Erythrodermic psoriasis and palmoplantar hyperkeratosis successfully treated with secukinumab: a case report

Erythrodermic psoriasis

Among the other forms of psoriasis, EP represents a rare and severe form that affects 1% to 2.25% of patients with psoriasis. The clinical characteristics of this form of psoriasis are the presence of erythematous, edematous, often exfoliative lesions that affect over 75% of the body surface area (4), and are often associated with numerous systemic symptoms such as fever, tachycardia, lymphadenopathy, arthralgia, and fatigue (5). There is a substantial risk of mortality due to transepidermal fluid and nutrient loss, and which in severe cases may lead to multiorgan failure and death (4).

EP generally develops in patients with poorly controlled psoriasis and as a result of the abrupt withdrawal of systemic medications such as corticosteroids, drug reactions to medications such as lithium, and underlying systemic infections (5). For a clear and correct diagnosis of EP, two general clinical subtypes that define the disease must be considered. The first subtype is characterized by psoriatic plaques that gradually differentiate and develop into generalized erythroderma, although, overall, the plaques remain differentiable from the erythroderma. This form of EP has a stable course and a good prognosis. In contrast, the second EP subtype is more common in a psoriatic arthritis setting and plaques usually cannot be distinguishable from whole-body erythema (6). As with psoriasis, the exact pathogenesis of EP is not fully clarified. The current literature suggests the involvement of an unbalanced T-helper (Th)1/Th2 differentiation in favor of the Th2 phenotype and its related cytokine secretion. Interleukin (IL)-4 and IL-13, in particular, have been shown to be elevated in EP relative to both psoriasis patients and healthy controls. Several studies have demonstrated that anti–tumor necrosis factor (TNF)-α agents improve EP outcomes, suggesting that TNF-α may play a role in the pathogenesis of EP (6).

Although difficult and challenging, the management of EP is possible through several treatment options. The US National Psoriasis Foundation had suggested, in 2010 in their consensus guidelines, the use of cyclosporine or infliximab as first-line therapy in unstable cases, with acitretin and methotrexate reserved for more stable cases. Since then, other therapies and treatment strategies have emerged, including topical treatment with steroids and vitamin D analogues, as well as phototherapy. Other studies have also demonstrated the efficacy of systemic agents, including second-generation retinoids (acitretin) and immunosuppressive drugs (methotrexate and cyclosporine), which showed complete remission and significant improvement in EP outcomes.

Recently, another class of drugs, called biological agents, has demonstrated high efficacy in EP management. Biological therapies represent an emerging class of immunosuppressive drugs, which, thanks to their enhanced selectivity to specific cytokines, may represent a valid alternative to the canonical treatments. Biological therapies include TNF-α inhibitors, IL-12/23 inhibitors, and IL-17 inhibitors (6).

Secukinumab: drug description and focus on the treatment of EP

As mentioned, an unbalanced proinflammatory response and massive cytokine secretion may promote and sustain worsening symptoms of EP. Besides Th1 and Th2, the recent discovery of the new class of T-helper cells, Th17, also highlighted the possible role of the proinflammatory cytokine IL-17 (secreted by Th17) in the pathogenesis of EP (7). Some environmental triggers, such as physical trauma, drugs, or infections, release proinflammatory cytokines, including IL-23 and TNF-α. Differentiation of T helper into Th17 cells and the release of cytokines, such as IL-17, promote keratinocyte proliferation, which, in the setting of EP, also release additional ILs and chemokines (8). The homodimeric glycoprotein IL-17A belongs to the IL-17 family and through its receptor complex IL-17RA/IL-17RC binds to keratinocytes, dendritic cells, dermal fibroblast, and endothelial cells.

Under physiological conditions, normal levels of IL-17A promote, upon binding, the proliferation of the keratinocytes necessary for healing, and protect against infectious agents. However, in psoriatic patients, levels of IL-17A are elevated, and correlate with the severity of the disease. Keratinocytes themselves, when stimulated, also synthesize many cytokines that can induce epidermal hyperplasia (autocrine growth factors) or neoangiogenesis (paracrine growth factors), resulting in worsening of EP and initiating a reverberating loop that perpetuates pro-proliferative and proinflammatory stimuli (9). Consistently, blocking IL-17A results in an improvement of psoriasis lesions, suggesting a key role in the pathogenesis of EP (8). Currently, one anti-IL-17A biological agent is approved for the treatment of plaque psoriasis, secukinumab, a monoclonal antibody that targets IL-17A (10).

Secukinumab is a novel biologic agent that specifically targets IL-17A. It is a fully human monoclonal antibody, and many clinical trials have demonstrated its efficacy in the treatment of plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis (AS) (11,12,13,14). Indications approved by the European Medicines Agency (EMA) include adult and pediatric psoriasis, psoriatic arthritis, axial spondyloarthritis (axSpA), AS and non-radiographic axial spondyloarthritis (nr-axSpA) (15). The rationale behind the efficacy and mechanism of the action of secukinumab is a targeted approach to block the disease process at a very early stage along with a safe adverse event profile (16). By targeting IL-17A, secukinumab thereby blocks its binding with IL-17R and consequent expression of cytokines. Blocking the IL-17A pathway leads to a normalization of the inflammatory processes and thus combats epidermal hyperproliferation, T-cell infiltration, and excessive expression of pathogenic genes (16).

Several clinical trials have demonstrated the efficacy of secukinumab in the treatment of psoriasis (11,12,13,14). Two phase III, double-blind, 52-week trials (ERASURE and FIXTURE) (17) evaluated the efficacy of secukinumab in patients with moderate-to-severe plaque psoriasis. The ERASURE study enrolled 738 patients, while FIXTURE study included 1,306 patients. In both studies patients received either placebo or secukinumab subcutaneously once a week for 5 weeks, but in the FIXTURE study patients also received etanercept (50 mg twice a week for 12 weeks, then once a week). Results from the ERASURE study showed that a psoriasis area and severity index (PASI) 75 score at week 12 was achieved by 81.6% and 71.6% of patients administered with 300 mg and 150 mg of secukinumab, respectively, and by 4.5% of placebo recipients. Corresponding results from FIXTURE showed that 77.1% of patients administered 300 mg of secukinumab, 67% of those administered 150 mg of secukinumab, 44% of etanercept recipients, and only 4.9% of placebo patients achieved PASI 75 score at week 12 (17).

Another multicenter, international, retrospective, pilot study enrolled 13 EP patients who were treated with a loading dose of 300 mg of subcutaneous secukinumab at weeks 0, 1, 2, 3, and 4, followed by 300 mg every 4 weeks (18). Results from this study showed that the response rate to secukinumab was 10/13 patients (77%), with a median time to clearance of 3 weeks (1.5-3 weeks). No recurrences were registered in the 52-week follow-up and a PASI score of 90 was achieved by 10/13 patients. These results demonstrated that secukinumab remains a valid and effective therapeutic option for EP (18).