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.     

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.     

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.     

Gastrointestinal bleeding with severe mucosal involvement in a patient with generalized pustular psoriasis without IL36RN mutation

Generalized pustular psoriasis (GPP) is a systemic inflammatory disease that presents with erythema and sterile pustules, pathologically characterized by Kogoj's spongiform pustules. GPP is sometimes accompanied by mucosal involvement, and the most common lesion is on the tongue. IL36RN mutation was found to contribute to the pathogenesis of GPP especially in patients who develop GPP without a past medical history of psoriasis vulgaris. The association of IL36RN mutation with mucosal involvement in GPP is controversial. We herein report a 60‐year‐old male GPP patient with no past history of plaque psoriasis presenting with not only severe skin lesions and arthritis but also severe mucosal involvements of pharyngeal and gastrointestinal lesions, which led to gastrointestinal bleeding. Our case did not have any mutation in the IL36RN gene. We should be aware that severe GPP can cause gastrointestinal bleeding. The relevancy of IL36RN mutation with mucosal involvement in GPP remains to be elucidated.     

Mutation in IL36RN impairs the processing and regulatory function of the interleukin‐36‐receptor antagonist and is associated with DITRA syndrome

The identification of loss‐of‐function mutations of the IL36RN gene encoding the interleukin‐36 receptor antagonist (IL‐36Ra) in generalized pustular psoriasis (GPP) emphasized the key role of this pathway in skin innate immunity and systemic inflammation. It has been previously shown in vitro that removal of the N‐terminal amino acid IL36Ra (M1) is critical to its biological activity, but the in vivo contribution of this processing remains unknown. We report herein a new homozygous (c4G>T, pV2F) missense IL36RN mutation segregating in a family with three GPP‐affected patients. The V2F mutation does not alter IL‐36Ra protein expression but was devoid of any antagonist activity. Mass spectrometry showed that the V2F IL‐36Ra mutant retains its first N‐terminal methionine. These results provide the first in vivo demonstration that removal of N‐terminal methionine of native IL‐36Ra is a mandatory step to reach optimal antagonist activity and to prevent sustained skin and systemic inflammation in humans.     

Granulocyte and monocyte apheresis can control juvenile generalized pustular psoriasis with mutation of IL36RN

Patients with deficiency of interleukin‐36 receptor antagonist (DITRA), due to mutation of IL36RN, exhibit psoriatic phenotypes, typically generalized pustular psoriasis (GPP). We report a paediatric patient with DITRA, whose cutaneous lesions varied from psoriasis vulgaris in infancy to annular pustular psoriasis with acute exacerbation to GPP at 13 years of age. Conventional systemic treatments for GPP, which include oral retinoids, ciclosporin and methotrexate, are controversial in paediatric cases, because of their adverse effects and uncertain long‐term consequences. Granulocyte monocyte apheresis, a process associated with few adverse events, promptly controlled the GPP of our paediatric patient, and has potential as a suitable alternative treatment for paediatric patients with DITRA.     

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.     

Clinical characteristics,genetics, comorbidities and treatment of palmoplantar pustulosis: A retrospective analysis of 66 cases in a single center in Taiwan

We retrospectively analyzed 66 patients with palmoplantar pustulosis (PPP) from January 1994 to September 2019 in our department. Interleukin-36 receptor antagonist gene (IL36RN) intron 3 c.115+6T>C mutation was present in two out of 27 patients (7.4%). Both cases developed generalized pustular psoriasis and/or acrodermatitis continua of Hallopeau later. Topical medications and phototherapy were used in 93.9% and 28.8% of patients, respectively, while 60.6% received systemic agents. The majority of patients (60.6%) responded to treatment, but episodes of flare-up existed. The demographic data of our patients with PPP showed female predominance (59.1%), middle-age onset (44.2 years old) and current smokers (62.1%). Generalized pustular psoriasis initially presenting as palmoplantar lesions may be misdiagnosed as PPP, and the presence of IL36RN mutation may serve to predict or confirm the diagnosis of future generalized pustular psoriasis or acrodermatitis continua of Hallopeau. To our knowledge, this is the largest demographic study of PPP in Taiwan.     

