Efficacy and safety of tildrakizumab in patients with active psoriatic arthritis: results of a randomised, double-blind, placebo-controlled, multiple-dose, 52-week phase IIb study.

OBJECTIVES: To evaluate efficacy and safety of the anti-interleukin-23p19 monoclonal antibody tildrakizumab in patients with psoriatic arthritis (PsA). METHODS: In this randomised, double-blind, placebo-controlled, phase IIb study, patients with active PsA were randomised 1:1:1:1:1 to tildrakizumab 200 mg every 4 weeks (Q4W); tildrakizumab 200, 100 or 20 mg Q12W; or placebo Q4W. Patients receiving tildrakizumab 20 mg or placebo switched to tildrakizumab 200 mg Q12W at W24; treatment continued to W52. The primary efficacy endpoint was proportion of patients with ACR20 response (≥20% improvement by American College of Rheumatology criteria) at W24. Secondary efficacy endpoints were assessed without adjustment for multiplicity. Safety was evaluated from treatment-emergent adverse events (TEAEs). RESULTS: 391/500 patients screened were randomised and treated. At W24, 71.4%-79.5% of tildrakizumab-treated versus 50.6% of placebo-treated patients achieved ACR20 (all p<0.01). Patients receiving tildrakizumab versus placebo generally achieved higher rates of ACR50, Disease Activity Score in 28 joints with C reactive protein <3.2, minimal disease activity and 75%/90%/100% improvement from baseline Psoriasis Area and Severity Index responses at W24 and through W52. Improvement in dactylitis and enthesitis was not observed; results were mixed for other outcomes. Responses in patients switched to tildrakizumab 200 mg at W24 were consistent with treatment from baseline. TEAEs and serious TEAEs occurred in 64.5% and 3.3%, respectively, of all patients through W52 and were comparable among treatment arms. CONCLUSIONS: Tildrakizumab treatment significantly improved joint and skin manifestations of PsA other than dactylitis and enthesitis. Treatment was generally well tolerated through W52. Clinicaltrials.gov NCT02980692.

Long-term efficacy and safety of tildrakizumab in Japanese patients with moderate to severe plaque psoriasis: Results from a 5-year extension of a phase 3 study (reSURFACE 1).

The three part, double-blind, randomized, controlled reSURFACE 1 trial and extension study (NCT01722331) evaluated efficacy and safety of tildrakizumab in adults with moderate to severe plaque psoriasis. Patients with ≥50% improvement from baseline in Psoriasis Area and Severity Index (PASI 50) following treatment with tildrakizumab 100 mg (TIL100) or 200 mg (TIL200) could enter the optional long-term extension study and continue treatment at the same dose for an additional 192 weeks. This subgroup analysis assessed the long-term efficacy and safety of tildrakizumab treatment for Japanese patients enrolled in reSURFACE 1 for up to 5 years of treatment. The primary efficacy outcomes were the proportions of patients who maintained PASI 75 and Physician Global Assessment (PGA) clear or minimal with ≥2-grade reduction from baseline (PGA 0/1) from base study week 64 to extension week 192. Secondary outcomes were the proportion of patients who maintained PASI 90/100 from base study week 64 to extension week 192. Adverse events (AEs) were monitored throughout the study and for up to 20 weeks after the last study visit. Of the 120 Japanese patients who entered the reSURFACE 1 extension study, 43 (79.6%) patients receiving tildrakizumab 100 mg and 58 (87.9%) patients receiving tildrakizumab 200 mg completed the extension study. Of all Japanese patients with PASI 75/90/100 and PGA 0/1 at week 64, 85%/88% receiving TIL100/TIL200 maintained PASI 75, 70%/96% maintained PASI 90, 63%/67% maintained PASI 100, and 68%/72% maintained PGA 0/1 at extension week 192. AEs led to discontinuation in 1.7 patients per 100 patient-years (P100PY) receiving tildrakizumab 100 mg and 0.8 P100PY receiving tildrakizumab 200 mg. Incidences of severe infections, malignancies, confirmed major adverse cardiac events, and hypersensitivity reactions were low in both treatment groups. Through 5 years of treatment, tildrakizumab maintained efficacy and was well tolerated with low rates of AEs of special interest.

Selective expansion of a monocyte subset expressing the CD11c dendritic cell marker in the Yaa model of systemic lupus erythematosus.

