A Human Interleukin-12/23 Monoclonal Antibody for the Treatment of Psoriasis

Krueger, Gerald G.; Langley, Richard; Leonardi, Craig L.; Yeilding, Newman; Guzzo, Cynthia; Wang, Yuhua; Dooley, Lisa T.; Lebwohl, Mark

doi:10.1056/nejmoa062382

Cited by 728 publications

(548 citation statements)

References 32 publications

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“…Recently, the therapeutic effect of an IL-12/ IL-23 monoclonal antibody has been demonstrated in psoriasis (24). Our findings suggest that the IL-23 pathway may also be a promising target for treatment of AS.…”

Section: Discussionsupporting

confidence: 51%

Association of interleukin‐23 receptor variants with ankylosing spondylitis

Rahman¹,

Inman²,

Gladman³

et al. 2008

Arthritis & Rheumatism

161

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Objective. Recent studies have shown that a nonsynonymous single-nucleotide polymorphism (SNP) (Arg381Gln; rs11209026) in the interleukin-23 receptor (IL-23R) gene on chromosome 1p31 is associated with Crohn's disease and psoriasis. Given the clinical and immunologic overlap between ankylosing spondylitis (AS) and these diseases, and the potential function of this candidate SNP, this study was undertaken to examine the association of IL-23R variants with AS in multiple Canadian populations.Methods. We examined 3 cohorts of AS patients from established rheumatic disease centers in Canada. The majority of AS patients were Caucasians of northern European descent, and all patients satisfied the modified New York classification criteria for AS or for juvenile spondylarthritis. We examined 424 AS probands and 401 controls from Alberta, 251 AS probands and 122 controls from Toronto, and 121 AS probands and 219 controls from Newfoundland. Ten IL-23R SNPs were genotyped, 9 of which were incorporated in the haplotype analysis. Allele and haplotype associations were calculated using the WHAP software package. P values for haplotype associations were calculated using a permutation test.Results. The primary SNP of interest in a previous study of inflammatory bowel disease (IBD) (Arg381Gln; rs11209026) was found to be protective against AS in the Newfoundland population (P ‫؍‬ 0.04) and in the Toronto population (P ‫؍‬ 0.04) in singlemarker univariate analysis. The strongest association, however, was with SNP rs11465804 (P ‫؍‬ 0.007 for the Newfoundland population and P ‫؍‬ 0.0007 for the Toronto population). A 3-marker sliding window omnibus test revealed a significant association with markers rs10489629, rs2201841, and rs11465804 in both the Newfoundland population (P ‫؍‬ 0.04) and the Alberta population (P ‫؍‬ 0.034). Our results were independent of the IBD and psoriasis status of the AS patients.Conclusion. This concurrent analysis of 3 distinct AS populations and their regional controls demonstrates a disease association with the IL-23R locus and implicates the same polymorphisms associated with IBD and psoriasis.Spondylarthritis (SpA) is a group of inflammatory conditions of which the main clinical feature is inflammation of the spine. Ankylosing spondylitis (AS) is regarded as the prototypic SpA and is a complex multifactorial disease resulting from gene-environment interaction. Genetic factors have a substantive role in AS susceptibility and expression (1). AS is highly heritable, as evidenced by the results of population-based epidemiologic studies. The sibling recurrence risk ( s ) in AS is Ͼ80, and heritability of Ն90% for AS has been estimated from twin studies (for review, see ref. 1). HLA-B27 is the major gene associated with AS and is present in Ͼ95% of Caucasians of northern European ancestry. Despite the prominence of HLA-B27 in genetic susceptibility to AS, its contribution to overall genetic predisposition is only ϳ16-40% (1). Furthermore, since the genetic contribution of the entire major histocompatibilit...

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Section: Discussionsupporting

confidence: 51%

Association of interleukin‐23 receptor variants with ankylosing spondylitis

Rahman¹,

Inman²,

Gladman³

et al. 2008

Arthritis & Rheumatism

161

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“…Understanding the complex, pleiotropic action of IL-23R and the specific variants that give rise to each of these autoimmune traits will undoubtedly increase progress in our understanding of the molecular pathophysiology underlying these chronic autoinflammatory conditions. Moreover, coupled with the recent advances in autoinflammatory biology, the IL23R variants described herein may lead to a deeper understanding of molecular action of targeted therapeutics such as the efficacious IL-12/IL-23 monoclonal antibodies [44][45][46] and prove useful in autoinflammatory pharmacogenetics.…”