Pneumocystis carinii pneumonia in patients receiving immunosuppressive drugs for dermatological diseases

In recent years, Pneumocystis carinii pneumonia (PCP) has been increasingly reported in patients without human immunodeficiency virus (HIV) infection. The increased occurrence of PCP in non-HIV-immunocompromised subjects has been attributed to several factors: use of stronger immunosuppressive regimens, higher awareness of PCP, advanced diagnostic technology and nosocomial spread of P. carinii. Appearance of PCP subsequent to the use of immunosuppressive drugs has been noticed in many inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus and ulcerative colitis. Dermatologists frequently use immunomodulating agents, but the occurrence of PCP in patients receiving immunosuppressive drugs for skin diseases is largely unknown. We report four cases where PCP appeared following the use of immunosuppressive drugs primarily for cutaneous diseases, namely pemphigus, cutaneous necrotizing vasculitis (two cases) and Behçet's syndrome. These cases were identified in a computerized database study (1979–95) to evaluate the occurrence of PCP among immunocompromised hosts without HIV infection.     

Pustular psoriasis and related pustular skin diseases

Patients with pustular psoriasis or related pustular diseases may have genetic abnormalities impairing the function of key players of the innate skin immune system. Recently, identification of these abnormalities has changed the paradigm of several of these diseases. These include generalized pustular psoriasis, palmoplantar pustular psoriasis and acrodermatitis continua of Hallopeau, and also drug‐induced acute exanthematous generalized pustular eruption. Identified mutations in IL36RN, CARD14 and AP1S3 in different groups of patients lead to enhanced inflammatory cascade in several cellular subtypes including keratinocytes, and to the recruitment and activation of neutrophils and macrophages. These insights have unveiled pathophysiological features that shift the existing paradigms and emphasize the autoinflammatory nature of skin pustular disorders. They also highlight the crucial role of the innate immune system across entities belonging to the psoriasis disease spectrum, allowing identification of new appealing therapeutic targets.     

Efficacy and safety of guselkumab in psoriasis patients who failed ustekinumab and/or anti‐interleukin‐17 treatment: A real‐life 52‐week retrospective study

Recent major research advancements have significantly expanded our understanding of psoriasis pathophysiology, resulting in the development of highly effective, targeted therapies. Guselkumab is the first interleukin (IL)‐23 inhibitor approved for the treatment of moderate‐to‐severe‐psoriasis, providing a new therapeutical option for psoriasis. The aim of our study was to evaluate the efficacy of guselkumab in psoriatic patients who previously failed anti‐IL‐12/23 and/or anti‐IL‐17 treatment. A 52‐week single‐center retrospective study was performed enrolling moderate‐to‐severe patients attending our Psoriasis Care Center from October 2018 to May 2020. Study population included 13 patients; 46.1% have been previously treated with ustekinumab, while 69.2% have previously failed an anti‐IL‐17 treatment (38.5% secukinumab, 30.8% ixekizumab, and 38.5% both). At baseline, mean Psoriasis Area and Severity Index was 13.2 ± 6.8, reducing up to 0.5 ± 0.7 at week 52 (P < .001). Body surface area reduced from 22.3 ± 10.5 (baseline) to 0.8 ± 1.1 at week 52 (P < .001). No statistically significant differences have been found between patients previously treated with anti‐IL‐12/23 compared to anti‐IL‐17 or both. Only one patient discontinued guselkumab at week 36 due to secondary inefficacy. This is a single institution study with a relatively small sample size. Our real‐life data confirm trial results, showing guselkumab as a safe and effective option in patients with moderate‐to‐severe psoriasis even in those who previously failed ustekinumab and/or anti‐IL‐17 treatment.     

