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Interleukin-17 inhibition in psoriatic arthritis
Comment
Interleukin-17 inhibition in psoriatic arthritis Psoriatic arthritis1 has struggled behind rheumatoid arthritis in terms of basic science, treatment, and national priorities. The disease is slightly less common than is rheumatoid arthritis, and the original series from Leeds, UK, suggested that psoriatic arthritis had a fairly benign outcome.2 More recently, it has become apparent that psoriatic arthritis can have an equivalently devastating effect on patient function and quality of life.3 However, important differences remain. Psoriatic arthritis is a heterogeneous disease with several musculoskeletal manifestations, and prominent extra-articular manifestations, such as psoriasis. When assessing treatment efficacy, all these features should be assessed, because all contribute to disease activity and impact. The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis has drawn attention to dilemmas of treatment guidelines in psoriatic arthritis.4 The evidence base for traditional treatments with drugs such as sulfasalazine and methotrexate is poor.4 The best evidence from controlled trials began to emerge in the early 2000s—eg, with the advent of tumour necrosis factor (TNF)α inhibitors. These drugs were shown to work well for peripheral arthritis and, importantly, the other manifestations of the disease, such as psoriasis, enthesitis, dactylitis, and spondylitis.5 TNFα inhibitors are the standard for efficacy of new drugs in this disease. Importantly, with a discontinuation rate of about 10% per year, and few data about switching,6 many patients taking these drugs are now finding that they no longer work, and few alternatives exist. Interleukin 17 has been of increasing interest in the spondyloarthritides and related disorders after the discovery of the key role of the T-helper 17 axis. Data from trials of interleukin-17 inhibitors in skin psoriasis have shown impressive rates of skin responses with a clear benefit for secukinumab7 and ixekizumab8 compared with both placebo and a TNFα inhibitor (etanercept). In The Lancet, Iain McInnes and colleagues9 report results from the FUTURE2 study on the efficacy and safety of secukinumab, a human monoclonal antibody targeting interleukin 17A, in patients with active psoriatic arthritis. In this randomised, double-blind, placebo-controlled, phase 3 trial, the investigators compared three doses: 75 mg, 150 mg, and 300 mg with placebo, with about 100 patients in each group (total n=397). Patients
received subcutaneous secukinumab with a weekly loading dose for 4 weeks, followed by administration every 4 weeks thereafter. The primary outcome was the proportion of patients achieving at least 20% improvement in the American College of Rheumatology response criteria (ACR20) at week 24, with any placebotreated patients entering the early escape group at week 16 being classified as non-responders. The trial met its primary outcome at week 24, with all doses of secukinumab being better than placebo (secukinumab 300 mg, 54 [54%] patients, odds ratio vs placebo 6·81 [95% CI 3·42–13·56]; 150 mg, 51 [51%] patients, 6·52 [3·25–13·08]; and 75 mg, 29 [29%] patients, 2·32 [1·14–4·73]). Responses with 150 mg and 300 mg seemed equivalent, whereas response rates in the 75 mg group were lower. The key secondary outcomes, response rates for skin manifestations and quality of life, were all significantly higher in the secukinumab 150 mg and 300 mg groups than in the placebo group, but the responses with the 75 mg dose were not significant for skin. This lack of efficacy of the 75 mg dose for psoriasis is not surprising because the licensed dose for psoriasis is 300 mg based on data from the ERASURE and FIXTURE trials.7 Interestingly, although the primary outcome was assessed at week 24, responses at weeks 12 and 16 were similar to those at week 24. This is important in a clinical situation in which patients and their treating physicians should get an idea of response (or non-response) at an early