Successful treatment with interleukin‐17A antagonists of generalized pustular psoriasis in patients without IL36RN mutations

Generalized pustular psoriasis (GPP) is a potentially life‐threatening disease that can be attributed to mutations in IL36RN in a subgroup of patients. In small trials, interleukin (IL)‐17A and IL‐17RA antagonists have been shown to be effective in patients with generalized pustular psoriasis in Japan. We identified seven patients who received the IL‐17A antagonists secukinumab (six cases) or ixekizumab (one case) in two dermatological centers. All patients showed a good or excellent clinical response. Anti‐IL‐17A therapy was well tolerated and ongoing in all patients after an average therapy duration of 12.9 months. Analysis of IL36RN mutation status was performed in six patients, one patient carried a heterozygous mutation, while the other five patients did not show a mutation in IL36RN. This is the first report of a successful treatment of GPP patients without IL36RN mutations responding to anti‐IL‐17A therapy.     

Recalcitrant eosinophilic pustular folliculitis of Ofuji with palmoplantar pustulosis: dramatic response to narrowband UVB phototherapy

Eosinophilic pustular folliculitis of Ofuji is a recalcitrant disease typified by non‐infective eosinophilic spongiosis involving the infundibular region of the hair follicle. We present a case of a 49‐year‐old Chinese man with known palmoplantar pustulosis and acrodermatitis continua of Hallopeau which was promptly resolved with methotrexate therapy. He returned with an erythematous papulopustular eruption with coalescence to annular plaques, occurring over the face, chest and back with active palmoplantar pustulation. Histology from skin biopsy of the palmar lesion was in keeping with palmoplantar psoriasis, while biopsy of the facial and truncal lesions revealed florid perifollicular eosinophilic congregation diagnostic of eosinophilic pustular folliculitis of Ofuji. Indomethacin was initiated with partial improvement of lesions with cyclical flares. A trial of narrowband ultraviolet‐B phototherapy at a frequency of thrice weekly achieved sustained clearance of both eosinophilic pustular folliculitis and palmoplantar lesions. Indomethacin was tailed down and eventually discontinued with maintenance of narrowband ultraviolet‐B therapy; this achieved successful control of the disease.     

Brodalumab: A new way to inhibit IL‐17 in psoriasis

Psoriasis is a chronic inflammatory disease that affects 2% to 4% of the population; about 20% of the patients present a moderate‐to‐severe form. The IL‐23/Th17/IL‐17 molecular axis is considered crucial in the pathogenesis of psoriasis and IL‐17 is fundamental in the maintenance of the immune and inflammatory alterations causing psoriasis. Expression of IL‐17A, IL‐17F, and IL‐17C is strongly increased in psoriatic plaques. Effective therapy leads to restoration of the expression of a wide range of genes (including effector cytokines and chemokines downstream of IL‐17) to near normal levels. Brodalumab is the first biologic drug targeting specifically the subunit A of the IL‐17 receptor (IL‐17RA) and thus inhibiting not only IL‐17A but also other members of the IL‐17 family. Brodalumab is very effective and safe in treating moderate‐to severe psoriasis.     

Mutation analysis of IL36RN gene in Japanese patients with palmoplantar pustulosis

Loss‐of‐function mutations of the IL36RN gene, encoding interleukin‐36 receptor antagonist (IL‐36Ra), have been reported as major pathogenic causes of generalized pustular psoriasis (GPP), especially in cases lacking previous histories of psoriasis vulgaris. Palmoplantar pustulosis (PPP), which is traditionally included among GPP‐related diseases, has a controversial association with IL36RN. While a negative view about the said association has been recently published from Europe, variations of the IL36RN gene show great ethnic differences. In this study, we performed mutation analysis of the IL36RN gene in 88 Japanese patients with PPP and identified three types of single base substitutions in four patients, namely, p.Pro82Leu in two patients, p.Asn47Ser in one and p.Thr123Met in another. All variations were heterozygous and different from previous European reports. We compared the immunohistochemical findings of IL‐36Ra on patients with and without variation of the IL36RN gene; however, no significant differences were observed. Our data and the previous European study suggest that PPP is not associated with mutations of the IL36RN gene.     

