Tildrakizumab in the treatment of psoriasis: latest evidence and place in therapy.

Psoriasis is a chronic inflammatory disorder that is clinically characterized by scaly cutaneous plaques. New evidence suggests that dysregulation of interleukin (IL)-23, a key cytokine in the T-helper-17 pathway, plays a vital role in the development of psoriatic systemic inflammation. The novel biologic medication tildrakizumab is among the first drugs with specific action against IL-23 that has recently been approved by the United States Food and Drug Administration and the European Medicines Agency for moderate-to-severe psoriasis. Tildrakizumab has been shown in large randomized controlled trials to be effective in improving skin manifestations as well as enhancing quality of life outcomes in patients with psoriasis. Its simple dosing, prolonged duration of action, and mild adverse event profile make it a practical option for patients; however, only a small number of trials have investigated the clinical effectiveness of tildrakizumab, and long-term data regarding the drug's efficacy and safety are currently limited. Hence, further research is needed to better understand the risks and benefits of tildrakizumab. This review summarizes and analyzes phase I, phase II, and phase III clinical trials that investigate the mechanism, pharmacokinetics, efficacy, and safety of tildrakizumab. It also identifies areas in which additional studies are warranted to further elucidate the advantages of tildrakizumab over other biologic therapies

Inhibition of TBK1/IKKε Promotes Regeneration of Pancreatic β-cells

β-cell proliferation induction is a promising therapeutic strategy to restore β-cell mass. By screening small molecules in a transgenic zebrafish model of type 1 diabetes, we identified inhibitors of non-canonical IκB kinases (IKKs), TANK-binding kinase 1 (TBK1) and IκB kinase ε (IKKε), as enhancers of β-cell regeneration. The most potent β-cell regeneration enhancer was a cinnamic acid derivative (E)-3-(3-phenylbenzo[c]isoxazol-5-yl)acrylic acid (PIAA), which, acting through the cAMP-dependent protein kinase A (PKA), stimulated β-cell-specific proliferation by increasing cyclic AMP (cAMP) levels and mechanistic target of rapamycin (mTOR) activity. A combination of PIAA and cilostamide, an inhibitor of β-cell-enriched cAMP hydrolyzing enzyme phosphodiesterase (PDE) 3, enhanced β-cell proliferation, whereas overexpression of PDE3 blunted the mitogenic effect of PIAA in zebrafish. PIAA augmented proliferation of INS-1β-cells and β-cells in mammalian islets including human islets with elevation in cAMP levels and insulin secretion. PIAA improved glycemic control in streptozotocin (STZ)-induced diabetic mice with increases in β-cell proliferation, β-cell area, and insulin content in the pancreas. Collectively, these data reveal an evolutionarily conserved and critical role of TBK1/IKKε suppression in expanding functional β-cell mass

Appearance of lentigines in psoriasis patient treated with guselkumab

Development of lentigines in areas of resolving psoriatic plaques is a rare phenomenon that has been reported following various treatment modalities including phototherapy, topical therapies, and biologics. Although the exact mechanism is unknown, evidence suggests that the cause may be multifactorial, with factors such as skin type, sun exposure, inflammation, and immunologic cytokines all playing a potential role. Herein, we present the first reported case of a patient developing multiple lentigines following treatment of psoriasis with the IL-23 inhibitor guselkumab

Tildrakizumab in the treatment of psoriasis: latest evidence and place in therapy.

Psoriasis is a chronic inflammatory disorder that is clinically characterized by scaly cutaneous plaques. New evidence suggests that dysregulation of interleukin (IL)-23, a key cytokine in the T-helper-17 pathway, plays a vital role in the development of psoriatic systemic inflammation. The novel biologic medication tildrakizumab is among the first drugs with specific action against IL-23 that has recently been approved by the United States Food and Drug Administration and the European Medicines Agency for moderate-to-severe psoriasis. Tildrakizumab has been shown in large randomized controlled trials to be effective in improving skin manifestations as well as enhancing quality of life outcomes in patients with psoriasis. Its simple dosing, prolonged duration of action, and mild adverse event profile make it a practical option for patients; however, only a small number of trials have investigated the clinical effectiveness of tildrakizumab, and long-term data regarding the drug's efficacy and safety are currently limited. Hence, further research is needed to better understand the risks and benefits of tildrakizumab. This review summarizes and analyzes phase I, phase II, and phase III clinical trials that investigate the mechanism, pharmacokinetics, efficacy, and safety of tildrakizumab. It also identifies areas in which additional studies are warranted to further elucidate the advantages of tildrakizumab over other biologic therapies

Severe and Progressive Cellulitis Caused by Following a Dog Scratch

Soft tissue infections occur in over 30% of patients with chemotherapy-induced neutropenia. Gram-positive bacterial infections predominate early in neutropenia, and likelihood of infection by resistant bacteria and fungi increases with prolonged neutropenia. Prior infections and exposures influence the risk of rare pathogens. A 55-year-old woman with chemotherapy-induced neutropenia was scratched on her forearm by a dog. She cleaned the wound with isopropanol and was treated empirically with amoxicillin-clavulanate. Over the next 4 days, she developed fever along with erythema, edema, and mild tenderness of the forearm without purulence or crepitus. She was hospitalized and received empiric treatment with intravenous vancomycin, piperacillin-tazobactam, tobramycin, and voriconazole. Despite therapy, her fevers persisted and the cellulitis progressed for over a week. After 10 days of hospitalization, her neutrophil count began to recover and a bulla developed at the wound site. Culture of the bullous fluid grew Serratia marcescens , and antibiotics were switched to cefepime based on susceptibility. She defervesced and showed substantial improvement of cellulitis within 48 hours and was discharged on oral ciprofloxacin. Serratia marcescens skin infections are rare, and this may be the first report of Serratia cellulitis associated with trauma from dog contact. This case highlights the need to consider unusual pathogens based on exposure history and immune status and to obtain cultures from fluid collections or tissue in cases of treatment-resistant soft tissue infections

Inhibition of TBK1/IKKε Promotes Regeneration of Pancreatic β-cells

Abstract β-cell proliferation induction is a promising therapeutic strategy to restore β-cell mass. By screening small molecules in a transgenic zebrafish model of type 1 diabetes, we identified inhibitors of non-canonical IκB kinases (IKKs), TANK-binding kinase 1 (TBK1) and IκB kinase ε (IKKε), as enhancers of β-cell regeneration. The most potent β-cell regeneration enhancer was a cinnamic acid derivative (E)-3-(3-phenylbenzo[c]isoxazol-5-yl)acrylic acid (PIAA), which, acting through the cAMP-dependent protein kinase A (PKA), stimulated β-cell-specific proliferation by increasing cyclic AMP (cAMP) levels and mechanistic target of rapamycin (mTOR) activity. A combination of PIAA and cilostamide, an inhibitor of β-cell-enriched cAMP hydrolyzing enzyme phosphodiesterase (PDE) 3, enhanced β-cell proliferation, whereas overexpression of PDE3 blunted the mitogenic effect of PIAA in zebrafish. PIAA augmented proliferation of INS-1β-cells and β-cells in mammalian islets including human islets with elevation in cAMP levels and insulin secretion. PIAA improved glycemic control in streptozotocin (STZ)-induced diabetic mice with increases in β-cell proliferation, β-cell area, and insulin content in the pancreas. Collectively, these data reveal an evolutionarily conserved and critical role of TBK1/IKKε suppression in expanding functional β-cell mass