Abstracts
Patients with psoriasis and psoriatic arthritis respond to anti-TNF therapy, but not all patients maintain effective response, and some do not respond. In this article, we demonstrate the role of a new pathogenetic pathway to some extent TNF-independent in these patients. Anti-IL12-23 is a new and alternate mode of therapy for patients with recalcitrant response to anti-TNF.
Psoriasis; Psoriatic arthrits; Biologic therapy
Pacientes com psoríase e artrite psoriásica respondem à terapia anti-TNF, mas nem todos os pacientes mantêm uma resposta efetiva e alguns não respondem. Nesse artigo, demonstramos o papel de uma nova via patogenética que, até certo ponto, independe de TNF nesses pacientes. Anti-IL-12-23 é um modo terapêutico novo e alternativo para pacientes com resposta recalcitrante à medicação com anti-TNF.
Psoríase; Artrite psoriásica; Terapia biológica
Introduction
Tumor necrosis factor alpha (TNF-α) is a proinflammatory cytokine involved in inflammation of the skin and synovium, making it a logical target for the treatment of psoriasis (Ps) and psoriatic arthritis (Psa). It has been demonstrated that this cytokine plays a fundamental role in the pathogenesis of both Ps and Psa through several pathogenetic mechanisms, including the expression of adhesion molecules to the surface of endothelial cells, keratinocytes, and dendritic cells promoting leukocyte migration.11. Bradley JR. TNF-mediated inflammatory disease. J Pathol. 2008;214:149-60.In the joints, it triggers the production of a variety of cytokines, which in turn increase the inflammatory cascade. In the skin, TNF-alpha also leads to a decrease in the apoptosis of keratinocytes, thus contributing to a hyperproliferative epidermis. Anti-TNF-alpha has the potential to provide symptomatic relief and help prevent disease progression in Ps and Psa by decreasing joint and skin inflammation.22. Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther. 2008;117:244-79.
Guidelines derived from evidence based clinical trials and from clinical practice
has established the clinical usefulness of all the three anti-TNF agents for the
treatment of axial and peripheral P and Psa. These agents selectively block the
role of TNF-alpha and proved to be effective in clinical trials and also in
clinical practice.33. Sfikakis PP. The first decade of biologic TNF antagonists in
clinical practice: lessons learned unresolved issues and future directions. Curr
Dir Autoimmun. 2010;11:180-210.All the three agents -
infliximab, etanercept, and adalimumab - have shown marked improvements in
disease activity in the PASI-75 of the skin and in disease activity indexes
ACR20, ACR50, ACR70 when compared to patients treated with placebo. However, in
our and others' experience, not all patients respond to these agents, and in
some of them, the initial response is lost after variable periods of time.44. Papagoras C, Voulgari PV, Drosos AA. Strategies after the failure
of the first anti-tumor necrosis factor alpha agent in rheumatoid arthritis.
Autoimmu Rev.2010;9:574-82.,55. Scheinberg M, Goldenberg J, Feldman DP, Nóbrega JL. Retrospective
study evaluating dose standards for infliximab in patients with rheumatoid
arthritis at Hospital Israelita Albert Einstein, São Paulo, Brazil. Clin
Rheumatol. 2008;27:1049-52.Although switching to another anti-TNF can boost a
secondary response, this may also be variable, and, in some patients, no
response at all can be observed. Currently, two new anti-TNFs are being
evaluated for the treatment of Psa a humanized form of infliximab by
subcutaneous route, golimumab and a pegylated form of anti-TNF, certolizumab
pegol. Phase-2 preliminary studies indicate efficacy similar to the conventional
anti-TNFs.66. Voulgari PV. Golimumab: a new anti-TNF-alpha agent for rheumatoid
arthritis, psoriatic arthritis and ankylosing spondylitis. Expert Rev Clin
Immunol. 2010;6:721-33.,77. Patel AM, Moreland LW. Certolizumab pegol: a new biologic
targeting rheumatoid arthritis. Expert Rev Clin Immunol.