Efficacy and safety of secukinumab in patients with generalized pustular psoriasis: A 52‐week analysis from phase III open‐label multicenter Japanese study

Generalized pustular psoriasis (GPP) is a severe inflammatory skin disease characterized by the presence of sterile pustules covering almost the entire body and systemic symptoms such as fever. Secukinumab, a fully human‐recombinant anti‐interleukin‐17A monoclonal antibody was indicated for psoriasis vulgaris and psoriatic arthritis in Japan but is not yet investigated for GPP. In this phase III, open‐label multicenter single arm study, the efficacy and safety of secukinumab as monotherapy or with co‐medication was evaluated in 12 Japanese patients with GPP. All the patients received secukinumab 150 mg s.c. at baseline, week 1, 2, 3 and 4, and then every 4 weeks. Two non‐responders were up‐titrated to 300 mg. Change in GPP severity from baseline was evaluated by clinical global impression (CGI) categorized as “worsened”, “no change”, “minimally improved”, “much improved” or “very much improved”. Treatment success was achieved by 83.3% (n = 10) of patients at week 16 (primary end‐point) with CGI evaluated as “very much improved” (n = 9) and “much improved” (n = 1). Moreover, the area of erythema with pustules improved as early as week 1 and resolved by week 16 in most of the patients. The improvements were sustained throughout 52 weeks. Over the 52‐week treatment period, secukinumab was well tolerated with no unexpected safety signals. Nasopharyngitis, urticaria, diabetes mellitus and arthralgia were the frequent adverse events reported. The data from this study shows that secukinumab can become one of the potent treatment options for GPP.     

Novel IL36RN mutation in a Japanese case of early onset generalized pustular psoriasis

Generalized pustular psoriasis is a distinct type of psoriasis characterized by recurrent febrile attacks with disseminated subcorneal pustules on generalized skin rashes. Recently, homozygous and compound heterozygous mutations of the IL36RN gene, which encodes the anti‐inflammatory cytokine interleukin (IL)‐36 receptor antagonist, were identified in familial and sporadic cases of various ethnicities with generalized pustular psoriasis. Here we report a 39‐year‐old Japanese male patient who had suffered from repeated attacks of generalized pustular psoriasis since infancy with intervals of several years. At presentation, erythematous lesions with a few pustules were found only on some parts of the body and controlled with topical corticosteroids. An analysis of the IL36RN gene revealed compound heterozygous mutations of c.28C>T and c.368C>T. While the former mutation causing the premature termination p.Arg10X is recurrent in Japanese cases, the latter missense mutation causing p.Thr123Met substitution is novel, but another mutation in the same position has been reported in one Japanese case. Our report further supports the presence of the Japanese‐specific hot spots in the IL36RN gene, 28C and 368C, and suggests the functional significance of Thr123. This special type of generalized pustular psoriasis caused by IL36RN mutations has been designated as deficiency for IL‐36 receptor antagonist, a new hereditary autoinflammatory disease, and its phenotypes have emerged to include other related pustular disorders, palmoplantar pustulosis, acrodermatitis continua of Hallopeau, and acute generalized exanthematous pustulosis. The genetic analysis of the cases with these diseases would be important for establishment and application of the specific treatments targeting the IL‐36 signaling.     

Rare association of pyoderma gangrenosum and palmoplantar pustulosis: A case report and review of the previous works

Pyoderma gangrenosum is a rare inflammatory, ulcerative skin disease that mainly involves the lower extremities. It frequently occurs in association with systemic diseases such as inflammatory bowel disease, myeloproliferative disorders and rheumatoid arthritis. Palmoplantar pustulosis is also an inflammatory dermatosis characterized by recurrent sterile pustules localized on the palms and soles. These two dermatoses are histologically characterized by neutrophilic infiltration into the lesional skin. Co‐occurrence of pyoderma gangrenosum and palmoplantar pustulosis in a single patient is extremely rare. We report a case of pyoderma gangrenosum occurred in a patient with palmoplantar pustulosis, with a review of the previously reported cases. A 68‐year‐old Japanese woman with a 10‐year history of palmoplantar pustulosis developed a skin ulcer on the left lower leg. The ulcer was diagnosed as pyoderma gangrenosum based on the clinical and histological findings, and rapidly improved in response to oral prednisolone. In addition to our case, five cases with palmoplantar pustulosis who developed pyoderma gangrenosum have been reported. These cases were thought to have some characteristics in common, such as marked female predominance, no association with inflammatory bowel disease and myeloproliferative disorders, and good response to less aggressive therapy. The co‐occurrence of pyoderma gangrenosum and palmoplantar pustulosis in our case may have an etiological link, rather than being a coincidental complication.     