Serum interleukin‐22 and vascular endothelial growth factor serve as sensitive biomarkers but not as predictors of therapeutic response to biologics in patients with psoriasis

The T‐helper (Th)17 cell plays a crucial role in the pathogenesis of psoriasis, and several biological therapies have shown to be highly efficient in the treatment. However, some patients respond poorly to these therapies and may even develop paradoxical adverse effects. To evaluate the significance of serum immunological factors or circulating competent cells for biomarkers or predictors to biological therapies, we retrospectively analyzed 28 patients with psoriasis (19 psoriasis vulgaris, three pustular psoriasis and six psoriasis arthropathica). The numbers of patients treated with each agents were 16 for ustekinumab, six for adalimumab and six for infliximab. Patients were classified into three types according to the responsiveness: 13 patients were high‐responders showing a 75% or more reduction of Psoriasis Area and Severity Index (PASI); 10 patients were moderate‐responders showing PASI reduction of less than 75%; and five patients were non‐responders showing PASI elevation. During the treatments, serum levels of interleukin (IL)‐22 and vascular endothelial growth factor (VEGF) were monitored. At baseline, serum IL‐22 levels were significantly higher in the psoriatic patients than the normal controls. Both serum IL‐22 and VEGF levels significantly correlated with PASI. After the treatment, the high‐responders showed significant decreases in serum IL‐22 and VEGF. On the other hand, serum IL‐22 levels in the non‐responders were elevated. However, the baseline levels of serum IL‐22 and VEGF were not significantly different between the three groups. These results suggest that serum IL‐22 and VEGF levels serve as sensitive biomarkers but not as predictors of therapeutic response to biologics in patients with psoriasis.     

Association of <Emphasis Type="Italic">IL36RN</Emphasis> mutations with clinical features,therapeutic response to acitretin,and frequency of recurrence in patients with generalized pustular psoriasis

Background

Previous studies have revealed that IL36RN mutations play a pivotal role in the pathogenesis of generalized pustular psoriasis (GPP), however, the clinical relevance is unclear.

Objectives

To investigate the correlation between IL36RN mutations and clinical features, recurrence frequency, and therapeutic response to acitretin in GPP patients with long-term follow-up.

Materials & Methods

This retrospective cohort study, lasting 2-4 years, included 61 GPP and 48 psoriasis vulgaris (PV) patients.

Results

Sequence analysis of all five exons of the IL36RN gene revealed two genetic variants (c.115+6 T>C and c.227C>T). The cohort was divided into three subgroups according to the c.115+6 T>C mutation (present in 52.5% of the patients): homozygous mutation group (HOMG), heterozygous mutation group (HEMG), and non-mutation group (NMG). Initially, 21/25 HOMG patients were diagnosed with GPP with provocative factors, but 13 developed erythrodermic psoriasis after the pustular phase. Patients in the HEMG (5/7) and NMG (23/29) maintained PV diagnosis before and after the pustular phase. Most patients exhibited a marked response to acitretin, but patients who were prescribed a maintenance dosage (10-30 mg/d) had mild recurrence (0-2 times/year) during follow-up. IL36RN mutations were strongly linked with early onset and hyponychial pustules, but not with therapeutic efficacy of acitretin or recurrence frequency.

Conclusions

Early onset and hyponychial pustules may be specific to IL36RN mutation, however this alone is an insufficient biomarker for acitretin therapy. Other provocative factors play important roles in disease onset, clinical manifestations, and disease outcome. Low-dose maintenance therapy with acitretin might help reduce the recurrence of GPP.

     

