- Email: [email protected]
New pathways of treatment for psoriatic arthritis
Comment
New pathways of treatment for psoriatic arthritis and measures of enthesitis, dactylitis, skin and nail disease, function, quality of life, and inhibition of progressive structural damage in all treatment groups compared with placebo.6 These studies add to the growing evidence that drugs targeting the interleukin-23 and interleukin-17 axis can benefit the various clinical aspects of psoriasis, active psoriatic arthritis, and ankylosing spondylitis, providing an additional option for effective biological treatment besides anti-TNF therapy. The interleukin-12 and interleukin-23 inhibitor, ustekinumab, approved for treatment of psoriasis and active psoriatic arthritis and another interleukin17A inhibitor, secukinumab, approved for treatment of psoriasis, active psoriatic arthritis, and ankylosing spondylitis, are effective, and other than an increase in infection risk, are safe.4 An interleukin-17 receptor antagonist recently approved for psoriasis, brodalumab, has shown efficacy in active psoriatic arthritis.4 An emerging group of interleukin-23 inhibitors, guselkumab, risankizumab, and tildrakizumab have shown psoriasis efficacy in clinical trials and are in development for active psoriatic arthritis.4 Is there an immunological basis for observations of efficacy of inhibition of the interleukin-23 and interleukin-17 pathway noted? Interleukin 17A, and to a lesser extent, interleukin 17F are important for host defence against specific micro-organisms, including candida as well as neutrophil production and trafficking. However, when dysregulated, excessive activity in this
www.thelancet.com Published online May 24, 2017 http://dx.doi.org/10.1016/S0140-6736(17)31427-7
Published Online May 24, 2017 http://dx.doi.org/10.1016/ S0140-6736(17)31427-7 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(17)31429-0
Cid-Ism/Science Photo Library
Psoriatic arthritis occurs in up to 30% of patients with psoriasis.1 The prevalence of psoriasis varies geographically, ranging between 1% and 3% of the population, depending on genetic variation.2 Since the discovery of the cytokine interleukin 17A in 1993, and the subsequent discovery of one of the key cells that produce interleukin 17A and related cytokines, the T-helper-17 cell, in 2005,3 this pathway has been a focus of research in the pathogenesis of psoriasis and closely related conditions, psoriatic arthritis and spondyloarthritis.4 In The Lancet, Peter Nash and colleagues on behalf of the SPIRIT-P2 Study Group5 provide further evidence for inhibition of interleukin 17A with ixekizumab in patients with psoriatic arthritis. In SPIRIT-P2,5 patients who had either inadequate response or adverse effects to previous biological therapy received placebo (n=118), ixekizumab (80 mg after a 160 mg starting dose) every 4 weeks (n=122), or ixekizumab (80 mg) every 2 weeks (n=123). More patients attained the primary endpoint of at least 20% improvement in the American College of Rheumatology response criteria (ACR-20) at week 24 with ixekizumab every 4 weeks (65 [53%] patients; effect size vs placebo 33·8% [95% CI 22·4–45·2]; p<0·0001) and ixekizumab every 2 weeks (59 [48%] patients; effect size vs placebo 28·5% [95% CI 17·1–39·8]; p<0·0001) than did patients with placebo (23 [20%] patients). There was also improvement with ixekizumab in clinical domains beyond inflammatory arthritis, including dactylitis in one dose group, psoriasis, nail disease, attainment of minimal disease activity, and measures of function and quality of life in both ixekizumab groups. Three (3%) patients with ixekizumab every 4 weeks, eight (7%) with ixekizumab every 2 weeks, and four (3%) with placebo had severe adverse events. Infections occurred in 47 (39%) patients with ixekizumab every 4 weeks, 47 (38%) with ixekizumab every 2 weeks, and 35 (30%) with placebo. There were three (2%) serious infections, all in patients in the ixekizumab every 2 weeks group. This study lends support to the findings of SPIRIT-P1 trial,6 in which patients with active psoriatic arthritis naive to biological therapy were treated with the same ixekizumab regimen versus placebo and the tumour necrosis factor (TNF) inhibitor, adalimumab. At 24 weeks, significant improvement was reported in ACR responses
