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Importance: Safe and effective long-term treatments for moderate to severe plaque psoriasis are needed., Objective: To evaluate the long-term safety and efficacy of deucravacitinib through 3 years (week 148) in the randomized POETYK PSO-1, PSO-2, and nonrandomized long-term extension (LTE) trials., Design, Setting, and Participants: PSO-1/PSO-2 were global, 52-week, randomized, double-blinded phase 3 trials in patients with moderate to severe plaque psoriasis. After completing 52 weeks of treatment in PSO-1/PSO-2, patients could enroll in the prespecified, ongoing, nonrandomized LTE trial. The peak of the global COVID-19 pandemic coincided with the LTE trial. Patient enrollment in the LTE started August 12, 2019; safety and efficacy were assessed through June 15, 2022; and these data were analyzed through June 28, 2024., Interventions: The PSO-1/PSO-2 trials randomized patients 1:2:1 to oral placebo, deucravacitinib, 6 mg once daily, or apremilast, 30 mg twice daily. Patients enrolling in the LTE trial received open-label deucravacitinib, 6 mg once daily., Main Outcomes and Measures: Safety outcomes were evaluated in patients who received 1 or more doses of deucravacitinib. Efficacy outcomes included 75% or greater or 90% or greater reduction from baseline in Psoriasis Area and Severity Index (PASI 75/90) and static Physician Global Assessment scores of 0 (clear) or 1 (almost clear) (sPGA 0/1) and were assessed in patients who received deucravacitinib treatment from day 1 of the parent trials who continued in the LTE trial., Results: Of 1519 patients who received 1 or more doses of deucravacitinib, 513 received continuous deucravacitinib treatment from day 1 and entered the LTE trial. Exposure-adjusted incidence rates (EAIRs) per 100 person-years were decreased or similar in the 1-year vs 3-year cumulative periods, respectively, for adverse events (AEs) (229.2 vs 144.8; 95% CI, 215.4-243.9 vs 137.1-153.0), serious AEs (5.7 vs 5.5; 95% CI, 4.4-7.4 vs 4.7-6.4), discontinuations due to AEs (4.4 vs 2.4; 95% CI, 3.3-5.9 vs 2.0-3.0), and deaths (0.2 vs 0.3; 95% CI, 0.1-0.8 vs 0.2-0.6). Incidence rates of the most common AEs (EAIR per 100 person-years ≥5) during the 1-year and 3-year cumulative periods, respectively, were nasopharyngitis (26.1 vs 11.4; 95% CI, 23.0-29.8 vs 10.2-12.7), COVID-19 (0.5 vs 8.0; 95% CI, 0.2-1.2 vs 7.1-9.1), and upper respiratory tract infection (13.4 vs 6.2; 95% CI, 11.3-16.0 vs 5.4-7.2). EAIRs for AEs of interest, including herpes zoster, major adverse cardiovascular events, and malignant diseases, remained low and were decreased or comparable between the 1-year and 3-year cumulative periods. Clinical response rates were maintained through 3 years., Conclusions and Relevance: The findings of this integrated analysis of the phase 3 POETYK PSO-1, PSO-2, and nonrandomized LTE trials demonstrate a consistent safety profile and durable clinical response of continuous treatment with deucravacitinib through 3 years of treatment in patients with psoriasis., Trial Registration: ClinicalTrials.gov Identifiers: NCT03624127, NCT03611751, and NCT04036435.

