a benzoxaborole phosphodiesterase 4 (PDE4)
with 7% in the placebo group (P <0.001); and pruritus scores inhibitor, which has been approved by the FDA as a 2% topical
30
decreased by 55.7% in the dupilumab group versus 15.1% in ointment in children and adults with mild to moderate AD.
the placebo group (P <0.001). In a combination study, 100% of The unique configuration of boron within the crisaborole
the patients in the dupilumab group had a 50% improvement in molecule enables selective targeting and inhibition of PDE4,
EASI (P = 0.002), compared with 50% of those in the placebo increasing cAMP levels and reducing inflammation. In addition,
group, even though the patients who received dupilumab used the boron molecule allowed for synthesis of a low-molecular-
less than half the amount of topical steroids compared with weight compound (251 daltons), thereby facilitating penetration
those in the placebo group (P = 0.16). Adverse events, such of crisaborole through human skin. In vitro experiments have
as skin infection, occurred more frequently with placebo; shown that crisaborole inhibits cytokine production by peripheral
nasopharyngitis and headache were the most frequent adverse blood mononuclear cells similar to other PDE4 inhibitors and
events with dupilumab. Of note, treatment with dupilumab distinct from corticosteroids. Randomized controlled clinical
monotherapy shifted the RNA expression profile of lesional skin trials have shown the efficacy and safety of crisaborole topical
to a more nonlesional signature. Dupilumab was well tolerated ointment 2% in children, adolescents, and adults with mild to
with no dose-limiting toxicity. Further dose ranging studies have moderate AD.
27
been reported, and studies in adolescents and children are
ongoing. Probiotics
Clinical trials in patients with AD show varying results. A meta-
Anti–IL-12/IL-23 analysis of randomized controlled trials that attempted to
Ustekinumab, an mAb used for treatment of psoriasis and overcome some of the limitations of prior reviews found a
psoriatic arthritis, binds to the common p40 subunit of IL-12/ reduction of approximately 20% in the incidence of AD and
IL-23. A recent study of Japanese and Korean patients with AD IgE-associated AD in infants and children with the use of probiot-
22
found overlapping features of both AD and psoriasis. The Asian ics. Although these results are encouraging, the use of probiotics
AD phenotype described presents a blended phenotype, including for the prevention of AD remains investigational.
increased hyperplasia, parakeratosis, higher Th17 activation, and
a strong Th2 component. Although these findings need to be PREVENTION
reproduced in a larger population of Asian patients, they do
suggest that ustekinumab may be of benefit in a subset of patients Two preliminary studies have suggested that emollient therapy
with similar features. started in early infancy in at-risk neonates can reduce the
incidence of AD. 31,32 Both studies were of relatively short-term
Other Biologics duration without follow-up off emollient therapy. It is noteworthy
A number of other biologics have been evaluated in preliminary that infants at risk for AD at 1 year of age could be identified
studies or are in early development in AD. 22,28 These include as early as day 2 of life by TEWL measurement, independent of
anti–IL-13 (lebrikizumab, tralokinumab), anti–IL-22, anti–IL-31, parental atopy or FLG mutation status. 33
and anti–IL-31-receptor, as well as anti-TSLP and anti–TSLP
receptor. New insights into AD phenotypes as well as better CONTACT DERMATITIS
understanding of underlying immunopathology will likely lead
to improved selection of appropriate patients for more targeted CD is a skin disorder caused by contact with an exogenous
therapies. substance that elicits an allergic and/or irritant response. The