timepoint. With a more stringent outcome (ACR50) there seemed to be an increase between weeks 12 and 24, suggesting an ongoing improvement in response. Improvement, albeit not significant, was also noted in dactylitis and enthesitis at week 24. Axial outcomes were not measured in this study. Although no direct comparison can be made, it does seem that secukinumab provides an equivalent improvement in the musculoskeletal manifestations to that seen in previous TNFα inhibitor studies. Radiological progression was not, surprisingly, assessed in McInnes and colleagues’ study, although inhibition of radiographic damage was noted in the unpublished FUTURE-1 trial (NCT01392326).10 Unlike rheumatoid arthritis, both erosion and new bone formation are prominent features of the structural consequences of
www.thelancet.com Published online June 29, 2015 http://dx.doi.org/10.1016/S0140-6736(15)61170-9
Published Online June 29, 2015 http://dx.doi.org/10.1016/ S0140-6736(15)61170-9 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(15)61134-5
1
Comment
psoriatic arthritis. In view of its position in the cytokine hierarchy, interleukin-17 inhibition might prevent both of these features, and future studies with this class of drug should investigate this issue in detail. The safety data in McInnes and colleagues’ trial9 seem reassuring, with similar rates of adverse events and serious adverse events in the secukinumab and placebo groups: most common adverse events were upper respiratory tract infections (four [4%], eight [8%], ten [10%], and seven [7%] with secukinumab 300 mg, 150 mg, 75 mg, and placebo, respectively) and nasopharyngitis (six [6%], four [4%], six [6%], and eight [8%], respectively). Serious adverse events were reported in five (5%), one (1%), and four (4%) patients in the secukinumab 300 mg, 150 mg, and 75 mg groups, respectively, compared with two (2%) patients in the placebo group. As expected with immunotherapy, there were some infections but no substantial increase in incidence compared with placebo, with the exception of candidosis, which was reported in 11 patients across the three secukinumab groups. Interleukin 17 is important in the defence against Candida spp infections, so this adverse event was predictable. In all cases, Candida infections resolved spontaneously or with oral therapy and patients continued on secukinumab in the trial. Only one patient had grade 3 neutropenia, but this was transient and did not necessitate stopping therapy. Although not formally assessed, such as with specific screening questionnaires, there were no reports of suicidal ideation during McInnes and colleagues’ study. The other key outcome reported by the investigators is that of the different responses in patients who were TNF-inhibitor naive (65% of the cohort) versus those who had received between one and three TNF-inhibitor treatments (35% of cohort). This analysis is limited by small numbers in each group, but it seems that a lower response occurred in patients who had previously received TNF inhibitors (TNF failure vs TNF naive: ACR20 responses at secukinumab 150 mg were 30% vs 63%, respectively, and ACR20 responses at 300 mg were 45% vs 58%). This difference is in keeping with data for other treatments such as ustekinumab that also suggested a lower response rate in individuals who did not respond to a previous TNF inhibitor.11 By contrast with the overall study data, a dose-response was noted with secukinumab 300 mg and 150 mg in patients previously treated with TNF inhibitors that was not evident in the TNF-inhibitornaive patients. This difference in response suggests two 2