Introduction: Deucravacitinib demonstrated superior efficacy to apremilast in patients with moderate to severe plaque psoriasis in the POETYK PSO-1 and PSO-2 clinical trials. In the study reported here, we aimed to determine the overall 52-week cumulative clinical benefit of treatment initiated with deucravacitinib versus apremilast and to compare the 52-week cumulative benefit of initiating and staying on deucravacitinib versus initiating apremilast and continuing or switching to deucravacitinib at week 24 of treatment., Methods: This post hoc analysis of POETYK PSO-1 data (ClinicalTrials.gov identifier: NCT03624127) determined the cumulative clinical benefit of deucravacitinib 6 mg once daily and apremilast 30 mg twice daily in adults with moderate to severe plaque psoriasis. Patients treated with apremilast who did not achieve a 50% reduction in the Psoriasis Area and Severity Index (PASI 50) at week 24 were switched to deucravacitinib. The cumulative clinical benefit of deucravacitinib versus apremilast over 52 weeks was based on cumulative measures of ≥ 75% improvement from baseline in PASI score (PASI 75) and the proportion of patients with a static Physician Global Assessment score of 0 or 1 (sPGA 0/1). Ratios of area under the curve estimates between treatments were calculated and compared based on analysis of covariance regression models., Results: Patients initiating deucravacitinib (N = 332) had a greater cumulative benefit as measured by the PASI 75 and sPGA 0/1 than those initiating apremilast (N = 168). Over 52 weeks, those initiating deucravacitinib experienced 50% more benefit as measured by PASI 75 and 58% more benefit as measured by sPGA 0/1 than those initiating apremilast. Results were consistent with the primary analysis when patients were classified by prior systemic and prior biologic therapy exposure., Conclusion: Results from this analysis corroborate the primary efficacy analysis supporting the use of deucravacitinib compared with apremilast for moderate to severe plaque psoriasis, regardless of prior systemic or biologic use., (© 2024. The Author(s).)

Introduction: Deucravacitinib is an oral, selective tyrosine kinase 2 inhibitor that demonstrated therapeutic benefit in a Phase 2 clinical trial of adults with moderate to severe plaque psoriasis. This analysis was designed to evaluate the effect of deucravacitinib on additional clinical and quality-of-life (QoL) outcomes and assess the relationship between these outcomes in adults with psoriasis., Methods: Post-hoc analysis of a 12-week Phase 2 trial was conducted for the three most efficacious dosage groups (3 mg twice daily, 6 mg twice daily, 12 mg once daily) and placebo. Investigator assessments for efficacy included Psoriasis Area and Severity Index (PASI), body surface area (BSA) involvement, and static Physician's Global Assessment; QoL was assessed using the Dermatology Life Quality Index (DLQI). Treatment responses and their associations were evaluated over time., Results: Deucravacitinib elicited improvement versus placebo as early as Week 4 for most efficacy measures (including changes in absolute PASI and BSA), with efficacy trends observed from Week 2 to Week 12. Improvements in QoL, assessed by achievement of a DLQI overall score of 0/1 (no effect at all on patient's life), followed a pattern similar to deucravacitinib-related clinical outcomes over 12 weeks. Overall, patients with greater improvements in psoriasis-related clinical signs and symptoms also reported greater improvement in QoL. However, complete skin clearance was not required for achieving DLQI 0/1., Conclusion: Deucravacitinib treatment produced early response and similar trends in improvements across multiple efficacy assessments and QoL in moderate to severe plaque psoriasis. Deucravacitinib has the potential to become a promising new oral therapy for this condition., Trial Registration: ClinicalTrials.gov identifier; NCT02931838., (© 2022. The Author(s).)

A common feature of B-cell chronic lymphocytic leukemia (CLL) is chromosomal loss of 13q14, containing the miR15a/16-1 locus controlling B-cell proliferation. However, CLL etiology remains unclear. CLL is an adult leukemia with an incidence that increases with advancing age. A unique feature of CLL is biased B-cell antigen receptor (BCR) usage, autoreactivity with polyreactivity and CD5 expression, all suggest a role for the BCR in driving CLL pathogenesis. Among human CLLs, BCRs autoreactive with non-muscle myosin IIA (AMyIIA) are recurrent. Here we identify an unmutated AMyIIA BCR in mouse, with distinctive CDR3 segments capable of promoting leukemogenesis. B cells with this AMyIIA BCR are generated by BCR-dependent signaling during B-1 fetal/neonatal development with CD5 induction, but not in adults. These early-generated AMyIIA B-1 B cells self-renew, increase during aging and can progress to become monoclonal B-cell lymphocytosis, followed by aggressive CLL in aged mice, often with the loss of a chromosomal region containing the miR15a/16-1 locus of varying length, as in human CLL. Thus, the ability to generate this defined autoreactive BCR by B-1 B cells is a key predisposing step in mice, promoting progression to chronic leukemia.