Patients with palmoplantar pustulosis have increased IL-17 and IL-22 levels both in the lesion and serum

Recent findings about the pathogenesis of pustulosis palmaris et plantaris (PPP), also known as palmoplantar pustulosis, suggest that IL-17 expression in the acrosyringium as well as infiltration of IL-17 positive cells, e.g. Langerhans cells may play important roles. However, to date, it has not been established whether circulating IL-17 related cytokines are involved in PPP. We studied the circulating IL-17 related cytokines as well as the mRNA levels in lesional skin. IL-17 related cytokine mRNAs were increased in the PPP lesions compared with the control tissues (five patients vs five controls). The serum levels of TNF-alpha, IL-17, IL-22 and IFN-gamma also were significantly increased in PPP, but not IL-23 and IL-8 (48 patients vs 20 controls). Our findings document that not only the serum IL-17 but also tissue IL-17 are elevated in PPP and may be in the pathogenesis of this disorder.     

Interleukin‐6 receptor alpha blockade improves skin lesions in a murine model of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease, characterized by antinuclear autoantibodies (ANA) and immunocomplexes, commonly affecting kidneys, skin, heart, lung or even the brain. We have shown that JunB^Δep mice develop a SLE phenotype linked to increased epidermal Interleukin (IL)‐6 secretion. Blocking of IL‐6 receptor alpha (IL‐6Rα) is considered as therapeutic strategy for the treatment of SLE. JunB^Δep and wild‐type mice were treated for short (5 weeks) or long term (21 weeks) with the IL‐6Rα‐blocking antibody MR16‐1. Skin and kidney of mice were investigated by histology and immunofluorescence, and in addition, kidneys were analysed by electron microscopy. Furthermore, soluble IL‐6R (sIL‐6R), antihistone and antinucleosome antibodies levels were measured and associated with disease parameters. Treatment with MR16‐1 resulted in significant improvement of SLE‐like skin lesions in JunB^Δep mice, compared to untreated mice. The sIL‐6R amount upon long‐term treatment with MR16‐1 was significantly higher in JunB^Δep versus untreated JunB^Δep (P = 0.034) or wild‐type mice (P = 0.034). MR16‐1 treatment over these time spans did not significantly improve kidney pathology of immunoglobulin deposits causing impaired function. Significantly higher antihistone (P = 0.028) and antinucleosome antibody levels (P = 0.028) were measured in MR16‐1‐treated JunB^Δep mice after treatment compared to levels before therapy. In conclusion, blockade of IL‐6Rα improves skin lesions in a murine SLE model, but does not have a beneficial effect on autoimmune‐mediated kidney pathology. Inhibition of IL‐6R signalling might be helpful in lupus cases with predominant skin involvement, but combinatorial treatment might be required to restrain autoantibodies.     

Interleukin‐17A affects extracellular vesicles release and cargo in human keratinocytes

Psoriasis is a chronic inflammatory systemic disease caused by deregulation of the interleukin‐23/‐17 axis that allows the activation of Th17 lymphocytes and the reprogramming of keratinocytes proliferative response, thereby inducing the secretion of cyto‐/chemokines and antimicrobial peptides. Beside cell‐to‐cell contacts and release of cytokines, hormones and second messengers, cells communicate each other through the release of extracellular vesicles containing DNA, RNA, microRNAs and proteins. It has been reported the alteration of extracellular vesicles trafficking in several diseases, but there is scarce evidence of the involvement of extracellular vesicles trafficking in the pathogenesis of psoriasis. The main goal of the study was to characterize the release, the cargo content and the capacity to transfer bioactive molecules of extracellular vesicles produced by keratinocytes following recombinant IL‐17A treatment if compared to untreated keratinocytes. A combined approach of standard ultracentrifugation, RNA isolation and real‐time RT‐PCR techniques was used to characterize extracellular vesicles cargo. Flow cytometry was used to quantitatively and qualitatively analyse extracellular vesicles and to evaluate cell‐to‐cell extracellular vesicles transfer. We report that the treatment of human keratinocytes with IL‐17A significantly modifies the extracellular vesicles cargo and release. Vesicles from IL‐17A‐treated cells display a specific pattern of mRNA which is undid by IL‐17A neutralization. Extracellular vesicles are taken up by acceptor cells irrespective of their content but only those derived from IL‐17A‐treated cells enable recipient cells to express psoriasis‐associated mRNA. The results imply a role of extracellular vesicles in amplifying the pro‐inflammatory cascade induced in keratinocyte by pro‐psoriatic cytokines.     