possible situations in which the higher 300 mg dose might be better: first, for people with moderate to severe psoriasis, and second, for individuals who have failed treatment with a TNF inhibitor. Now is an exciting and encouraging time for physicians and patients with psoriatic arthritis. However, despite all the recent advances, many questions still remain about how to treat patients with this disorder. Although many treatments have proven efficacy, there is little research to compare therapies or investigate treatment strategies. Indeed, the Tight Control of Psoriatic Arthritis (TICOPA) trial12 is the only powered randomised controlled trial in which treatment strategy for psoriatic arthritis was investigated; the results showed that treating to an objective target can improve clinical and patient-reported outcomes. However, no evidence exists to guide the sequencing of drugs or which therapies are best for subgroups of patients, such as those with asymmetrical oligoarthritis or predominant enthesitis or axial disease. From the current perspective, it seems likely that interleukin-17 inhibitors will be used after failure of, or intolerance to, a TNF inhibitor. However, because of the availability of other biological agents, such as interleukin 12/23 inhibitors, and targeted synthetic drugs, such as apremilast, just how these drugs should be used for optimum management of patients with psoriatic arthritis is a key research question. *Philip Helliwell, Laura Coates Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Chapel Allerton Hospital, Leeds LS7 4SA, UK [email protected] PH has received grants and non-financial support from AbbVie, grants from Amgen, Janssen, Pfizer, Merck Sharp & Dohme, UCB, and Celgene, and a payment to a charity account for advice on outcomes in psoriatic arthritis from Novartis; and has served on an advisory board for Bristol-Myers Squibb. LC has received grants and personal fees from Janssen, AbbVie, and Pfizer, and personal fees from Celgene, Merck Sharp & Dohme, Boehringer Ingelheim, and UCB. 1 2 3 4 5
6
Moll JM, Wright V. Psoriatic arthritis. Semin Arthritis Rheum 1973; 3: 55–78. Roberts ME, Wright V, Hill AG, Mehra AC. Psoriatic arthritis. Follow-up study. Ann Rheum Dis 1976; 35: 206–12. Sokoll KB, Helliwell PS. Comparison of disability and quality of life in rheumatoid and psoriatic arthritis. J Rheumatol 2001; 28: 1842–46. Ritchlin C, Kavanaugh A, Gladman DD, et al. Treatment recommendations for psoriatic arthritis. Ann Rheum Dis 2009; 68: 1387–94. Kavanaugh AF, Ritchlin CT, and GRAPPA Treatment Guideline Committee. Systematic review of treatments for psoriatic arthritis: an evidence based approach and basis for treatment guidelines. J Rheumatol 2006; 33: 1417–21. Saad AA, Ashcroft DM, Watson KD, Hyrich KL, Noyce PR, Symmons DP, and the British Society for Rheumatology Biologics Register. Persistence with anti-tumour necrosis factor therapies in patients with psoriatic arthritis: observational study from the British Society of Rheumatology Biologics Register. Arthritis Res Ther 2009; 11: R52.
www.thelancet.com Published online June 29, 2015 http://dx.doi.org/10.1016/S0140-6736(15)61170-9
Comment
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Langley RG, Elewski BE, Lebwohl M, et al. Secukinumab in plaque psoriasis—results of two phase 3 trials. N Engl J Med 2014; 371: 326–38. Griffiths CE, Reich K, Lebwohl M, et al, for the UNCOVER-2 UNCOVER-3 investigators. Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. Lancet 2015; published online June 10. http://dx.doi.org/10.1016/S0140-6736(15)60125-8. McInnes IB, Mease PJ, Kirkham B, et al, on behalf of the FUTURE 2 Study Group. Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2015; published online June 29. http://dx.doi.org/10.1016/S0140-6736(15)61134-5. Mease PJ, McInnes IB, Kirkham B, et al. Secukinumab, a human anti-interleukin-17A monoclonal antibody, improves active psoriatic arthritis and inhibits radiographic progression: efficacy and safety data from a phase 3 randomized, multicenter, double-blind, placebo-controlled study. Arthritis Rheum 2014; 66 (suppl): S423 (abstr 923).
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Ritchlin C, Rahman P, Kavanaugh A, et al. Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial. Ann Rheum Dis 2014; 73: 990–99. Coates LC, Moverley AR, McParland L, et al. Results of a randomised controlled trial comparing tight control of early psoriatic arthritis (TICOPA) with standard care: tight control improves outcome. Arthritis Rheum 2013; 65: S346.