OBJECTIVE: Monocytosis is a unique cellular abnormality associated with the Yaa (Y-linked autoimmune acceleration) mutation. The present study was designed to define the cellular mechanism responsible for the development of monocytosis and to characterize the effect of the Yaa mutation on the development of monocyte subsets. METHODS: We produced bone marrow chimeras reconstituted with a mixture of Yaa and non-Yaa bone marrow cells bearing distinct Ly-17 alloantigens, and determined whether monocytes of Yaa origin became dominant. Moreover, we defined the 2 major inflammatory (Gr-1+,CD62 ligand [CD62L]+) and resident (Gr-1-,CD62L-) subsets of blood monocytes in aged BXSB Yaa male mice, as compared with BXSB male mice lacking the Yaa mutation. RESULTS: Analysis of the Ly17 allotype of blood monocytes in chimeric mice revealed that monocytes of both Yaa and non-Yaa origin were similarly involved in monocytosis. Significantly, the development of monocytosis paralleled a selective expansion of the resident monocyte subset compared with the inflammatory subset, and the former expressed CD11c, a marker of dendritic cells. Neither monocytosis nor the change in monocyte subpopulations, including CD11c expression, was observed in Yaa-bearing C57BL/6 mice, in which systemic lupus erythematosus (SLE) fails to develop. CONCLUSION: Our results suggest that Yaa-associated monocytosis is not attributable to an intrinsic abnormality in the growth potential of monocyte lineage cells bearing the Yaa mutation and that the Yaa mutation could lead to the expansion of dendritic cells, thereby contributing to the accelerated development of SLE.

A novel locus regulates both retroviral glycoprotein 70 and anti-glycoprotein 70 antibody production in New Zealand mice when crossed with BALB/c.

Lupus-prone New Zealand Black and New Zealand White mice produce high serum levels of the endogenous retroviral envelope protein gp70 and develop an Ab response to this autoantigen as part of their autoimmune disease. Linkage analysis of two crosses involving New Zealand and BALB/c mice mapped these traits to a group of overlapping loci, including a novel locus on proximal chromosome 12. This locus was linked with serum gp70 and the autoimmune response against it. The linkage of serum gp70 levels to a previously described locus on distal chromosome 4 was also confirmed. Sequence analysis of a candidate gene on distal chromosome 4, Fv1, provided support that this gene may be associated with the control of serum gp70 levels in both New Zealand Black and New Zealand White mice. Linkage data and statistical analysis confirmed a close correlation between gp70 Ag and anti-gp70 Ab levels, and together gave support to the concept that a threshold level of gp70 is required for the production of anti-gp70 Abs. Serum levels of anti-gp70 Abs were closely correlated with the presence of renal disease, more so than anti-dsDNA Abs. Understanding the genetic basis of this complex autoantigen-autoantibody system will provide insight into the pathogenesis of lupus in mice, which may have implications for human disease.

Aging-dependent exclusion of antigen-inexperienced cells from the peripheral B cell repertoire.

Aging is accompanied by greatly reduced B cell production in the bone marrow, yet peripheral B cell numbers do not decline. We hypothesize that this may reflect filling of the peripheral pool with B cells that are long-lived as a consequence of specificity for, and chronic stimulation by, environmental Ags. To begin to explore this possibility, we analyzed the effects of aging on B cell population dynamics in the anti-H2(k/b) 3-83 mu-delta Ig-transgenic mouse. We predicted that, because they presumably do not bind environmental Ags, B cells bearing the transgenic receptor may be lost in aged animals. As seen in nontransgenic animals, total splenic B cell numbers remained constant with age in the Ig-transgenic animals despite reduced B cell production. Importantly, although the few newly produced B cells in the bone marrow of aged mice are 3-83 positive, the peripheral compartment of these mice is dominated by B cells that express endogenous Ig genes rather than the transgenes. This population includes large numbers of marginal zone-like and CD21(low/-)CD23(low/-)IgM(low) B cells, as well as elevated numbers of CD5+ B cells. Many of these cells express only non-B220 CD45 isoforms, suggesting that they may be memory cells. A significant proportion of aged transgenic animals produce autoantibodies that are reactive with ssDNA, dsDNA, or histones. Results support the hypothesis that, in the face of severely reduced production with age, B cells are selected based on reactivity to environmental Ags, accumulate, and display activated phenotypes. Cells bearing 3-83-transgenic receptors are excluded from this population due to their specificity. Beyond their importance in aging, these findings define a novel form of receptor revision in which B cells are selected rather than deleted based on Ag reactivity.