Spesolimab. Anti-IL-36R monoclonal antibody, Treatment of generalized pustular psoriasis, Treatment of immune-mediated inflammatory diseases

Successful use of secukinumab in pustular psoriasis

Introduction: Generalized pustular psoriasis (GPP) is a rare, severe variant of psoriasis that is uncommon in pediatric patients and can be refractory to many therapies. Ixekizumab, a monoclonal antibody that selectively inhibits interleukin 17-A, has been reported as safe and efficacious in patients with GPP, though minimal data exists on its use in the pediatric population.
 Case presentation: A 17-year-old female with history of alopecia areata and pustular psoriasis, on ustekinumab, was admitted for a severe pustular psoriasis flare with systemic symptoms including fever and tachycardia which progressed to erythroderma and required vasopressor support. After minimal improvement with 24 hours on broad-spectrum antibiotics, she received cyclosporine 5mg/kg/day. On day three of admission, and after two days of cyclosporine with minimal improvement, she received a 160 mg loading dose of ixekizumab. She defervesced and transferred out of the ICU within 24 hours. She was successfully weaned off cyclosporine after her second dose of ixekizumab. She experienced no adverse reactions.
 Discussion: Generalized pustular psoriasis is less common and often more severe than plaque psoriasis, associated with increased morbidity and mortality in both pediatric and adult patients. Clinical trials and case series have reported rapid and sustained improvement in patients with pustular psoriasis refractory to other therapies, though there is little data on the pediatric population. This case demonstrates the rapid efficacy of ixekizumab for severe erythrodermic pustular psoriasis in a pediatric patient, highlighting its use not only for refractory disease, but also as a rescue therapy in an emergent setting.

Generalized pustular psoriasis (GPP) is a rare, but severe form of psoriasis characterized by febrile illness, sudden eruption of erthema, sterile pustules, sever psoriatic arthritis. We report a case of 21 year old female patient having recalcitrant GPP, resistant to usual line of treatment who has been successfully treated with secukinumab. Treatment of GPP include steroids, acitretin or methotrexate, which still comprise the first-line treatment. Secukinumab is a first in class, recombinant, fully human monoclonal antibody that targets and blocks the actions of Interleukin 17-A (IL-17A). It is approved for the treatment of moderate to severe plaque psoriasis, psoriatic arthritis and rheumatoid arthritis from 2015. The recalcitrant pustular psoriasis responded well to secukinumab with disappearance of steroid induce complications, after 3 doses and no recurrence during follow-up period. Keywords: Impetigo herpetiformis, Pustular psoriasis, Secukinumab, IL17, Biologics.

Tumour necrosis factor (TNF)-alpha is thought to play a major role in the pathophysiology of psoriasis. Good clinical responses of psoriasis to anti-TNF-alpha-based therapies have recently been demonstrated. We studied the effect of infliximab, a monoclonal antibody against TNF-alpha, on chemokine expression in pustular psoriasis. A 61-year-old man with a 2-year history of severe pustular psoriasis of von Zumbusch type who did not respond to conventional therapies responded rapidly to treatment with infliximab. The clinical response was reflected by an immediate and effective reduction of the neutrophil-attractant chemokines interleukin (IL)-8 and growth-related oncogene (Gro)-alpha as well as of monocyte chemoattractant protein (MCP)-1, as determined by mRNA in situ hybridization of lesional skin. No expression before or after treatment was seen for monokine induced by interferon (IFN)-gamma (MIG) and IFN-inducible protein (IP)-10. Thus, in pustular psoriasis the chemokine expression pattern is dominated by neutrophil-attractant chemokines and MCP-1 while, in contrast to plaque psoriasis, IFN-gamma-inducible lymphocyte-attractant chemokines such as IP-10 and MIG are not abundant. We conclude that anti-TNF-alpha treatment with infliximab is an effective therapy in severe pustular psoriasis which is reflected by downregulation of disease-promoting chemokines such as IL-8, Gro-alpha and MCP-1.

BackgroundGeneralized pustular psoriasis (GPP) usually presents with fever, generalized flushing, and multiple sterile pustules on the skin, which histopathologically form subcorneal pustules characterized by Kogoj spongiform pustules. Granulocyte/monocyte adsorption apheresis (GMA) was approved in Japan in 2012. The use of biologics for psoriasis treatment is increasing. Several case reports have evaluated the combination of GMA and cyclosporine (CyA) for GPP. However, very few English reports on combining biologics and GMA in treating GPP exist.Case presentationA 79-year-old man with a history of hypertension, diabetes mellitus, chronic kidney disease, and atrial fibrillation was admitted. He had been consulting a dermatologist for psoriasis vulgaris (PV) since the age of 44. The patient was diagnosed with severe GPP and treated with 300 mg secukinumab (SEC) on day 3. SEC is a fully human monoclonal IgG1 antibody that targets IL-17A. Five doses were administered. In addition, GMA was administered once a week, three times from day 4. After the first administration of GMA, the inflammatory response and skin condition improved markedly. The patient was discharged from the hospital on day 34.ConclusionsThe present study is the first English-written report on the combined administration of SEC and GMA both instituted since admission for severe GPP, with immediate patient response to treatment. Notably, IL-17A plays a vital role in the pathogenesis of GPP. GMA can eliminate activated leukocytes, and the early introduction of combined IL-17 monoclonal antibody and GMA may allow disease suppression in patients with severe GPP, thus avoiding progression to multiorgan failure. Further studies may verify the effects of IL-17 monoclonal antibodies and GMA on severe GPP.