Sequential Stevens-Johnson syndrome and photo-recall phenomenon

Summary Background Ustekinumab is a monoclonal antibody that targets interleukin (IL)‐12/23 p40 to treat psoriasis. The IL‐12 pathway is also important in regulating immunity to Mycobacterium tuberculosis. Objectives To evaluate the safety of isoniazid (INH) prophylaxis for newly identified latent tuberculosis infection (LTBI) in ustekinumab‐treated patients with psoriasis. Methods Safety data from 3177 psoriasis patients evaluated across five phase III trials of ustekinumab (45 or 90 mg) conducted in North America, Europe and Asia were analysed. LTBI was diagnosed based on positive tuberculin skin test or QuantiFERON^®‐TB test (Cellestis, Carnegie, Vic., Australia) without evidence of active tuberculosis. Results At baseline, 101/2898 (3·5%) non‐Asian and 66/279 (23·7%) Asian patients were newly identified with LTBI, and all were treated with INH. Through week 12, among patients who received INH, rates of adverse events (AEs) representative of INH toxicity were generally comparable between control and ustekinumab‐treated patients, as well as between ustekinumab dose groups. Markedly abnormal alanine transaminase values occurred with comparable incidences between control and ustekinumab‐treated patients. The rate of study agent discontinuation due to INH toxicity was low (5/167, 3·0%) and comparable between control and ustekinumab groups through week 12. The rate of INH‐related AEs did not increase disproportionately through week 28. No cases of active tuberculosis were reported in patients who received concomitant INH starting at baseline. Conclusions Across five trials of ustekinumab‐treated patients with psoriasis, no cases of LTBI reactivation were observed in patients receiving concomitant INH prophylaxis for LTBI. INH prophylaxis was generally well tolerated by these patients with psoriasis.     

Management of long‐term therapy with biological drugs in psoriatic patients with latent tuberculosis infection in real life setting

Psoriatic patients with latent tuberculosis infection (LTBI) need a prophylaxis before starting a treatment with biological drugs. The aim of this study is to investigate the safety and efficacy of prophylaxis of LTBI in psoriatic patients receiving long‐term biological drugs. The study included 56 patients (42 male and 14 female) affected by moderate‐to‐severe psoriasis (mean PASI: 12.8 ± 6.9 SD) treated with anti‐TNF‐α and/or anti IL 12, 23 and/or anti‐CD11 drugs with a diagnosis of LTBI. LTBI diagnosis was based on tuberculin skin test and/or QuantiFERON TB Gold test positivity and chest X‐ray suggestive, without clinical, or microbiological evidence of active disease. All patients received prophylactic therapy for 9 months with isoniazid (INH) 300 mg/day, starting 3 weeks before the beginning of biological treatment. Fifty‐four patients completed prophylaxis with INH without any adverse events or intolerance; they continue the biological treatment without appearance of active tuberculosis. One patient developed tuberculosis pleurisy in course of treatment with etanercept. The infection has been treated and after a stable remission, treatment was restarted without tuberculosis reactivation. In this retrospective analysis, the prophylaxis of LTBI whit INH was effective and safe in longer follow‐up period.     

Elevated serum levels of interleukin 21 are associated with disease severity in patients with psoriasis

Background  Psoriasis is an immune disorder involving numerous cytokines. Recent studies have shown that interleukin (IL)‐21 plays an important role in a variety of inflammatory and autoimmune diseases. It is highly expressed in psoriatic plaques and promotes the proliferation of epidermis in mice. It seems that IL‐21 plays an important role in the pathogenesis of psoriasis. However, whether or not it is elevated in the peripheral blood of patients with psoriasis and is associated with disease severity is unclear. Therefore, our study focuses on serum IL‐21 levels and their correlation with disease severity. Objectives  To detect serum IL‐21 levels in patients with psoriasis and investigate the correlation between these and the Psoriasis Area and Severity Index (PASI) scores. Methods  Blood samples were collected from patients with plaque psoriasis and from healthy control subjects. Serum IL‐21 levels were measured by enzyme‐linked immunosorbent assay in 37 patients with psoriasis and 37 healthy controls. The PASI scores of patients with psoriasis and their correlation with serum IL‐21 levels were evaluated. Results  Serum IL‐21 levels were higher in patients with psoriasis than in healthy controls (P < 0·01). Serum IL‐21 levels were positively correlated with PASI scores in the patients with psoriasis (r = 0·471, P < 0·01). Conclusions  Serum IL‐21 levels in patients with psoriasis are elevated and positively correlate with PASI scores. These results indicate that IL‐21 may play an important role in the pathogenesis of psoriasis.     