1
Comment
pathway might promulgate inflammatory disease. There is now evidence that interleukin 17 might also be made by a number of innate immune cells, including natural killer cells, γδT cells, intestinal Paneth cells, neutrophils, and mast cells, some of which line the gut mucosa, lung epithelia, and skin, and can be activated by dendritic cell and macrophage interleukin-23 production. By producing interleukin 17, these cells, along with T-helper-17 cells, might have a role in preserving barrier function and integrity of epithelial surfaces, but inadvertently might contribute to autoinflammatory or autoimmune reactions.7,8 Genome-wide association studies have shown that genes encoding for variants of interleukin 23R are important risk factors for psoriasis, active psoriatic arthritis, and ankylosing spondylitis.9,10 Translational studies have shown increased numbers of T-helper-17 cells and expression of interleukin 23, interleukin 17, and interleukin 22 in psoriatic skin lesions and synovium of patients with active psoriatic arthritis and ankylosing spondylitis, promoting key pathophysiological features such as hyperproliferation of keratinocytes, synovitis, and activation of a variety of immunological cells producing proinflammatory cytokines.11 Presumably, various factors, including perturbations of the gut or skin microbiome, biomechanical stress, infection, and aberrations in human leukocyte antigen-B27 biology, lead to induction of interleukin 23 and subsequent activation of T-helper-17 and other effector immune cells, acting prominently through innate as well as adaptive immune mechanisms.12 Limitations of the study by Nash and colleagues5 include the fact that inhibition of structural damage progression was not assessed by joint radiograph analysis, partly because this factor was assessed and showed benefit in the ixekizumab groups in a biologic-naive population in SPIRIT-P1.6 The number of patients with active dactylitis was relatively small (14 in the placebo vs 28 in the ixekizumab 4 weeks vs 20 in the ixekizumab 2 weeks), which might have contributed to absence of a statistical effect in one dose arm. It will also be useful to test this treatment approach in patients with early disease, as opposed to 9–11 years of disease duration, to see if higher levels of disease response and even remission can be achieved. A strength of the study is the benefit in a tumour necrosis inhibitor experienced population, a
2
set of patients that tend to be more difficult to treat the more they lose response to serial biological treatment. This study further confirms the importance of the interleukin-23 and interleukin-17 axis in the pathogenesis of psoriasis and active psoriatic arthritis and the efficacy and reasonable safety of inhibition of interleukin 17A in active psoriatic arthritis, encouraging further exploration of the drugs that target this pathway. Philip Mease Seattle Rheumatology Associates, Swedish Providence-St Joseph Health Systems, Seattle, WA 98122, USA [email protected] I have received grants and consulting fees from AbbVie related to risankizumab and upadacitinib, from Bristol-Myers Squibb related to abatacept, from Janssen related to ustekinumab and guselkumab, and from Lilly related to ixekizumab and baricitinib; grants, speaker fees, and consulting fees from Pfizer related to tofacitinib; speaker fees from Amgen related to etanercept, from Novartis related to secukinumab; consulting and speaker fees from Celgene related to apremilast; speaker fees from Genentech related to tocilizumab; consulting fees from SUN Pharmaceutical related to tildrakizumab; and consulting fees from UCB related to bimekizumab and speaker fees from UCB related to certolizumab. I was consultant and lead author on the SPIRIT 1 trial6 on ixekizumab in biologicnaive active psoriatic arthritis sponsored by Lilly. 1
