Profile of ustekinumab and its potential in the treatment of active psoriatic arthritis

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Abstract

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis and considered to be a less severe condition than rheumatoid arthritis. PsA patients have been treated for a long time with a number of different agents, from non-steroidal anti-inflammatory drugs to one or more disease-modifying antirheumatic drugs. In the last decade, recognition of the central role of tumor necrosis factor-alpha (TNFα) in the immunopathogenesis of many rheumatic diseases, including PsA, has led to the development of TNFα blockers. In PsA, these agents are uniquely efficacious in the treatment of different patterns of the disease, as well as slowing progression of erosive damage in the peripheral joints. However, a significant number of patients withdraw from therapy because of failure or poor tolerability. Among the novel therapeutic targets, interleukin (IL)-23/IL-12 has been investigated for the treatment of chronic inflammatory disease. In particular, ustekinumab is a human monoclonal antibody that prevents human IL-12 and IL-23 from binding to the IL-12Rβ1 receptor chain of IL-12 (IL-12Rβ1/β2) and IL-23 (IL-12Rβ1/23R) receptor complexes on the surface of natural killer cells and T-cells. Ustekinumab has been approved only for treatment of chronic plaque psoriasis, but also represents an interesting agent for treatment of PsA.

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Most cited references 33

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Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2).

Kim Papp, Richard Langley, Mark G. Lebwohl … (2008)

Ustekinumab, a human monoclonal antibody against interleukins 12 and 23, has shown therapeutic potential for psoriasis. This study assessed the efficacy and safety of ustekinumab in psoriasis patients and assessed dosing intensification in partial responders. In this multicentre, phase III, double-blind, placebo-controlled study, 1230 patients with moderate-to-severe psoriasis (defined by a psoriasis area and severity index [PASI] score > or =12, and at least 10% total body surface area involvement) were randomly assigned to receive ustekinumab 45 mg (n=409) or 90 mg (n=411) at weeks 0 and 4, then every 12 weeks, or placebo (n=410). Partial responders (ie, patients achieving > or =50% but <75% improvement from baseline in PASI) were re-randomised at week 28 to continue dosing every 12 weeks or escalate to dosing every 8 weeks. Both randomisations were done with a minimisation method via a centralised interactive voice response. The primary endpoint was the proportion of patients achieving at least 75% improvement in PASI (PASI 75) at week 12. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00307437. All randomised patients were included in the efficacy analysis. 273 (66.7%) patients receiving ustekinumab 45 mg, 311 (75.7%) receiving ustekinumab 90 mg, and 15 (3.7%) receiving placebo achieved the primary endpoint (difference in response rate 63.1%, 95% CI 58.2-68.0, p<0.0001 for the 45 mg group vs placebo and 72.0%, 67.5-76.5, p<0.0001 for the 90 mg group vs placebo). More partial responders at week 28 who received ustekinumab 90 mg every 8 weeks achieved PASI 75 at week 52 than did those who continued to receive the same dose every 12 weeks (22 [68.8%] vs 11 [33.3%]; difference in response rate 35.4%, 95% CI 12.7-58.1, p=0.004). There was no such response to changes in dosing intensity in partial responders treated with ustekinumab 45 mg. During the placebo-controlled phase, 217 (53.1%) patients in the 45 mg group, 197 (47.9%) in the 90 mg group, and 204 (49.8%) in the placebo group experienced adverse events; serious adverse events were seen in eight (2.0%) patients in the 45 mg group, five (1.2%) in the 90 mg group, and eight (2.0%) in the placebo group. Although treatment with ustekinumab every 12 weeks is effective for most patients with moderate-to-severe psoriasis, intensification of dosing to once every 8 weeks with ustekinumab 90 mg might be necessary to elicit a full response in patients who only partially respond to the initial regimen.

