Summary

Resident lesional T cells in moderate to severe psoriasis are well studied. Less is known about T cells in never-lesional skin from patients with mild psoriasis (NLP), investigated here by confocal imaging and flow cytometry. Tissue responses to T cell stimulation were furthermore measured by multiplex and NanoString technology. Interestingly, T cell activation ex vivo triggered psoriasiform and type I interferon tissue responses in NLP psoriasis. NLP-derived keratinocytes responded to IFN-g stimulation with myxovirus 1 expression and IFN-a release. CCR6-expressing resident T cells producing IFN-g and IL-17 were enriched in NLP-epidermis. Keratinocytes from NLP exposed to IL-17 and skin explants exposed to common fungal antigens responded with upregulation of the CCR6 ligand CCL20. Taken together, this implies that epidermal resident T cells capable of triggering psoriasiform tissue responses accumulate in NLP-epidermis. The interaction of the microbial microenvironment with genetically susceptible keratinocytes appears to shape the NLP T cells.

IPC Expert Commentary

The microbial microenvironment has in the last years been one of the main interests in medicine, and psoriasis is not excluded from this trend. In order to investigate the early changes in the complex etiology of psoriasis, this study went not to the crowded place of T cells in the established plaque in moderate to severe psoriasis but tried to analyze the early events by focusing on never-lesional skin from patients with mild psoriasis. The clear disturbance of T cells and microenvironment described here encourages the search for therapeutic options that, following the intellectual concept behind the design of this study, might be able to interfere in these early subclinical stages of psoriasis or maybe even the microenvironment itself. – Marcus Schmitt-Egenolf

Link to PubMed

Summary

Pustular psoriasis can be defined as the heterogenous family of pustular skin diseases that are associated with psoriasis vulgaris (PV). According to this generous definition of pustular psoriasis, even palmoplantar pustulosis (PPP) is included. Mutations in the IL36RN and AP1S3 genes have been described in this group. Pustular psoriasis manifests with repeated eruptions of neutrophil-filled pustules. The most severe form of this condition is generalized pustular psoriasis (GPP). Acrodermatitis continua of Hallopeau (ACH) affects the tips of fingers and toes and palmoplantar pustulosis (PPP) affects the palms and soles. In this study, the clinical and genetic features of pustular psoriasis were investigated by the analysis of an extended patient cohort. A total of 863 unrelated patients with pustular psoriasis were clinically investigated (GPP=251, PPP=560, ACH=28, multiple diagnoses=24). Psoriasis vulgaris occurred in about half of patients with GPP or ACH (54% GPP; 46% ACH) but only in 16% of PPP cases. The percentage of female patients was greater in PPP (77%) than in GPP (63%); likewise, the percentage of smokers was greater in PPP (80%) than in GPP (28%). GPP patients had the lowest mean onset age, 31 years (PPP 44 years and ACH 52 years). Mutation screening was performed in a subset of this cohort comprising 475 patients. IL36RN disease alleles were associated with earlier age of onset in all subtypes (P=0.003). IL36RN mutations were more common in GPP patients (0.19) and ACH patients (0.16) compared to PPP patients (0.03). AP1S3 alleles had similar frequency (0.03 - 0.05) across disease subtypes.

IPC Expert Commentary

This is an important study, as the rarity of generalized pustular psoriasis and acrodermatitis continua of Hallopeau has previously limited this kind of combined genetic and clinical analysis across the extended pustular psoriasis family. This study underlines the clinical and genetic differences between PPP on the one hand and GPP and ACH on the other. Facts such as the comparatively weak association of PPP with psoriasis vulgaris and its strong association with smoking has earlier led to the conclusion that PPP should be separated from the psoriasis family and be seen as a unique entity on its own. This genetic investigation does not enlighten us on this question. IL36RN disease alleles were associated with earlier age of onset in all subtypes, pointing toward a disease-promoting function. However, the relative rarity of IL36RN mutations among patients with PPP may imply that future treatments with IL36 inhibitors are more likely to be therapeutically relevant in the group of GPP and ACH patients. In March 2019, the first-in-class investigational treatment with the monoclonal antibody BI 655130 against the interleukin-36 receptor was published in The New England Journal of Medicine.¹ In this proof-of-concept study, 7 GPP patients were treated with a single, open-label, intravenous dose. Only 3 patients carried the IL36RN mutation. The pustules were completely cleared in 6 patients by week two. The efficacy of BI 655130 regardless of the presence of the IL36RN mutation suggests that the interleukin-36 pathway may play a pathogenic role among patients with generalized pustular psoriasis with different genetic backgrounds, including those without target mutations. This could imply that IL36RN screening before treatment is not necessary. – Marcus Schmitt-Egenolf

¹ Bachelez H, Choon SE, Marrakchi S, et al. N Engl J Med. 2019 Mar 7;380(10):981-983. doi: 10.1056/NEJMc1811317.