B cells generated early during fetal/neonatal B-1 development in mice include autoreactive cells with detectable CD5 upregulation induced by B cell receptor (BCR) signaling (B1a cells). A fraction of B1a cells are maintained by self-renewal for life, with the potential risk of dysregulated growth and progression to chronic lymphocytic leukemia (CLL)/lymphoma during aging. In studies using the Eμ-hTCL1 transgenic mouse system, it became clear that this B1a subset has a higher potential than other B cell subsets for progression to CLL. We have generated several autoreactive germline BCR gene models to compare B cells generated under conditions of natural exposure to autoantigen. Analysis of the mice has been key in understanding the importance of the BCR and BCR signaling for generating different B cell subsets and for investigating the cellular origin of B-CLL., (© 2015 New York Academy of Sciences.)

The critical role of IgM in controlling pathogen burden has been demonstrated in a variety of infection models. In the murine model of Borrelia hermsii infection, IgM is necessary and sufficient for the rapid clearance of bacteremia. Convalescent, but not naïve, B1b cells generate a specific IgM response against B. hermsii, but the mechanism of IgM-mediated protection is unknown. Here, we show that neither Fcα/μR, a high-affinity receptor for IgM, nor IgM-dependent complement activation is required for controlling B. hermsii. Bacteria in diffusion chambers with a pore size impermeable to cells were killed when diffusion chambers were implanted into either convalescent or passively immunized mice. Furthermore, adoptively transferred convalescent B1b cells in Rag1(-/-) mice produced specific IgM that also cleared B. hermsii in diffusion chambers independent of complement. These results demonstrate that IgM-mediated clearance of B. hermsii does not require opsonophagocytosis and indicate that a mechanism for in vivo B1b cell-mediated protection is through the generation of bactericidal IgM.

The dynamic movement of B cells increases the probability of encountering specific antigen and facilitates cell-cell interactions required for mounting a rapid antibody response. B1a and B1b cells are enriched in the coelomic cavity, contribute to T-cell-independent (TI) antibody responses, and increase in number upon antigen exposure. B1 cell movement is largely governed by Cxc ligand 13 (Cxcl13), and mice deficient in this chemokine have a severe reduction in peritoneal B1 cells. In this study, we examined the role of Cxcl13-dependent B cell migration using Borrelia hermsii infection or intraperitoneal immunization with pneumococcal polysaccharide or 4-hydroxy-3-nitrophenyl-acetyl (NP)-Ficoll, all of which induce robust antibody responses from B1b cells. Surprisingly, we found that antibody responses to B. hermsii or to FhbA, an antigenic target of B1b cells, and the resolution of bacteremia were indistinguishable between wild-type and Cxcl13-/- mice. Importantly, we did not observe an expansion of peritoneal B1b cell numbers in Cxcl13-/- mice. Nonetheless, mice that had resolved infection were resistant to reinfection, indicating that the peritoneal B1b cell reservoir is not required for controlling B. hermsii. Furthermore, despite a reduced peritoneal B1b compartment, immunization with pneumococcal polysaccharide vaccine yielded comparable antigen-specific antibody responses in wild-type and Cxcl13-/- mice and conferred protection against Streptococcus pneumoniae. Likewise, immunization with NP-Ficoll elicited similar antibody responses in wild-type and Cxcl13-/- mice. These data demonstrate that homing of B1 cells into the coelomic cavity is not a requirement for generating protective TI antibody responses, even when antigen is initially localized to this anatomical compartment.

Vaccination is the most effective way to control infectious diseases. A variety of microbial pathogens use antigenic variation, an immune evasion strategy that poses a challenge for vaccine development. To understand protective immune responses against such pathogens, we have been studying Borrelia hermsii, a bacterium that causes recurrent bacteremia due to antigenic variation. An IgM response is necessary and sufficient to control B. hermsii infection. We have recently found a selective expansion of B1b cells concurrent with the resolution of B. hermsii bacteremia. B1b cells from convalescent but not naive mice confer long-lasting immunity, but the Ag(s) driving the protective IgM responses is unknown. Herein we demonstrate that convalescent B1b cell-derived IgM recognizes complement factor H-binding protein (FhbA), a B. hermsii outer-surface protein and putative virulence factor that does not undergo antigenic variation and is expressed by all clinical isolates. A progressive increase in the IgM response to FhbA correlated with the kinetics of B1b cell expansion, diminished the severity of bacteremic episodes, and led to the eventual resolution of the infection. These data indicate that FhbA is a specific target for protective B1b cell responses. Ags recognized by B1b cells may be considered as an important component in vaccination strategies.