Ogdie A, Weiss. The epidemiology of psoriatic arthritis. Rheum Dis Clin North Am 2015; 41: 545–68. 2 Michalek IM, Loring B, John SM. A systematic review of worldwide epidemiology of psoriasis. Eur Acad Dermatol Venereol 2017; 31: 205–12. 3 Miossec P, Korn T, Kuchroo VK. Interleukin-17 and type 17 helper T cells. N Engl J Med 2009; 361: 888–98. 4 Mease PJ. Inhibition of interleukin-17, interleukin-23 and the TH17 cell pathway in the treatment of psoriatic arthritis and psoriasis. Curr Opin Rheumatol 2015; 27: 127–33. 5 Nash P, Kirkham B, Okada M, et al, on behalf of the SPIRIT-P2 Study Group. Ixekizumab for the treatment of patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors: results from the 24-week randomised, double-blind, placebo-controlled period of the SPIRIT-P2 phase 3 trial. Lancet 2017; published online May 24, 2017. http://dx.doi.org/10.1016/S0140-6736(17)31429-0. 6 Mease PJ, van der Heijde D, Ritchlin CT, et al. Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase III trial SPIRIT-P1. Ann Rheum Dis 2017; 76: 79–87. 7 Gaffen SL, Jain R, Garg AV, et al. The IL-23–IL-17 immune axis: from mechanisms to therapeutic testing. Nature Rev Immunol 2014; 14: 585–600. 8 Smith JA, Colbert RA. Review: the interleukin-23/interleukin-17 axis in spondyloarthritis pathogenesis: Th17 and beyond. Arthritis Rheumatol 2014; 66: 231–41. 9 Frleta M, Siebert S, McInnes IB. The interleukin-17 pathway in psoriasis and psoriatic arthritis: disease pathogenesis and possibilities of treatment. Curr Rheumatol Rep 2014; 16: 414. 10 Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med 2009; 361: 496–509. 11 Raychaudhuri SP, Raychaudhuri SK. IL-23/IL-17 axis in spondyloarthritisbench to bedside. Clin Rheumatol 2016; 35: 1437–41. 12 Lories RJ, McInnes IB. Primed for inflammation: enthesis-resident T cells. Nat Med 2012; 18: 1018–19.
www.thelancet.com Published online May 24, 2017 http://dx.doi.org/10.1016/S0140-6736(17)31427-7
New pathways of treatment for psoriatic arthritis and measures of enthesitis, dactylitis, skin and nail disease, function, quality of life, and inhibition of progressive structural damage in all treatment groups compared with placebo.6 These studies add to the growing evidence that drugs targeting the interleukin-23 and interleukin-17 axis can benefit the various clinical aspects of psoriasis, active psoriatic arthritis, and ankylosing spondylitis, providing an additional option for effective biological treatment besides anti-TNF therapy. The interleukin-12 and interleukin-23 inhibitor, ustekinumab, approved for treatment of psoriasis and active psoriatic arthritis and another interleukin17A inhibitor, secukinumab, approved for treatment of psoriasis, active psoriatic arthritis, and ankylosing spondylitis, are effective, and other than an increase in infection risk, are safe.4 An interleukin-17 receptor antagonist recently approved for psoriasis, brodalumab, has shown efficacy in active psoriatic arthritis.4 An emerging group of interleukin-23 inhibitors, guselkumab, risankizumab, and tildrakizumab have shown psoriasis efficacy in clinical trials and are in development for active psoriatic arthritis.4 Is there an immunological basis for observations of efficacy of inhibition of the interleukin-23 and interleukin-17 pathway noted? Interleukin 17A, and to a lesser extent, interleukin 17F are important for host defence against specific micro-organisms, including candida as well as neutrophil production and trafficking. However, when dysregulated, excessive activity in this
www.thelancet.com Published online May 24, 2017 http://dx.doi.org/10.1016/S0140-6736(17)31427-7
Published Online May 24, 2017 http://dx.doi.org/10.1016/ S0140-6736(17)31427-7 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(17)31429-0
Cid-Ism/Science Photo Library
