Response to Interleukin-17A Inhibitors According to Prior Biologic Exposures: A Danish Nationwide Study.

Whether response to an interleukin (IL-17) inhibitor is different in patients with previous exposure to an IL-17 inhibitor compared with patients with exposure to biologics with other cytokine targets remains to be elucidated. Therefore, the aim of this study was to  assess whether previous exposure to an IL-17A inhibitor was associated with worse response than exposure to (an)other biologic(s). All patients in the DERMBIO register treated with an IL-17A inhibitor (secukinumab or ixekizumab) were included. With an absolute Psoriasis Area and Severity Index (PASI) ≤ 2 as response, the proportion of responders treated with IL-17A inhibitors was assessed in patients previously treated with another IL-17A inhibitor and compared with patients with previous exposure to (an)other biologic(s), using a χ2 test. In total, 100, 93 and 83 patients with  previous exposure to an IL-17A inhibitor and 414, 372 and 314 patients with previous exposure to (an) other biologic(s) were assessed after 3, 6 and 12 months, respectively. No differences in the proportion of  patients achieving PASI ≤ 2 were observed between the 2 groups after 3 months (54% vs 57%, p = 0.59), 6months (70% vs 66%, p = 0.42) and 12 months (69% vs 60%, p = 0.14). In conclusion, when treating patients with IL-17A inhibitors the cytokine target of the previous biologic does not appear to affect the  response.

Drug Survival of Adalimumab, Secukinumab, and Ustekinumab in Psoriasis as Determined by Either Dose Escalation or Drug Discontinuation during the First 3 Years of Treatment - a Nationwide Cohort Study.

The real-world efficacy of biologics may be insufficiently assessed through common drug survival studies. The objective was thus to examine the real-world performance of biologics in the treatment of psoriasis using the composite endpoint of either discontinuation or off-label dose escalation. Using a prospective nationwide registry (DERMBIO, 2007-2019), we included patients with psoriasis treated with adalimumab, secukinumab, and/or ustekinumab, which have all been used as first-line therapy during the inclusion period. The primary endpoint was a composite of either off-label dose escalation or discontinuation of treatment, whereas the secondary outcomes were dose escalation and discontinuation, respectively. Kaplan-Meier curves were used for the presentation of unadjusted drug survival curves. Cox-regression models were used for risk assessment. In 4,313 treatment series (38.8% women, mean age 46.0 years, and 58.3% bio-naivety), we found that the risk of the composite endpoint was lower for secukinumab when compared with ustekinumab (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.59-0.76), but higher for adalimumab (HR 1.15, 95% CI 1.05-1.26). However, the risk of discontinuation was higher for secukinumab (HR 1.24, 95% CI 1.08-1.42) and adalimumab (HR 2.01, 95% CI 1.82-2.22). For bio-naive patients treated with secukinumab, the risk of discontinuation was comparable to that of ustekinumab (HR 0.95, 95% CI 0.61-1.49).

Dimethyl Fumarate Targets MSK1, RSK1, 2 and IKKα/ß Kinases and Regulates NF-κB /p65 Activation in Psoriasis: A Demonstration of the Effect on Peripheral Blood Mononuclear Cells, Drawn from Two Patients with Severe Psoriasis Before and After Treatment with Dimethyl Fumarate.

BACKGROUND: Dimethyl fumarate (DMF) has an inhibitory effect on the production of pro-inflammatory proteins from different cells which participate in the immune reaction in psoriatic skin. Most recently it was shown that DMF is an allosteric covalent inhibitor of the p90 ribosomal S6 kinases (RSK1, 2), determined by X-ray crystallography. DMF binds to a specific cysteine residue in RSK2 and in the closely related mitogen and stress-activated kinases 1 (MSK1) which inhibits further downstream activation. OBJECTIVES: The aim of this study was to review the literature on the effects of DMF on activation of MSK1, RSK1, 2 kinases, and downstream transcription factors NF-κB/p65 and IκBα in cells contributing to the pathogenesis of psoriasis. We also hypothesized and studied if treatment with DMF would inhibit the activation of MSK1, RSK1, 2 kinases in peripheral blood mononuclear cells (PBMCs) in psoriatic patients. METHODS: PBMCs were purified from patients with severe psoriasis before and after 90 days of treatment with DMF. Cells were stimulated with anisomycin, IL-1ß or EGF for 10 and 20 minutes. The levels of phosphorylation of MSK1, RSK1, 2 or NF-κB/p65, IκBα were analyzed by Western blotting. RESULTS: Our case study showed that treatment with DMF inhibited the activation of MSK1 and RSK1, 2 kinases in PBMCs in patients. This supports that DMF is the active metabolite in vivo in psoriatic patients during DMF treatment. CONCLUSION: Pro-inflammatory proteins are induced through activation of MSK1 and NF-κB/p65 at (S276). The extracellular signal-regulated kinases (ERK1/2) control cell survival by activating both MSK1 and RSK1, 2 kinases. P-RSK1, 2 activates P-κBα and NF-κB/p65 at (S536). The phosphorylation of NF-κB/p65 at (S276) and (S536) controls different T cell and dendritic cell functions. DMF´s inhibitory effect on MSK1 and RSK1, 2 kinase activations reduces multiple immune reactions in psoriatic patients.

