The IL-17A monoclonal antibodies secukinumab, ixekizumab, and brodalumab have been shown in open-label phase 3 studies to result in disease remission at 12 weeks.46-48 Treatment with guselkumab, an IL-23 monoclonal antibody, also has demonstrated efficacy in patients with GPP.49 Ustekinumab, an IL-12/23 inhibitor, in combination with acitretin also has been shown to be successful in achieving disease remission after a few weeks of treatment.50
More recent case reports have shown the efficacy of IL-1 inhibitors including gevokizumab, canakinumab, and anakinra in achieving GPP clearance, though more prospective studies are needed to evaluate their efficacy.51-53 Given the etiologic association between IL-1 disinhibition and GPP, future investigations of these therapies as well as those that target the IL-36 pathway may prove to be particularly interesting.
Phototherapy and Combination Therapies—Phototherapy may be considered as maintenance therapy after disease control is achieved, though it is not considered appropriate for acute cases.28 Combination therapies with a biologic plus a nonbiologic systemic agent or alternating among various biologics may allow physicians to maximize benefits and minimize adverse effects in the long term, though there is insufficient evidence to suggest any specific combination treatment algorithm for GPP.28
Treatment Recommendations for Pediatric Patients
Based on a small number of case series and case reports, the first-line treatment strategy for children with GPP is similar to adults. Given the notable adverse events of most oral systemic agents, biologic therapies may emerge as first-line therapy in the pediatric population as more evidence accumulates.28
Treatment Recommendations for Pregnant Patients
Systemic corticosteroids are widely considered to be the first-line treatments for the management of impetigo herpetiformis.7 Low-dose prednisone (15–30 mg/d) usually is effective, but severe cases may require increasing the dosage to 60 mg/d.6 Given the potential for rebound flares upon withdrawal of systemic corticosteroids, these agents must be gradually tapered after the resolution of symptoms.
Certolizumab pegol also is an attractive option in pregnant patients with impetigo herpetiformis because of its favorable safety profile and negligible mother-to-infant transfer through the placenta or breast milk. It has been shown to be effective in treating GPP and impetigo herpetiformis during pregnancy in recently published case reports.54,55 In refractory cases, other TNF-α inhibitors (eg, adalimumab, infliximab, etanercept) or cyclosporine may be considered. However, cautious medical monitoring is warranted, as little is known about the potential adverse effects of these agents to the mother and fetus.28,56 Data from transplant recipients along with several case reports indicate that cyclosporine is not associated with an increased risk for adverse effects during pregnancy at a dose of 2 to 3 mg/kg.57-59 Both methotrexate and retinoids are known teratogens and are therefore contraindicated in pregnant patients.56
If pustules do not resolve in the postpartum period, patients should be treated with standard GPP therapies. However, long-term and population studies are lacking regarding the potential for infant exposure to systemic agents in breast milk. Therefore, the NPF recommends avoiding breastfeeding while taking systemic medications, if possible.56
Limitations of Treatment Recommendations
The ability to generate an evidence-based treatment strategy for GPP is limited by a lack of high-quality studies investigating the efficacy and safety of treatments in patients with GPP due to the rarity and relapsing-remitting nature of the disease, which makes randomized controlled trials difficult to conduct. The quality of the available research is further limited by the lack of validated outcome measures to specifically assess improvements in patients with GPP, such that results are difficult to synthesize and compare among studies.31
Conclusion
Although limited, the available research suggests that treatment with various biologics, especially infliximab, is effective in achieving rapid clearance in patients with GPP. In general, biologics may be the most appropriate treatment option in patients with GPP given their relatively favorable safety profiles. Other oral systemic agents, including acitretin, cyclosporine, and methotrexate, have limited evidence to support their use in the acute phase, but their safety profiles often limit their utility in the long-term. Emerging evidence regarding the association of GPP with IL36RN mutations suggests a unique role for agents targeting the IL-36 or IL-1 pathways, though this has yet to be thoroughly investigated.