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Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes

SC Clark, L Fitz, RM Hewick … (1989)

We have identified and purified a novel cytokine, NK cell stimulatory factor (NKSF), from the cell-free supernatant fluid of the phorbol diester-induced EBV-transformed human B lymphoblastoid cell line RPMI 8866. NKSF activity is mostly associated to a 70-kD anionic glycoprotein. The purified 70-kD protein, isolated from an SDS-PAGE gel, yields upon reduction two small species of molecular masses of 40 and 35 kD, suggesting that this cytokine is a heterodimer. When added to human PBL, purified NKSF preparations induce IFN-gamma production and synergize with rIL-2 in this activity, augment the NK cell-mediated cytotoxicity of PBL preparations against both NK-sensitive and NK- resistant target cell lines, and enhance the mitogenic response of T cells to mitogenic lectins and phorbol diesters. The three activities remain associated through different purification steps resulting in a 9,200-fold purification, and purified NKSF mediates the three biological activities at concentrations in the range of 0.1-10 pM. These data strongly suggest that the same molecule mediates these three activities, although the presence of traces of contaminant peptides even in the most purified NKSF preparations does not allow us to exclude the possibility that distinct biologically active molecules have been co-purified. The absence of other known cytokines in the purified NKSF preparations, the unusual molecular conformation of NKSF, the high specific activity of the purified protein, and the spectrum of biological activities distinguish NKSF from other previously described cytokines.

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Understanding the IL-23-IL-17 immune pathway.

Brent McKenzie, Robert Kastelein, Daniel Cua (2006)

Interleukin (IL)-23 is a heterodimeric cytokine closely related to IL-12. Yet, despite a strong structural relationship that includes a shared p40 subunit, this does not translate into functional similarity. In fact, the opposite is true, in that these two cytokines appear to have profoundly different roles in regulating host immune responses. It is now clear that IL-23 has key roles in autoimmune destruction in experimental allergic encephalomyelitis, collagen-induced arthritis and inflammatory bowel disease. IL-23 drives the development of autoreactive IL-17-producing T cells and promotes chronic inflammation dominated by IL-17, IL-6, IL-8 and tumor necrosis factor as well as neutrophils and monocytes. It is unlikely that IL-23 and its downstream effects evolved just to cause autoimmunity, but its real benefit to the host and the lineage relationship between IL-17-producing cells and T helper 1 cells remain unclear. By comparing the pathophysiological function of IL-12 and IL-23 in the context of host defense and autoimmune inflammation, we are beginning to understand the novel IL-23-IL-17 immune pathway.

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Author and article information

Journal

Journal ID (nlm-ta): Open Access Rheumatol

Journal ID (iso-abbrev): Open Access Rheumatol

Journal ID (publisher-id): Open Access Rheumatology: Research and Reviews

Title: Open Access Rheumatology : Research and Reviews

Publisher: Dove Medical Press

ISSN (Electronic): 1179-156X

Publication date Collection: 2014

Publication date (Electronic): 20 February 2014

Volume: 6

Pages: 7-13

Affiliations

[1 ]Unità Operativa Complessa di Reumatologia, Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Rome

[2 ]Academic Rheumatology Unit, Department of Medicine and Health Sciences, University of Molise, Campobasso, Italy

Author notes

Correspondence: Antonio Spadaro, Dipartimento di Medicina Interna e Specialità Mediche, UOC di Reumatologia, Sapienza Università di Roma, Azienda Policlinico Umberto I, Viale del Policlinico 155, 00161 Rome, Italy, Tel +39 06 4997 4642, Fax +39 06 4997 4642, Email a.spadaro.reuma@ 123456virgilio.it

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Publisher ID: oarrr-6-007

DOI: 10.2147/OARRR.S56048

PMC ID: 5045109

PubMed ID: 27790030

SO-VID: 558c1b62-dda3-4588-ad6e-424eb9a0dbe4

License:

The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

Profile of ustekinumab and its potential in the treatment of active psoriatic arthritis

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Most cited references 33

Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2).

Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes

Understanding the IL-23-IL-17 immune pathway.

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