www.thelancet.com Published online June 29, 2015 http://dx.doi.org/10.1016/S0140-6736(15)61170-9
3
Interleukin-17 inhibition in psoriatic arthritis Psoriatic arthritis1 has struggled behind rheumatoid arthritis in terms of basic science, treatment, and national priorities. The disease is slightly less common than is rheumatoid arthritis, and the original series from Leeds, UK, suggested that psoriatic arthritis had a fairly benign outcome.2 More recently, it has become apparent that psoriatic arthritis can have an equivalently devastating effect on patient function and quality of life.3 However, important differences remain. Psoriatic arthritis is a heterogeneous disease with several musculoskeletal manifestations, and prominent extra-articular manifestations, such as psoriasis. When assessing treatment efficacy, all these features should be assessed, because all contribute to disease activity and impact. The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis has drawn attention to dilemmas of treatment guidelines in psoriatic arthritis.4 The evidence base for traditional treatments with drugs such as sulfasalazine and methotrexate is poor.4 The best evidence from controlled trials began to emerge in the early 2000s—eg, with the advent of tumour necrosis factor (TNF)α inhibitors. These drugs were shown to work well for peripheral arthritis and, importantly, the other manifestations of the disease, such as psoriasis, enthesitis, dactylitis, and spondylitis.5 TNFα inhibitors are the standard for efficacy of new drugs in this disease. Importantly, with a discontinuation rate of about 10% per year, and few data about switching,6 many patients taking these drugs are now finding that they no longer work, and few alternatives exist. Interleukin 17 has been of increasing interest in the spondyloarthritides and related disorders after the discovery of the key role of the T-helper 17 axis. Data from trials of interleukin-17 inhibitors in skin psoriasis have shown impressive rates of skin responses with a clear benefit for secukinumab7 and ixekizumab8 compared with both placebo and a TNFα inhibitor (etanercept). In The Lancet, Iain McInnes and colleagues9 report results from the FUTURE2 study on the efficacy and safety of secukinumab, a human monoclonal antibody targeting interleukin 17A, in patients with active psoriatic arthritis. In this randomised, double-blind, placebo-controlled, phase 3 trial, the investigators compared three doses: 75 mg, 150 mg, and 300 mg with placebo, with about 100 patients in each group (total n=397). Patients
received subcutaneous secukinumab with a weekly loading dose for 4 weeks, followed by administration every 4 weeks thereafter. The primary outcome was the proportion of patients achieving at least 20% improvement in the American College of Rheumatology response criteria (ACR20) at week 24, with any placebotreated patients entering the early escape group at week 16 being classified as non-responders. The trial met its primary outcome at week 24, with all doses of secukinumab being better than placebo (secukinumab 300 mg, 54 [54%] patients, odds ratio vs placebo 6·81 [95% CI 3·42–13·56]; 150 mg, 51 [51%] patients, 6·52 [3·25–13·08]; and 75 mg, 29 [29%] patients, 2·32 [1·14–4·73]). Responses with 150 mg and 300 mg seemed equivalent, whereas response rates in the 75 mg group were lower. The key secondary outcomes, response rates for skin manifestations and quality of life, were all significantly higher in the secukinumab 150 mg and 300 mg groups than in the placebo group, but the responses with the 75 mg dose were not significant for skin. This lack of efficacy of the 75 mg dose for psoriasis is not surprising because the licensed dose for psoriasis is 300 mg based on data from the ERASURE and FIXTURE trials.7 Interestingly, although the primary outcome was assessed at week 24, responses at weeks 12 and 16 were similar to those at week 24. This is important in a clinical situation in which patients and their treating physicians should get an idea of response (or non-response) at an early timepoint. With a more stringent outcome (ACR50) there seemed to be an increase between weeks 12 and 24, suggesting an ongoing improvement in response. Improvement, albeit not significant, was also noted in dactylitis and enthesitis at week 24. Axial outcomes were not measured in this study. Although no direct comparison can be made, it does seem that secukinumab provides an equivalent improvement in the musculoskeletal manifestations to that seen in previous TNFα inhibitor studies. Radiological progression was not, surprisingly, assessed in McInnes and colleagues’ study, although inhibition of radiographic damage was noted in the unpublished FUTURE-1 trial (NCT01392326).10 Unlike rheumatoid arthritis, both erosion and new bone formation are prominent features of the structural consequences of
www.thelancet.com Published online June 29, 2015 http://dx.doi.org/10.1016/S0140-6736(15)61170-9
Published Online June 29, 2015 http://dx.doi.org/10.1016/ S0140-6736(15)61170-9 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(15)61134-5