Mononuclear cells in skin lesions were characterized using an indirect immunofluorescence test with monoclonal antibodies. Most cells in the dermal infiltrates were stained with OKT3 (pan T cell) antibodies and with OKT4 (helper/inducer T cell) antibodies. Fewer cells were stained with OKT8 (suppressor/cytotoxic T cell) antibodies. Results obtained using a double marking technique with monoclonal antibodies and a hetero-anti-T lymphocyte serum showed that suppressor/cytotoxic cells comprised 15-25% of the T lymphocytes in lesions of psoriasis and discoid lupus erythematosus (DLE), and 25-35% in lesions of lichen planus. OKM1 (monocyte) antibodies stained few of the infiltrating cells in sections of the various skin lesions. The highest numbers of OKM1+ cells were found in sections of lesional skin from patients with erythrodermic and pustular psoriasis. Some T lymphocytes were also demonstrated in the epidermis in the various skin lesions. The highest numbers were found in the psoriatic lesions. The epidermal T lymphocytes were mainly suppressor/cytotoxic cells, and may be involved in a cell-mediated immune reaction of importance in the pathogenesis of these dermatoses.

Treatment of autoimmune disorders such as psoriasis, rheumatoid arthritis, and Crohn's disease with so called biologics (selective immunomodulatory drugs) has become a standard way to treat severe or recalcitrant forms...

Conflicts of interest: E.D. has been an advisory board member and consultant, received grants, research support and honoraria for speaking, or participated in clinical trials, with Abbott, Astellas, Biogen, Centocor Ortho Biotech Inc., Galderma, Glaxo, Janssen‐Cilag, Leo Pharma, Merck‐Serono, Novartis, Pfizer, Schering‐Plough, Stiefel, Wyeth Pharmaceuticals and 3M. A.G.‐D. has been an advisory board member and consultant, and received research support from Abbott and Serono. The other authors declare no conflicts of interest. Madam, Generalized pustular psoriasis is a rare and disabling variant of psoriasis. Its treatment is often challenging, as an unsatisfactory response is frequent. Ustekinumab, a fully human monoclonal antibody that binds to the shared p40 subunit of interleukin 12/23, has proven to be effective and safe for the treatment of moderate‐to‐severe plaque‐type psoriasis.1–4 A 47‐year‐old man presented with recurrent episodes of widespread and often generalized flares of classic plaque‐type psoriasis, which he had experienced since the age of 14. His medical history included hypertension, dyslipidaemia, hyperuricaemia and depression. His psoriasis was first treated with multiple topical agents, etretinate, acitretin, retinoids with psoralen plus ultraviolet A and methotrexate, with only partial response. In February 2007, he started treatment with infliximab, achieving an almost complete clearance of the plaques. However, withdrawal of the drug after seven infusions was necessary because of an elevation of transaminases up to six times the baseline values. Efalizumab was then initiated, but owing to only a slight improvement with this drug and the suspension of commercialization, therapy was withdrawn. A gradual deterioration of his skin involvement led, one and a half months later, to a significant flare of pustular psoriasis. Physical examination was remarkable for diffusely scattered pruriginous pustules on an erythematous base involving his head, trunk and upper/lower limbs (Fig. 1). A biopsy showed the characteristic findings of pustular psoriasis. Complementary tests were normal or negative except for a slight increase in cholesterol and triglycerides. His weight was 92 kg. The baseline situation was as follows: Psoriasis Area and Severity Index (PASI) score modified for pustular psoriasis manifestations (scaling substituted by pustules) 23·3; body surface area (BSA) 25%; Physician's Global Assessment (PGA) very severe; visual analogue scale (VAS, 0–10) for pruritus 7.

Acrodermatitis continua of Hallopeau is a rare variant of localized pustularpsoriasis characterized by the recurrent eruption of sterile pustules involvingthe distal portions of the fingers and toes that can lead to the destruction ofthe nail apparatus. Acrodermatitis continua of Hallopeau is a chronic, relapsingcondition that is resistant to most topical and systemic psoriasis therapies,making it notoriously difficult to manage. Interleukin-36 and interleukin-17 arethought to play a pivotal role in the pathophysiology of pustular psoriasis, andevidence suggests that interleukin-17 inhibition can be an effective therapy forpustular psoriasis variants, including acrodermatitis continua of Hallopeau.Bimekizumab, a monoclonal antibody that inhibits the interleukin-17 pathway, maybe a safe and effective treatment option for patients with acrodermatitiscontinua of Hallopeau. We present the first documented case of a patient withacrodermatitis continua of Hallopeau of the bilateral thumbnails who experiencedan excellent response to bimekizumab treatment.