2010;6:855-66.Surprise as it may be, a few patients
develop Ps after the treatment with anti-TNFs, and several explanations are
being developed for this enigmatic observation. One of the most attractive is
the switch to another inflammatory pathway after prolonged blockade of TNF.88. Grinblat B, Scheinberg M. Unexpected onset of psoriasis during
infliximab treatment: comment on the article by Beuthien et al. Arthritis Rheum.
2005;52:1333-4.
9. Grinblat B, Scheinberg M. The enigmatic development of psoriasis
and psoriasiform lesions during anti-TNF therapy: a review. Semin Arthritis
Rheum. 2008;37:251-5.-1010. Laurindo IM, Scheinberg M. Why do some biologic agents induce
psoriasis or psoriasiform lesions? Nat Clin Pract Rheumatol.
2008;4:168-9.
Ustekinumab is an immunoglobulin, a human monoclonal antibody that binds with great affinity to the shared p40 subunit of human interleukin 12 and 23.1111. Gandhi M, Alwawi E, Gordon KB. Anti-p40 antibodies ustekinumab and briakinumab: blockade of interleukin-12 and interleukin-23 in the treatment of psoriasis. Semin Cutan Med Surg. 2010;29:48-52.,1212. Elliott M, Benson J, Blank M, Brodmerkel C, Baker D, Sharples KR, Szapary P. 13. Ann N Y. Ustekinumab: lessons learned from targeting interleukin-12/23p40 in immune-mediated diseases. Acad Sci. 2009;1182:97-110.Increased production of IL-23 (but not of IL-12 mRNA) production can be observed in the skin of Ps patients. IL-23 is essential for the survival and proliferation of Th17 cells. Previous published data have shown CD4 and CD8 cells in Ps lesions, and Ps is considered a Th1 disease. However, it has been demonstrated that the CD4 cells secrete excessive amounts of IL17; they are Th17 cells, therefore, and one scenario consists in considering Ps as a Th1/Th17-mixed disease.1314. Fitch E, Harper E, Skorcheva I, Kurtz SE, Blauvelt A. Pathophysiology of psoriasis: recent advances on IL-23 and Th17 cytokines. Curr Rheumatol Rep. 2007;9:461-7.
Two clinical studies known as PHOENIX 1 and 2 evaluated patients with moderate to
severe Ps. PHOENIX 1 studied 66 patients randomized to receive 45 mg or 90 mg at
the weeks zero, four, and every 12 weeks. In PHOENIX 2, a similar study was
performed, but in this time with adjustable doses in case of partial responses,
totaling 70% of the patients in both studies against 3% in the group treated
with placebo. After 52 weeks, besides a good index of response, no serious
adverse events happened, except minor symptoms at upper respiratory tract
(apparently common with the use of any immunobiological agents), neither
anaphylaxis nor presence of tuberculosis, being these symptoms still associated
with a very convenient way of administration subcutaneously every two to three
months. When compared with etanercept, it was demonstrated that the response
observed with ustekinumab was superior in efficacy and side effects (Figs. 1, 2, and 3).1415. Leonardi CL, Kimball AB, Papp KA, Yeildin N, Guzzo C, Wang Y, Li
S, Dooley LT, Gordon KB, PHOENIX 1 study investigators. Efficacy and safety of
ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with
psoriasis: 76-week results from a randomized, double-blind, placebo-controlled
trial (PHOENIX 1). Lancet. 2008;37:1665-74.
16. Papp KA, Langley RG, Lebwohl M, Krueger GG, Szapary P, Yeilding
N, Guzzo C, Hsu MC, Wang Y, Li S, Dooley LT, Reich K; PHOENIX 2 study
investigators. 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). Lancet.
2008;371:1675-84.
17. Young MS, Horn EJ, Cather JC. The ACCEPT study: ustekinumab
versus etanercept in moderate-to-severe psoriasis patients. Expert Rev Clin
Immunol. 2011;7:9-13.-1718. Farhi D. Ustekinumab for the treatment of psoriasis: review of
three multicenter clinical trials. Drugs Today (Barc).
