Older non-specific immunomodulatory drugs and off-label use of several biologic agents offer treatment options for children with severe atopic dermatitis (AD). However, the future should bring therapies specifically developed for treatment of AD investigated in children.
Although atopic dermatitis (AD) in children can usually be controlled with topical-based regimens, the minority of patients with refractory disease who require systemic immunomodulatory therapy still represents a sizeable population.
For decades, cyclosporine, methotrexate, azathioprine, and mycophenolate mofetil have represented the standard treatments for children with severe AD, even despite the safety concerns associated with these medications and the limited, if any, evidence-basis for their pediatric use. Now, with a burgeoning pipeline of investigational drugs for AD and the FDA helping to pave the way for including children in premarketing clinical trials, there is reason to be optimistic about the future, according to Elaine C. Siegfried, MD.
“The increased number of drugs being developed specifically for eczema, and the FDA’s recent support of pediatric clinical trials, mark the beginning of a new era of research that should enable us to better help children with severe AD overcome their disease,” says Dr. Siegfried, professor of pediatrics and dermatology, Saint Louis University Health Sciences Center, St. Louis, Mo.
Increased understanding of the pathogenesis of AD underlies the development of a number of new therapeutic candidates with novel mechanisms of action. Although not being considered for treating severe AD, there are several investigational topical medications at various stages of clinical development. Most of these compounds are phosphodiesterase 4 (PDE4) inhibitors, but there are some other proprietary molecules targeting phospholipase A2 and tropomyosin-related kinase A.
Also under development are several oral small molecule drugs, including the oral PDE4 inhibitor apremilast (Otezla, Celgene), a chymase inhibitor, and an essential fatty acid (dihomo-gamma linolenic acid).
Dr. Siegfried says that apremilast, which was recently approved for treatment of adults with moderate to severe plaque psoriasis or active psoriatic arthritis, is in a phase 2 trial of adults with AD.
“We now have level I data on apremilast that supports an excellent safety profile. However, it is hard to predict if it will be effective for treating AD,” she says.
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In addition, Dr. Siegfried says that there are safety concerns with roflumilast (Daliresp, Forest Pharmaceuticals), another commercially available oral PDE4 inhibitor, approved for treatment of adults with severe chronic obstructive pulmonary disease. Relatively common side effects of roflumilast include weight loss and GI disturbances, and it has also been associated with rare but more serious issues of depression and suicidal ideation.
There are also 10 biologics being investigated for treatment of severe AD in active trials. Of those, only one – dupilumab (Regeneron) – has advanced to phase 3 testing. Dupilumab is a monoclonal antibody targeting interleukin-4receptorα that inhibits both IL-4 and IL-13.
Other biologics in earlier phase clinical trials include the IL-12/23 inhibitor ustekinumab (Stelara, Janssen), which is in a phase 2 study enrolling adults, inhibitors of IL-13 and IL-31, and some proprietary molecules in phase 1 testing.
Currently, cyclosporine, methotrexate, azathioprine, and mycophenolate mofetil are generally considered as the first-line medications for children with severe AD needing systemic therapy and, since these agents have been around for so many years, clinicians have a reasonable level of comfort with their use in children.
Another option is off-label use of subcutaneous recombinant interferon gamma (Actimmune, Horizon Therapeutics), for which there is evidence of efficacy in treating AD from placebo-controlled clinical trials.
Dr. Siegfried says that for pediatric patients with severe AD for whom other options are contraindicated, poorly tolerated, or associated with long-term risks, consideration may be given to using apremilast or ustekinumab. However, there are often obstacles to getting payer approval for off-label use of these newer and expensive medications.
In theory, the IL-17a antagonist secukinumab (Cosentyx, Novartis), which was recently approved for treatment of adults with moderate to severe plaque psoriasis, may also be effective for treating AD. A study evaluating secukinumab in children with psoriasis has been deferred, and a trial evaluating its potential to preserve pancreatic beta cells in patients with newly diagnosed type 1 diabetes mellitus included children 8 years and older. However, that study was terminated.
Omalizumab (Xolair, Genentech/Novartis) and rituximab (Rituxan, Genentech) are other possible off-label options for treatment of severe treatment-refractory AD in children. Omalizumab is an anti-IgE compound approved for the treatment of both steroid-dependent asthma and chronic idiopathic urticaria in adults and adolescents (≥12 years of age). It, too, is expensive; as another consideration, it is unclear what dosage would be appropriate for treating AD, especially for children with very high serum levels of IgE.
Dr. Siegfried explained, “Omalizumab dosing for treatment of asthma is based on body weight and pre-treatment total plasma IgE for levels ranging up to 1,500 IU/mL. However, the majority of children with severe AD have much higher total IgE levels.”
For rituximab, which has approved indications for lymphomas and autoimmune diseases, there are data about its use in children with post-transplant lymphoproliferative disorders. Dr. Siegfried says she has used rituximab for one child with severe AD. However, it is a difficult drug to use because it must be given by IV infusion and has significant side effects.
Dr. Siegfried cautions that before deciding on a systemic treatment for a child with severe AD, it is important to screen the patient carefully for evidence of a primary immune deficiency. Use of immunosuppressant agents like cyclosporine, methotrexate, azathioprine, and mycophenolate mofetil, put such children at risk for infections and potentially serious adverse effects.
“We are increasingly recognizing primary immune deficiencies in children with severe AD, and I have seen several patients who developed lymphopenia, frequent upper and lower respiratory infections and transaminitis suggestive of acute infection after starting an immunosuppressive agent,” Dr. Siegfried says.
She also says that while eczema is a well-recognized feature of several genetically defined immunodeficiency conditions (eg., hyperIgE syndrome, DOCK 8 deficiency, Wiskott-Aldrich, Netherton’s syndrome and others), there are many children with AD who have an immune deficiency of a less severe phenotype. Many of these children develop recurrent eczema herpeticum.
It is important for clinicians to keep this association in mind to allow targeted treatment.
“Eczema herpeticum can resemble staphylococcal or streptococcal impetigo clinically, and culture from a surface swab is often positive for those bacteria, whereas herpes can only be detected with the directed laboratory tests,” Dr. Siegfried explains.
“Accurate diagnosis of eczema herpeticum is critical, because treatment requires antiviral therapy and systemic immunosuppressants may potentiate the infection.”
Another special situation to consider is the child with AD/psoriasis overlap. Children with overlap may be less responsive to topical treatment alone. While TNFa inhibitors are an effective choice for treating psoriasis, their use in the setting of overlap should be avoided because they can make the eczema worse.
“The newer biologics for treating psoriasis that target IL12/23 or IL-17a have more potential to treat both eczema and psoriasis and should be a better choice for children with overlap,” Dr. Siegfried says.
Disclosure: Dr. Siegfried serves as a consultant for Valeant, Promius, Pierre-Fabre and Celgene, and as a principle investigator for Anacor and Amgen.