The interleukin-1 (IL-1) family is involved in the correct functioning and regulation of the innate immune system, linking innate and adaptative immune responses. This complex family is composed by several cytokines, receptors, and co-receptors, all working in a balanced way to maintain homeostasis. Dysregulation of these processes results in tissue inflammation and is involved in the pathogenesis of common inflammatory dermatoses such as psoriasis, hidradenitis suppurativa, and atopic dermatitis. Therefore, therapeutic targeting of IL-1 pathways has been studied, and several monoclonal antibodies are currently being assessed in clinical trials. So far, promising results have been obtained with anti-IL-36R spesolimab and imsidolimab in pustular psoriasis, and their efficacy is being tested in other conditions.

Seven patients with pustular psoriasis, three with mutations in IL36RN, were treated with a monoclonal antibody against interleukin-36 receptor and had amelioration of their skin disease.

Background: Generalized pustular psoriasis (GPP) is a rare form of psoriasis that may either be preceded by plaque psoriasis or arise de novo, classically after withdrawal of systemic glucocorticosteroids. Adalimumab is a fully human, anti‐TNF‐α monoclonal antibody that specifically blocks the interaction of TNF‐α with the p55 and the p75 TNF‐α cell surface receptors. Aim: To demonstrate the efficacy and tolerability of adalimumab in the treatment of GPP. Case report: A 50‐year‐old woman had suffered from severe pustular psoriasis for 10 years and psoriatic arthritis for 8 years and received treatment with adalimumab, in monotherapy, 40 mg subcutaneously once a week for 72 weeks. DLQI, PDI and SKINDEX 29 score were used to assess patient compliance and satisfaction. Results: In our case, control of disease manifestations was rapid and clinical remission persisted during the treatment course until the 72th week. Treatment tolerability and compliance were consistent. The patient experienced a dramatic improvement of quality of life instruments. Conclusion: In this case, adalimumab has been demonstrated to be effective, safe and appropriate for long‐term use, indicating a beneficial effect on quality of life parameters.

We read with interest the letter from Bonekamp et al 1 reporting two children with severe deficiency of interleukin-36 receptor antagonist (DITRA) treated with high dose of Ustekinumab. DITRA, an...

Psoriasis is a chronic immune-mediated inflammatory skin disease in which the alteration of the interleukin-23 (IL-23)/IL-17 cytokine axis appears to be crucial from a pathogenetic perspective. This has been confirmed by the efficacy of monoclonal antibodies blocking IL-17A, such as secukinumab and ixekizumab. Brodalumab is a human anti-IL-17 receptor A (IL-17RA) monoclonal antibody that inhibits the biological activity of IL-17A, IL-17F and other IL-17 isoforms, and has been approved (210 mg s.c. at weeks 0, 1, 2 and every 2 weeks thereafter) for the treatment of psoriasis vulgaris, psoriatic arthritis, pustular psoriasis and psoriatic erythroderma in Japan (Lumicef). The U.S. Food and Drug Administration has also recently approved brodalumab (Siliq) for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy and have failed to respond or have lost response to other systemic therapies. Regulatory applications are under review in the E.U. and Canada. The phase III clinical trials in moderate to severe plaque psoriasis met their primary endpoints after 12 weeks' treatment, with PASI 75 (75% improvement in the Psoriasis Area and Severity Index) response rates ranging between 83% and 86% (210 mg) and PASI 100 response rates ranging between 37% and 44%, significantly higher than those achieved with ustekinumab in the head-to-head trials AMAGINE-1 and AMAGINE-2. The most frequently reported adverse events in brodalumab clinical trials consisted of nasopharyngitis, headache, upper respiratory tract infection and arthralgia. In the head-to-head trials, rates of neutropenia were higher with both active drugs than with placebo, and mild or moderate Candida infections were more frequent with brodalumab than with ustekinumab or placebo. Clinical development was terminated by Amgen after adverse events of suicidal ideation and behavior were observed ls involving several indications, but data are inconclusive regarding potential drug causality, and brodalumab has recently been approved in the U.S. with a black box warning and a risk-management program regarding suicidal issues. Blocking IL-17RA provides a highly efficacious therapeutic alternative for moderate to severe psoriasis with a satisfactory safety profile.

Clinical efficacy and safety of brodalumab (KHK4827), antiinterleukin-17-receptor a monoclonal antibody, in Japanese patients with pustular psoriasis (generalized) and psoriatic erythroderma: A phase 3, open-label, long-term study (4827-004 study)