Summary

Psoriatic arthritis (PsA) occurs in about one-third of psoriasis patients. In this study, the authors use state-of-the-art statistical and machine-learning techniques to capitalize on the multitude of differences in the genetic architecture between PsA and cutaneous-only psoriasis (PsC) to predict the risk of developing PsA in the PsC population. The genetic data that populated their model were derived from 6 combined cohorts, resulting in 7,000 genotyped PsA and PsC patients. In their best predictions, the investigators achieved >90% precision with 100% specificity and 16% recall for predicting PsA among PsC patients, using conditional inference forest or shrinkage discriminant analysis, proving that genetic differences can potentially be used to predict PsA risk.

IPC Expert Commentary

This study shows that despite the lack of a relevant single genetic marker for PsA, a multitude of markers can be employed to predict this risk with impressive precision. Given the fast development and diminishing analysis costs in the fields of genetics and machine learning, personalized diagnostics for PsA may well enter clinical praxis soon and inform treatment decisions. From a clinical point of view, it would be interesting to be able to predict the risk of PsA in advance of symptoms and signs in PsC patients. However, as physicians, we should remember that genetic-derived statistical risk prediction does not necessarily translate to real-world clinical risk. We should not see the disease course of the patient in front of us in a deterministic way. On the contrary, we should always encourage and empower our patients, as lifestyle decisions have a value both within and far beyond the treatment of psoriasis. – Marcus Schmitt-Egenolf

Link to PubMed

Summary

The strategy of identifying and targeting various key signaling pathways in psoriasis pathogenesis has been outstandingly successful in bringing powerful new therapies to benefit patients. Papp et al report on yet another approach, aiming at the enzyme tyrosinase kinase 2 (TYK2). Normally, TYK2 activates transcription (STAT)-dependent gene expression and activates functional responses of interleukin-12, interleukin-23, and type I and III interferon receptors. These pathways are involved in the pathogenesis of psoriasis and other immune-mediated disorders; hence, the logic of aiming at TYK2. BMS-986165 is the current catchy name of this latest creation from Bristol-Myers Squibb. It binds to the “pseudokinase” domain of TYK2, blocking further signal transduction. This study was a phase 2, double-blind trial, comparing 5 different dose regimens and one placebo group. As often in these early phase 2 studies, there were only 12 weeks of active therapy, with a 30-day follow-up. Randomization was stratified with respect to geographic region (Japan or the rest of the world), though the reason for this was not given. The study reported on a total of 267 patients. A Psoriasis Area and Severity Index (PASI) score of 75 was reached in 7% of the placebo group, 9% of the lowest-dose group (3 mg per day), and 75% of the highest-dose group (12 mg per day). There was a clear relationship between dose and effectiveness. There were 3 serious adverse events in patients receiving the active drug, as well as 1 case of malignant melanoma 96 days after the start of treatment. Eight patients (3%) developed mild to moderate acne and 12 (4.5%) reported diarrhea.

IPC Expert Commentary

Results of this study showed that in the highest-dose group, which had an average age of 47 years, 4 out of 44 patients developed mild to moderate acne. The authors speculate that this could be due to the inhibition of cytokines involved in resistance to these organisms, resulting in proliferation of commensal bacteria and inflammation in the pilosebaceous units. Or, it might be chance. At the highest-dose investigated, 12 mg daily, 75% of 44 patients reached a 75% reduction in PASI and 64% reached a Dermatology Life Quality Index (DLQI)* score of 0 or 1. This sounds very promising, especially for a drug taken by mouth, but as the authors cautiously conclude: Safety and durability of effect remain to be determined. And this highest-dose group experienced the highest percentage of adverse effects.