Psoriatic arthritis occurs in up to 30% of patients with psoriasis.1 The prevalence of psoriasis varies geographically, ranging between 1% and 3% of the population, depending on genetic variation.2 Since the discovery of the cytokine interleukin 17A in 1993, and the subsequent discovery of one of the key cells that produce interleukin 17A and related cytokines, the T-helper-17 cell, in 2005,3 this pathway has been a focus of research in the pathogenesis of psoriasis and closely related conditions, psoriatic arthritis and spondyloarthritis.4 In The Lancet, Peter Nash and colleagues on behalf of the SPIRIT-P2 Study Group5 provide further evidence for inhibition of interleukin 17A with ixekizumab in patients with psoriatic arthritis. In SPIRIT-P2,5 patients who had either inadequate response or adverse effects to previous biological therapy received placebo (n=118), ixekizumab (80 mg after a 160 mg starting dose) every 4 weeks (n=122), or ixekizumab (80 mg) every 2 weeks (n=123). More patients attained the primary endpoint of at least 20% improvement in the American College of Rheumatology response criteria (ACR-20) at week 24 with ixekizumab every 4 weeks (65 [53%] patients; effect size vs placebo 33·8% [95% CI 22·4–45·2]; p<0·0001) and ixekizumab every 2 weeks (59 [48%] patients; effect size vs placebo 28·5% [95% CI 17·1–39·8]; p<0·0001) than did patients with placebo (23 [20%] patients). There was also improvement with ixekizumab in clinical domains beyond inflammatory arthritis, including dactylitis in one dose group, psoriasis, nail disease, attainment of minimal disease activity, and measures of function and quality of life in both ixekizumab groups. Three (3%) patients with ixekizumab every 4 weeks, eight (7%) with ixekizumab every 2 weeks, and four (3%) with placebo had severe adverse events. Infections occurred in 47 (39%) patients with ixekizumab every 4 weeks, 47 (38%) with ixekizumab every 2 weeks, and 35 (30%) with placebo. There were three (2%) serious infections, all in patients in the ixekizumab every 2 weeks group. This study lends support to the findings of SPIRIT-P1 trial,6 in which patients with active psoriatic arthritis naive to biological therapy were treated with the same ixekizumab regimen versus placebo and the tumour necrosis factor (TNF) inhibitor, adalimumab. At 24 weeks, significant improvement was reported in ACR responses
1
Comment
pathway might promulgate inflammatory disease. There is now evidence that interleukin 17 might also be made by a number of innate immune cells, including natural killer cells, γδT cells, intestinal Paneth cells, neutrophils, and mast cells, some of which line the gut mucosa, lung epithelia, and skin, and can be activated by dendritic cell and macrophage interleukin-23 production. By producing interleukin 17, these cells, along with T-helper-17 cells, might have a role in preserving barrier function and integrity of epithelial surfaces, but inadvertently might contribute to autoinflammatory or autoimmune reactions.7,8 Genome-wide association studies have shown that genes encoding for variants of interleukin 23R are important risk factors for psoriasis, active psoriatic arthritis, and ankylosing spondylitis.9,10 Translational studies have shown increased numbers of T-helper-17 cells and expression of interleukin 23, interleukin 17, and interleukin 22 in psoriatic skin lesions and synovium of patients with active psoriatic arthritis and ankylosing spondylitis, promoting key pathophysiological features such as hyperproliferation of keratinocytes, synovitis, and activation of a variety of immunological cells producing proinflammatory cytokines.11 Presumably, various factors, including perturbations of the gut or skin microbiome, biomechanical stress, infection, and aberrations in human leukocyte antigen-B27 biology, lead to induction of interleukin 23 and subsequent activation of T-helper-17 and other effector immune cells, acting prominently through innate as well as adaptive immune mechanisms.12 Limitations of the study by Nash and colleagues5 include the fact that inhibition of structural damage progression was not assessed by joint