2010;46:259-64.Studies with ustekinumab in Psa are underway. The
superiority of this agent has been demonstrated versus placebo
in controlled trials, reducing signs and symptoms in the joints and also in the
skin. Phase-3 results are still pending.1819. Kavanaugh A, Menter A, Mendelsohn A, Shen YK, Lee S, Gottlieb
AB. Effect of ustekinumab on physical function and health-related quality of
life in patients with psoriatic arthritis: a randomized, placebo-controlled,
phase II trial. Curr Med Res Opin. 2010;26:2385-92.,1920. Cuchacovich R, Espinoza LR.: Ustekinumab for Psa.The Lancet.
2009;373:605-606.Briakinumab
(ABT-974) is another fully human monoclonal antibody against the p40 subunit of
IL12-23, that is currently under evaluation for Ps.2021. Lima XT, Abuabara K, Limball AB, Lima HC. Briakinumab. Expert
Opin Biol Ther. 2009;9:1107-13.Preliminary results are similar to those observed with
ustekinumab. Finally, as the activation of IL-23 depends on Th17,future
biological agents for Ps and Psa might be directed at Th17 and their secreted
product IL-17, a pathway still not taken in Psoriasis.2122. Weinberg JM. The path not taken. Cutis.
2010;86:115-116.In summary, the current status on the therapy of Ps and
Psa should now include new medications despite the fact that after TNF failure,
we still lack proper guidelines.2223. Weger W. Current status and new developments in the treatment of
psoriasis and psoriatic arthritis with biological agents. Br J Pharmacol.
2010;160:810-20.,2324. Deighton C. Therapy: what should we do after the failure of a
first anti-TNF? Nat Rev Rheumatol. 2009;5:596-7.
Conclusions
It is conceivable that we are not ready to replace anti-TNF as an alternative for
the treatment of Ps, but it is a possibility, in case of Psa, until the ongoing
phase-3 studies are available, it may also become a possibility in reducing
articular signs and symptoms. So, what is the alternative if anti-TNF fails in
patients suffering from Ps and Psa? Our understanding is that until comparative
studies be performed, inhibition of new pathogenetic pathways should be
considered and evaluated at the individual level; moreover, blocking IL12-23 is
an alternative pathway initially indicated for the skin, although it also seems
to be helpful in alleviating symptoms of arthritis.2425. Mease P. Update on treatment of psoriatic arthritis. Bull NYU
Hosp Jt Dis. 2012;70:167-71.,2526.Wallis DE, Waldron NM, Korendowych E. Ustekinumab for resistant
psoriatic arthritis. J Rheumatol. 2013 Feb;40:207. doi:
10.3899/jrheum.121152.
https://doi.org/10.3899/jrheum.121152...
REFERÊNCIAS
-
1Bradley JR. TNF-mediated inflammatory disease. J Pathol. 2008;214:149-60.
-
2Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther. 2008;117:244-79.
-
3Sfikakis PP. The first decade of biologic TNF antagonists in clinical practice: lessons learned unresolved issues and future directions. Curr Dir Autoimmun. 2010;11:180-210.
-
4Papagoras C, Voulgari PV, Drosos AA. Strategies after the failure of the first anti-tumor necrosis factor alpha agent in rheumatoid arthritis. Autoimmu Rev.2010;9:574-82.
-
5Scheinberg M, Goldenberg J, Feldman DP, Nóbrega JL. Retrospective study evaluating dose standards for infliximab in patients with rheumatoid arthritis at Hospital Israelita Albert Einstein, São Paulo, Brazil. Clin Rheumatol. 2008;27:1049-52.
-
6Voulgari PV. Golimumab: a new anti-TNF-alpha agent for rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. Expert Rev Clin Immunol. 2010;6:721-33.