Protein phosphatase 2Cδ/Wip1 regulates phospho-p90RSK2 activity in lesional psoriatic skin.

OBJECTIVES: P90 ribosomal S6 kinase (RSK) 1 and 2 are serine/threonine protein kinases believed to mediate proliferation and apoptosis via the extracellular signal-regulated kinases (ERK1/2) signaling pathway. Macrophage migration inhibitory factor (MIF) and epidermal growth factor (EGF) are activators of this pathway and are elevated in the serum of patients with psoriasis compared with healthy controls. Studies on COS-7 cell cultures have shown that protein phosphatase 2Cδ (PP2Cδ) decreases the activity of RSK2 following EGF stimulation. We therefore hypothesize that PP2Cδ regulates RSK2 activity in psoriasis. METHODS: In paired biopsies from nonlesional (NL) and lesional (L) skins, we analyzed the level of RSK1, 2 phosphorylation and the expression of PP2Cδ isoforms, integrin-linked kinase-associated serine/threonine phosphatase (ILKAP) and wild-type p53-induced phosphatase 1 (Wip1) by Western blotting, immunofluorescence and coimmunoprecipitation with monoclonal antibody for RSK2. The induction of Wip1 by MIF or EGF was studied in cultured normal human keratinocytes. RESULTS: The protein level of RSK1, 2 phosphorylated at T573/T577 was significantly increased in L compared with NL psoriatic skin, while phosphorylation at S380/S386 was reduced in L compared with NL psoriatic skin when assayed by Western blotting and immunofluorescence microscopy. ILKAP expression was significantly higher in L than in NL skin, whereas Wip1 was expressed in similar amounts but showed increased coimmunoprecipitation with RSK2 in L compared with NL psoriatic skin. In cultured normal human keratinocytes stimulated with MIF, Wip1 phosphorylation and Wip1 expression were increased after 24 hours, but not when costimulated with dimethyl fumarate (DMF). The increased coimmunoprecipitation of Wip1 with RSK2 was significantly induced by EGF or MIF activation at 24 hours and could be significantly inhibited by DMF or the ERK1/2 inhibitor PD98059. CONCLUSION: The complex formation of Wip1 with RSK2 indicates a direct interaction reducing P-RSK2 (S386) activation in L skin and indicates that Wip1 has a role in the pathogenesis of psoriasis.

Dimethylfumarate specifically inhibits the mitogen and stress-activated kinases 1 and 2 (MSK1/2): possible role for its anti-psoriatic effect.

The p38 mitogen-activated protein kinase (MAPK) signaling pathway, which regulates the activity of different transcriptions factors including NF-kappaB, is activated in lesional psoriatic skin. The purpose of this study was to investigate the effect of fumaric acid esters (FAEs) on the p38 MAPK and the downstream kinases mitogen- and stress-activated protein kinase (MSK)1 and 2 in cultured human keratinocytes. Cell cultures were incubated with dimethylfumarate (DMF), methylhydrogenfumarate (MHF), or fumaric acid (FA) and then stimulated with IL-1beta before kinase activation was determined by Western blotting. A significant inhibition of both MSK1 and 2 activations was seen after preincubation with DMF and stimulation with IL-1beta, whereas MHF and FA had no effect. In addition, DMF decreased phosphorylation of NF-kappaB/p65 (Ser276), which is known to be transactivated by MSK1. Furthermore, incubation with DMF before stimulation with IL-1beta resulted in a significant decrease in NF-kappaB binding to the IL-8 kappaB and the IL-20 kappaB-binding sites as well as a subsequent decrease in IL-8 and IL-20 mRNA expression. Our results suggest that DMF specifically inhibits MSK1 and 2 activations and subsequently inhibits NF-kappaB-induced gene-transcriptions, which are believed to be important in the pathogenesis of psoriasis. These effects of DMF explain the anti-psoriatic effect of FAEs.