Section: Discussionmentioning

confidence: 98%

“…In sum, these studies demonstrate several key aspects of IL-23/T H -17 pathobiology related to psoriasis: (1) Both IL-12p40 and IL-23p19 mRNA expression levels are significantly elevated in both nonlesional psoriatic skin versus normal skin as well as lesional psoriatic skin versus non-lesional psoriatic skin. 37,38 (2) (5) clinical studies have shown dramatic efficacy of IL-12p40 antibodies in reducing symptoms in a high percentage of psoriatic subjects 44,45 and those with active Crohn's disease. 46 These diverse studies have conspired to highlight the central function of the IL-23/T H -17 axis in mediating chronic inflammatory disease pathogenesis, downplaying the role of IL-12.…”

Section: Discussionmentioning

confidence: 99%

Detailed genetic characterization of the interleukin-23 receptor in psoriasis

García¹,

Chang²,

Brandon³

et al. 2008

Genes Immun

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Using a multi-tiered, case-control association design, scanning 25 215 gene-centric SNPs, we previously identified two psoriasis susceptibility genes: IL12B and IL23R. These results have recently been confirmed. To better characterize the IL23R psoriasis-association, we used a fine mapping strategy to identify 59 additional IL23R-linked SNPs, which were genotyped in our three independent, white North American sample sets (42800 individuals in toto). A sliding window of haplotype association demonstrates colocalization of psoriasis susceptibility effects within the boundaries of IL23R across all sample sets, thereby decreasing the likelihood that neighboring genes, particularly IL12RB2, are driving the association at this region. Additional haplotype work identified two 5-SNP haplotypes with strong protective effects, consistent across our three sample sets (OR common ¼ 0.67; P comb ¼ 4.32E-07). Importantly, heterogeneity of effect was extremely low between sample sets for these haplotypes (P Het ¼ 0.961). Together, these protective haplotypes attain a frequency of 16% in controls, declining to 11% in cases. The characterization of association patterns within IL23R to specific predisposing/protective variants will play an important role in the elucidation of psoriasis etiology and other related phenotypes. Further, this work is essential to lay the foundation for the role of IL23R genetics in response to pharmaceutical therapy and dosage.

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“…KC-derived IL-1β, IL-6, and TNF-α and pDC-derived IFN-α are thought to activate local dDCs, leading to IL-23 secretion to prime naive T cells into 1 and/or 17 sets in dLNs [4,60]. Recently, the signi cance of IL-23/ IL-17/IL-22 axis in psoriasis has become more evident from genome wide studies, the e cacy of biologics targeting these cytokines, and reduction in these cytokines a er disease amelioration [61,62,63]. It has attracted the attention again which DC subsets play a pivotal role in producing IL-23 and in [64,65].…”

Section: Dermismentioning

confidence: 99%

Novel insights into the role of immune cells in skin and inducible skin-associated lymphoid tissue (iSALT)

Ono¹,

Kabashima²

2015

Allergo J

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Summarye skin is equipped with serial barriers that provide rapid and e cient protection against external intruders. Beneath the epidermal physical barriers of the stratum corneum and the tight junctions, the integrated immune systems in both the epidermis and the dermis act in a coordinated manner to protect the host.is "immunological" barrier is composed of various cells, including skin-resident cells, such as keratinocytes, dendritic cells, tissue-resident macrophages, resident memory T cells, mast cells, and innate lymphoid cells. Additionally, in ltrating memory T cells, monocytes, neutrophils, basophils, and eosinophils are recruited in support of the host immunity.In addition to discussing the role of each of these cellular populations, we describe the concept of skin associated lymphoid tissue (SALT), which reminds us that the skin is an important component of the lymphatic system. We further describe the newly discovered phenomenon of multiple cell gathering under skin in ammation, which can be referred to as inducible SALT (iSALT). iSALT contributes to our understanding of SALT by highlighting the importance of direct cell-cell interaction in skin immunity.Cite this as Ono S, Kabashima K. Novel insights into the role of immune cells in skin and inducible skin-associated lymphoid tissue (iSALT). Allergo J Int 2015;24:170-9

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A Human Interleukin-12/23 Monoclonal Antibody for the Treatment of Psoriasis

Cited by 728 publications

References 32 publications

Association of interleukin‐23 receptor variants with ankylosing spondylitis

Association of interleukin‐23 receptor variants with ankylosing spondylitis

Detailed genetic characterization of the interleukin-23 receptor in psoriasis

Novel insights into the role of immune cells in skin and inducible skin-associated lymphoid tissue (iSALT)

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