IL‐17A synergistically enhances TLR3‐mediated IL‐36γ production by keratinocytes: A potential role in injury‐amplified psoriatic inflammation

Skin injury can trigger formation of new lesions in psoriasis (Koebner phenomenon). The mechanisms through which injury exacerbates psoriasis are unclear. During wound repair, epidermal keratinocytes are activated and produce abundant IL‐36γ, further promoting the skin inflammation. IL‐17A is the cornerstone cytokine in the pathogenesis of psoriasis. We sought to investigate the effects of IL‐17A on injury‐induced keratinocyte activation and IL‐36γ production. Here, we demonstrated that dsRNA released from necrotic keratinocytes induced the expression of IL‐36γ. Silencing of TLR3 by siRNA decreased the IL‐36γ induction by necrotic keratinocyte supernatant. Co‐stimulation with dsRNA and IL‐17A synergistically increased the expression of IL‐36γ and other proinflammatory mediators (CCL20, CXCL8, DEFB4 and LCN2) in keratinocytes. The synergistic effects were not dependent on TLR3 upregulation, TNF receptor signalling and mRNA stabilization. Co‐stimulation with dsRNA and IL‐17A resulted in an accumulation of IκBζ. The synergistic upregulation of IL‐36γ and proinflammatory mediators were inhibited by IκBζ siRNA. Co‐stimulation with IL‐17A and poly(I:C) markedly activated the p38 MAPK and NF‐κB pathway, compared with poly(I:C). Blockade of p38 MAPK and NF‐κB suppressed dsRNA/IL‐17A–mediated IκBζ and IL‐36γ induction. These findings demonstrated that IL‐17A synergistically enhanced the dsRNA‐mediated IL‐36γ production through a p38 MAPK‐, NF‐κB–, and IκBζ‐dependent mechanism.     

Acute generalized exanthematous pustulosis and polyarthritis associated with a novel CARD14 mutation

Acute generalised exanthematous pustulosis (AGEP) is a rare toxicoderma characterised by an acute onset rash, with many sterile pustules on the surface, high fever and increased acute phase reactants. We report the case of a patient who presented to the dermatology department with an AGEP and polyarthritis, in which a novel CARD14 mutation was identified. The pathophysiological mechanism of AGEP remains unclear, although mutations in the IL36RN gene have been identified in a small subset of AGEP patients. Similarly, mutations in the CARD14 gene have been linked to pustular types of psoriasis and familiar cases of pityriasis rubra pilaris; however, there are no reports associating mutations in the CARD14 gene with AGEP.     

IL‐36 receptor antagonistic antibodies inhibit inflammatory responses in preclinical models of psoriasiform dermatitis

Psoriasis vulgaris (PV) results from activation of IL‐23/Th17 immune pathway and is further amplified by cytokines/chemokines from skin cells. Among skin‐derived pro‐inflammatory cytokines, IL‐36 family members are highly upregulated in PV patients and play a critical role in general pustular psoriasis. However, there is limited data showing crosstalk between the IL‐23 and IL‐36 pathways in PV. Herein, potential attenuation of skin inflammation in the IL‐23‐induced mouse model of psoriasiform dermatitis by functional inhibition of IL‐36 receptor (IL‐36R) was interrogated. Anti‐mouse IL‐36R monoclonal antibodies (mAbs) were generated and validated in vitro by inhibiting IL‐36α‐induced secretion of CXCL1 from NIH 3T3 cells. Antibody target engagement was demonstrated by inhibition of CXCL1 production in a novel acute model of IL‐36α systemic injection in mice. In addition, anti‐IL‐36R mAbs inhibited tissue inflammation and inflammatory gene expression in an IL‐36α ear injection model of psoriasiform dermatitis demonstrating engagement of the target in the ear skin. To elucidate the possible role of IL‐36 signalling in IL‐23/Th17 pathway, the ability of anti‐IL‐36R mAbs to inhibit skin inflammation in an IL‐23 ear injection model was assessed. Inhibiting the IL‐36 pathway resulted in significant attenuation of skin thickening and psoriasis‐relevant gene expression. Taken together, these data suggest a role for IL‐36 signalling in the IL‐23/Th17 signalling axis in PV.