Note: A recent article in the British Journal of Dermatology praised the New England Journal of Medicine for most often reporting confidence intervals (CIs) rather than p values in dermatology reports.¹ The gist of that BJD article was to encourage wider reporting of CIs by researchers to improve clinical interpretation of study results. So, it’s disappointing that in this NEJM article about TYK2, p values are given prominence. CIs provide a range in which the true value lies with a certain degree of probability as well as the strength and direction of the effect. So, statistical plausibility and clinical relevance of the study can be inferred. Admittedly, p values may appear to be clearer, but the 2 methods are complementary.

It was good to see that the investigators correctly defined the use of a “handprint” rather than a “palm,” as approximately 1% of body surface area. I admit I am biased over this, having struggled (mostly unsuccessfully) to help people understand this often wrongly or imprecisely defined concept. – Andrew Y. Finlay

* Dr. Finlay is joint copyright owner of the DLQI. He and Cardiff University receive royalties.
¹ Hopkins ZH, Moreno C, Secrest AM. Lack of confidence interval reporting in dermatology: a call to action. Br J Dermatol. 2019 Apr;180(4):910-915.

Summary

Risankizumab is a humanized IgG1 monoclonal antibody that binds to the p19 subunit of interleukin-23. It therefore inhibits this cytokine, which plays a key role in psoriatic inflammation. The aim of this study was to compare the efficacy and safety of risankizumab with placebo and with ustekinumab in moderate to severe chronic plaque psoriasis. Two replicate, multi-center, phase 3 studies across 14 countries involved 506 and 491 patients who were randomly assigned (3:1:1) to risakizumab 150 mg, ustekinumab 45 or 90 mg, or placebo for the initial double-blind 16 weeks. At week 16, the placebo group switched to risankizumab and the other patients continued on their original drug up to week 52. A Psoriasis Area and Severity Index (PASI) score of 90 was achieved at 16 weeks by 75.3% in the first study and 74.8% in the second study of patients on risakizumab, by 42% and 47.5% respectively, of patients on ustekinumab, and by 4.9% and 2.0% of patients on placebo. Confidence intervals were reported and demonstrated clear differences between the treatment groups. Secondary outcome measures included the Dermatology Life Quality Index (DLQI)* and the Psoriasis Symptom Scale (PSS), which scores the severity of pain, redness, itching, and burning. A DLQI score of 0 or 1 was achieved at week 16 by 66% and 67% of patients on risakizumab, by 43% and 46% on ustekinumab, and by 8% and 4% patients on placebo. A PSS score of 0 was achieved at 16 weeks by 29% and 31% of patients on risakizumab, 15% and 15% patients on ustekinumab, and 2% and 0% patents on placebo. Treatment-emergent adverse events were similar across patients treated with risakizumab, ustekinumab, and placebo.

IPC Expert Commentary

This is another well-organized and well-reported study adding major new evidence of the outstanding effectiveness of risankizumab and of superior effectiveness compared to ustekinumab. Interleukin- (IL-) 23 drives the development of psoriasis by stimulating T-helper-17 and innate immunity cells, which are major sources of pro-inflammatory cytokines. Whereas ustekinumab blocks the p40 subunit that both IL-12 and IL-23 share, risankizumab targets the p19 subunit, specific for only IL-23. The study is notable and especially valuable clinically, as it is one of the very few major studies to directly compare, head-to-head, two biologics with differing modes of action. Clinicians are now overwhelmed with choice of biologics for psoriasis, all providing greater benefit than our previous systemics. For each, the evidence of individual effectiveness may be clear, but the clinician needs to know how they directly compare: We need many more similar head-to-head studies. Pharmaceutical companies Boehringer Ingelheim and AbbVie closely cooperated over this study: Boehringer Ingelheim had sold the commercialization rights of risankizumab to AbbVie in 2016. It is not stated whether the maker of ustekinumab was involved in the study. The baseline demographics table reveals that 72% of the 996 patients weighed >100kg, regrettably reflecting accurately the reality of this comorbidity in patients with severe psoriasis. However, the ethnic origin of study participants in these international studies was 78% white, 17% Asian and only 1.6% black or African-American. This raises the general broader question of what steps clinical study organizers take to ensure recruitment of an appropriate racial mix. – Andrew Y. Finlay

*Dr. Finlay is joint copyright owner of the DLQI. He and Cardiff University receive royalties.

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