radiograph analysis, partly because this factor was assessed and showed benefit in the ixekizumab groups in a biologic-naive population in SPIRIT-P1.6 The number of patients with active dactylitis was relatively small (14 in the placebo vs 28 in the ixekizumab 4 weeks vs 20 in the ixekizumab 2 weeks), which might have contributed to absence of a statistical effect in one dose arm. It will also be useful to test this treatment approach in patients with early disease, as opposed to 9–11 years of disease duration, to see if higher levels of disease response and even remission can be achieved. A strength of the study is the benefit in a tumour necrosis inhibitor experienced population, a
2
set of patients that tend to be more difficult to treat the more they lose response to serial biological treatment. This study further confirms the importance of the interleukin-23 and interleukin-17 axis in the pathogenesis of psoriasis and active psoriatic arthritis and the efficacy and reasonable safety of inhibition of interleukin 17A in active psoriatic arthritis, encouraging further exploration of the drugs that target this pathway. Philip Mease Seattle Rheumatology Associates, Swedish Providence-St Joseph Health Systems, Seattle, WA 98122, USA [email protected] I have received grants and consulting fees from AbbVie related to risankizumab and upadacitinib, from Bristol-Myers Squibb related to abatacept, from Janssen related to ustekinumab and guselkumab, and from Lilly related to ixekizumab and baricitinib; grants, speaker fees, and consulting fees from Pfizer related to tofacitinib; speaker fees from Amgen related to etanercept, from Novartis related to secukinumab; consulting and speaker fees from Celgene related to apremilast; speaker fees from Genentech related to tocilizumab; consulting fees from SUN Pharmaceutical related to tildrakizumab; and consulting fees from UCB related to bimekizumab and speaker fees from UCB related to certolizumab. I was consultant and lead author on the SPIRIT 1 trial6 on ixekizumab in biologicnaive active psoriatic arthritis sponsored by Lilly. 1
Ogdie A, Weiss. The epidemiology of psoriatic arthritis. Rheum Dis Clin North Am 2015; 41: 545–68. 2 Michalek IM, Loring B, John SM. A systematic review of worldwide epidemiology of psoriasis. Eur Acad Dermatol Venereol 2017; 31: 205–12. 3 Miossec P, Korn T, Kuchroo VK. Interleukin-17 and type 17 helper T cells. N Engl J Med 2009; 361: 888–98. 4 Mease PJ. Inhibition of interleukin-17, interleukin-23 and the TH17 cell pathway in the treatment of psoriatic arthritis and psoriasis. Curr Opin Rheumatol 2015; 27: 127–33. 5 Nash P, Kirkham B, Okada M, et al, on behalf of the SPIRIT-P2 Study Group. Ixekizumab for the treatment of patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors: results from the 24-week randomised, double-blind, placebo-controlled period of the SPIRIT-P2 phase 3 trial. Lancet 2017; published online May 24, 2017. http://dx.doi.org/10.1016/S0140-6736(17)31429-0. 6 Mease PJ, van der Heijde D, Ritchlin CT, et al. Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase III trial SPIRIT-P1. Ann Rheum Dis 2017; 76: 79–87. 7 Gaffen SL, Jain R, Garg AV, et al. The IL-23–IL-17 immune axis: from mechanisms to therapeutic testing. Nature Rev Immunol 2014; 14: 585–600. 8 Smith JA, Colbert RA. Review: the interleukin-23/interleukin-17 axis in spondyloarthritis pathogenesis: Th17 and beyond. Arthritis Rheumatol 2014; 66: 231–41. 9 Frleta M, Siebert S, McInnes IB. The interleukin-17 pathway in psoriasis and psoriatic arthritis: disease pathogenesis and possibilities of treatment. Curr Rheumatol Rep 2014; 16: 414. 10 Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med 2009; 361: 496–509. 11 Raychaudhuri SP, Raychaudhuri SK. IL-23/IL-17 axis in spondyloarthritisbench to bedside. Clin Rheumatol 2016; 35: 1437–41. 12 Lories RJ, McInnes IB. Primed for inflammation: enthesis-resident T cells. Nat Med 2012; 18: 1018–19.
www.thelancet.com Published online May 24, 2017 http://dx.doi.org/10.1016/S0140-6736(17)31427-7