Hereditary lactate dehydrogenase M‐subunit deficiency with late‐developing pustular psoriasis‐like lesions

Hereditary lactate dehydrogenase (LDH) M‐subunit deficiency is very rare and we have found reports of close to a dozen cases in the published work, two of which were associated with pustular psoriasis‐like lesions. We report a third case of pustular psoriasis‐like eruptions associated with LDH M‐subunit deficiency, which occurred 24 years after the diagnosis of LDH M‐subunit deficiency. These cases indicate that abnormal activity of LDH can induce pustular psoriatic lesions in the long term. Some patients with symptoms of hereditary LDH M‐subunit deficiency have antecedent annular scaly plaque lesions, that resemble psoriatic lesions. We discuss a hypothesis to explain this scenario.     

Efficacy and safety of secukinumab in Taiwanese patients with moderate to severe plaque psoriasis: Subanalysis from ERASURE phase III study

The efficacy and safety of secukinumab, a fully human anti‐interleukin‐17A monoclonal antibody, has been evaluated for moderate to severe plaque psoriasis in global trials which have included a low proportion of Asian subjects. We analyzed the efficacy and safety of secukinumab in Taiwanese patients in a phase III global clinical trial (ERASURE). Fifty‐one Taiwanese patients were randomized into s.c. placebo, 150 and 300 mg secukinumab treatment groups. The proportions of patients who achieved 75% or more improvement in Psoriasis Area and Severity Index (PASI‐75) at week 12 were 87.5% with 300 mg secukinumab, 70% with 150 mg secukinumab, 0% with placebo. Of the patients receiving 300 mg secukinumab, 68.8% achieved PASI‐90 at week 12. Analysis of overall patients receiving 300 mg secukinumab for 12 weeks showed that the proportion of PASI‐75 responders was less in patients with body mass index of 25 or more than less than 25. During the entire 52 weeks, the incidence of adverse events (AE) was consistent with the overall population in ERASURE. The most common AE (cases/per 100 patient‐year) during the entire treatment period were upper respiratory tract infection and pruritus. The duration of upper respiratory tract infection per 100 patient‐year was approximately 399 days in placebo, 1261 days in 150 mg secukinumab and 1805 days in 300 mg secukinumab. The safety and efficacy of secukinumab in Taiwanese patients was compatible with the global phase III study in the treatment of moderate to severe plaque psoriasis.     

The plot thickens while the scope broadens: a holistic view on IL‐17 in psoriasis and other inflammatory disorders

Psoriasis is an instructive example highlighting our growing knowledge about pathophysiological functions of interleukin (IL)‐17. IL‐17A is the predominant isoform implicated in key pathogenic features in this and other chronic inflammatory disorders. Several monoclonal antibodies targeting IL‐17A (secukinumab, ixekizumab) or its IL‐17RC/RA receptor (brodalumab) are currently in late stages of clinical development, where they have shown impressive efficacy. While the eponymous IL‐17 has been thought to originate primarily from T helper (Th)17 cells, more recent investigations by several groups suggest that other cell types in psoriatic lesions, such as neutrophils and mast cells, are rich sources of IL‐17, thus presumably contributing to the disease process to an as yet underestimated extent. This recent paradigm shift provides a plausible explanation for the rapid and strong efficacy of the novel compounds targeting IL‐17 functions in psoriasis and other inflammatory disorders, and provide a more comprehensive view on the complex cytokine network in these conditions.     

Case of pityriasis rubra pilaris progressed to generalized erythroderma following blockade of interleukin‐17A,but improved after blockade of interleukin‐12/23 p40

We report herein a case of a 72‐year‐old man with pityriasis rubra pilaris (PRP) that was refractory to conventional therapies. His skin lesions progressed to generalized erythroderma despite anti‐interleukin (IL)‐17A antibody therapy. Topical corticosteroids, emollients, systemic retinoid, methotrexate, cyclosporin and phototherapy yielded no therapeutic response. However, blockade of IL‐12/23 p40 dramatically improved his cutaneous lesions. Complete remission was achieved 4 weeks after the first injection of ustekinumab and maintained for more than 48 weeks. Our data indicate that IL‐12 was associated with the onset of PRP in this patient, rather than IL‐23. IL‐12 is critical for the differentiation of T‐helper (Th)1 cells. Thus, the Th1 pathway may be associated with the onset of PRP.     