-
7Patel AM, Moreland LW. Certolizumab pegol: a new biologic targeting rheumatoid arthritis. Expert Rev Clin Immunol. 2010;6:855-66.
-
8Grinblat B, Scheinberg M. Unexpected onset of psoriasis during infliximab treatment: comment on the article by Beuthien et al. Arthritis Rheum. 2005;52:1333-4.
-
9Grinblat B, Scheinberg M. The enigmatic development of psoriasis and psoriasiform lesions during anti-TNF therapy: a review. Semin Arthritis Rheum. 2008;37:251-5.
-
10Laurindo IM, Scheinberg M. Why do some biologic agents induce psoriasis or psoriasiform lesions? Nat Clin Pract Rheumatol. 2008;4:168-9.
-
11Gandhi M, Alwawi E, Gordon KB. Anti-p40 antibodies ustekinumab and briakinumab: blockade of interleukin-12 and interleukin-23 in the treatment of psoriasis. Semin Cutan Med Surg. 2010;29:48-52.
-
12Elliott M, Benson J, Blank M, Brodmerkel C, Baker D, Sharples KR, Szapary P. 13. Ann N Y. Ustekinumab: lessons learned from targeting interleukin-12/23p40 in immune-mediated diseases. Acad Sci. 2009;1182:97-110.
-
14Fitch E, Harper E, Skorcheva I, Kurtz SE, Blauvelt A. Pathophysiology of psoriasis: recent advances on IL-23 and Th17 cytokines. Curr Rheumatol Rep. 2007;9:461-7.
-
15Leonardi CL, Kimball AB, Papp KA, Yeildin N, Guzzo C, Wang Y, Li S, Dooley LT, Gordon KB, PHOENIX 1 study investigators. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomized, double-blind, placebo-controlled trial (PHOENIX 1). Lancet. 2008;37:1665-74.
-
16Papp KA, Langley RG, Lebwohl M, Krueger GG, Szapary P, Yeilding N, Guzzo C, Hsu MC, Wang Y, Li S, Dooley LT, Reich K; PHOENIX 2 study investigators. 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). Lancet. 2008;371:1675-84.
-
17Young MS, Horn EJ, Cather JC. The ACCEPT study: ustekinumab versus etanercept in moderate-to-severe psoriasis patients. Expert Rev Clin Immunol. 2011;7:9-13.
-
18Farhi D. Ustekinumab for the treatment of psoriasis: review of three multicenter clinical trials. Drugs Today (Barc). 2010;46:259-64.
-
19Kavanaugh A, Menter A, Mendelsohn A, Shen YK, Lee S, Gottlieb AB. Effect of ustekinumab on physical function and health-related quality of life in patients with psoriatic arthritis: a randomized, placebo-controlled, phase II trial. Curr Med Res Opin. 2010;26:2385-92.
-
20Cuchacovich R, Espinoza LR.: Ustekinumab for Psa.The Lancet. 2009;373:605-606.
-
21Lima XT, Abuabara K, Limball AB, Lima HC. Briakinumab. Expert Opin Biol Ther. 2009;9:1107-13.
-
22Weinberg JM. The path not taken. Cutis. 2010;86:115-116.
-
23Weger W. Current status and new developments in the treatment of psoriasis and psoriatic arthritis with biological agents. Br J Pharmacol. 2010;160:810-20.
-
24Deighton C. Therapy: what should we do after the failure of a first anti-TNF? Nat Rev Rheumatol. 2009;5:596-7.
-
25Mease P. Update on treatment of psoriatic arthritis. Bull NYU Hosp Jt Dis. 2012;70:167-71.
-
26Wallis DE, Waldron NM, Korendowych E. Ustekinumab for resistant psoriatic arthritis. J Rheumatol. 2013 Feb;40:207. doi: 10.3899/jrheum.121152.
» https://doi.org/10.3899/jrheum.121152
Publication Dates
-
Publication in this collection
May-Jun 2014
History
-
Received
12 Apr 2013 -
Accepted
16 Oct 2013