Trichophyton tonsurans‐induced kerion celsi with decreased defensin expression and paradoxically increased interleukin‐17A production

We report a case of kerion celsi due to Trichophyton tonsurans. An 18‐year‐old male student judo practitioner had alopecic patches, black dots and subcutaneous abscesses on the right temporal region. The damaged hair represented endothrix infection with T. tonsurans, as assessed by mycological examinations. He was treated with oral itraconazole without any therapeutic effect, followed by terbinafine with good effect. A skin biopsy showed neutrophil, lymphocyte and histiocyte infiltration into the dermis and subcutaneous tissue with abscesses around a number of dilated hair follicles. Immunostaining showed that the expression level of human β‐defensin 2 (HBD‐2) was decreased in the epidermis of the alopecic and adjacent skin. Because interleukin (IL)‐17A generally induces HBD‐2 production by epidermal keratinocytes, we also immunohistochemically investigated IL‐17A expression. Unexpectedly, many IL‐17A‐bearing cells were found around destructed hair follicles, indicating that IL‐17A expression was not attenuated, but rather increased in the skin lesion. Our case suggests that IL‐17A‐upregulated antimicrobial peptide expression is disordered in kerion celsi, and severe inflammation with IL‐17A may cause tissue damage and resultant scar.     

Coinheritance of generalized pustular psoriasis and familial Behçet‐like autoinflammatory syndrome with variants in IL36RN and TNFAIP3 in the heterozygous state

Generalized pustular psoriasis (GPP) is now known to be caused by biallelic variants in IL36RN and monoallelic variants in CARD14 and AP1S3. The presence of a modifier locus or oligogenic inheritance have been hypothesized. We report on a patient with a unique coinheritance of pathogenic variants in IL36RN (c.115+6T>C) and TNFAIP3 (c.547C>T, p.R183 * ) causing the genetic entities GPP and familial Behçet‐like autoinflammatory syndrome (AISBL). The heterozygous variant in IL36RN identified by Sanger sequencing was inherited from his unaffected father, while the heterozygous variant in TNFAIP3 was detected by whole‐exome sequencing and was also identified in the patient's AISBL‐affected maternal relatives. Further functional studies are required to research whether the variant of TNFAIP3 plays a part in the development of GPP or simply causes the Behçet's disease phenotype. However, our data suggest that whole‐exome sequencing for the heterozygous carrier of the IL36RN gene in GPP be used to find the potential second genetic locus.     

Evaluation of the efficacy of granulocyte and monocyte adsorption apheresis on skin manifestation and joint symptoms of patients with pustulotic arthro‐osteitis

Pustulotic arthro‐osteitis, occasionally complicated with palmoplantar pustulosis, affects patients’ activities of daily living. Granulocyte and monocyte adsorption apheresis selectively removes activated granulocytes and monocytes by means of extracorporeal circulation. Although the efficacy of granulocyte and monocyte adsorption apheresis in the treatment of generalized pustular psoriasis has been proved, very few reports have assessed its efficacy in the treatment of palmoplantar pustulosis and pustulotic arthro‐osteitis. Ten pustulotic arthro‐osteitis patients with five palmoplantar skin manifestations were treated with weekly granulocyte and monocyte adsorption apheresis over 5 weeks. Skin manifestations were assessed using palmoplantar pustulosis area and severity index, and joint symptoms were assessed using a visual analog scale of joint pain, tender joint count, swollen joint count and C‐reactive protein immediately before, after and at the 3‐month follow up of the five granulocyte and monocyte adsorption apheresis sessions. Two out of five patients with skin manifestations achieved more than 50% improvement in their score (remarkably improved). However, in two patients, deterioration was noted, in one of whom the skin manifestations remained unchanged at the 3‐month follow up. In five out of the 10 patients, the joint symptoms were assessed as better than improved at the 3‐month follow up. No deterioration was noted at the 3‐month follow up. In three patients, reduction or cessation of medication for arthralgia was possible. We concluded that granulocyte and monocyte adsorption apheresis is a therapeutic option to consider when pustulotic arthro‐osteitis is recalcitrant to conventional therapy.