1
Comment
psoriatic arthritis. In view of its position in the cytokine hierarchy, interleukin-17 inhibition might prevent both of these features, and future studies with this class of drug should investigate this issue in detail. The safety data in McInnes and colleagues’ trial9 seem reassuring, with similar rates of adverse events and serious adverse events in the secukinumab and placebo groups: most common adverse events were upper respiratory tract infections (four [4%], eight [8%], ten [10%], and seven [7%] with secukinumab 300 mg, 150 mg, 75 mg, and placebo, respectively) and nasopharyngitis (six [6%], four [4%], six [6%], and eight [8%], respectively). Serious adverse events were reported in five (5%), one (1%), and four (4%) patients in the secukinumab 300 mg, 150 mg, and 75 mg groups, respectively, compared with two (2%) patients in the placebo group. As expected with immunotherapy, there were some infections but no substantial increase in incidence compared with placebo, with the exception of candidosis, which was reported in 11 patients across the three secukinumab groups. Interleukin 17 is important in the defence against Candida spp infections, so this adverse event was predictable. In all cases, Candida infections resolved spontaneously or with oral therapy and patients continued on secukinumab in the trial. Only one patient had grade 3 neutropenia, but this was transient and did not necessitate stopping therapy. Although not formally assessed, such as with specific screening questionnaires, there were no reports of suicidal ideation during McInnes and colleagues’ study. The other key outcome reported by the investigators is that of the different responses in patients who were TNF-inhibitor naive (65% of the cohort) versus those who had received between one and three TNF-inhibitor treatments (35% of cohort). This analysis is limited by small numbers in each group, but it seems that a lower response occurred in patients who had previously received TNF inhibitors (TNF failure vs TNF naive: ACR20 responses at secukinumab 150 mg were 30% vs 63%, respectively, and ACR20 responses at 300 mg were 45% vs 58%). This difference is in keeping with data for other treatments such as ustekinumab that also suggested a lower response rate in individuals who did not respond to a previous TNF inhibitor.11 By contrast with the overall study data, a dose-response was noted with secukinumab 300 mg and 150 mg in patients previously treated with TNF inhibitors that was not evident in the TNF-inhibitornaive patients. This difference in response suggests two 2
possible situations in which the higher 300 mg dose might be better: first, for people with moderate to severe psoriasis, and second, for individuals who have failed treatment with a TNF inhibitor. Now is an exciting and encouraging time for physicians and patients with psoriatic arthritis. However, despite all the recent advances, many questions still remain about how to treat patients with this disorder. Although many treatments have proven efficacy, there is little research to compare therapies or investigate treatment strategies. Indeed, the Tight Control of Psoriatic Arthritis (TICOPA) trial12 is the only powered randomised controlled trial in which treatment strategy for psoriatic arthritis was investigated; the results showed that treating to an objective target can improve clinical and patient-reported outcomes. However, no evidence exists to guide the sequencing of drugs or which therapies are best for subgroups of patients, such as those with asymmetrical oligoarthritis or predominant enthesitis or axial disease. From the current perspective, it seems likely that interleukin-17 inhibitors will be used after failure of, or intolerance to, a TNF inhibitor. However, because of the availability of other biological agents, such as interleukin 12/23 inhibitors, and targeted synthetic drugs, such as apremilast, just how these drugs should be used for optimum management of patients with psoriatic arthritis is a key research question. *Philip Helliwell, Laura Coates Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Chapel Allerton Hospital, Leeds LS7 4SA, UK [email protected] PH has received grants and non-financial support from AbbVie, grants from Amgen, Janssen, Pfizer, Merck Sharp & Dohme, UCB, and Celgene, and a payment to a charity account for advice on outcomes in psoriatic arthritis from Novartis; and has served on an advisory board for Bristol-Myers Squibb. LC has received grants and personal fees from Janssen, AbbVie, and Pfizer, and personal fees from Celgene, Merck Sharp & Dohme, Boehringer Ingelheim, and UCB. 1 2 3 4 5
6
Moll JM, Wright V. Psoriatic arthritis. Semin Arthritis Rheum 1973; 3: 55–78. Roberts ME, Wright V, Hill AG, Mehra AC. Psoriatic arthritis. Follow-up study. Ann Rheum Dis 1976; 35: 206–12. Sokoll KB, Helliwell PS. Comparison of disability and quality of life in rheumatoid and psoriatic arthritis. J Rheumatol 2001; 28: 1842–46. Ritchlin C, Kavanaugh A, Gladman DD, et al. Treatment recommendations for psoriatic arthritis. Ann Rheum Dis 2009; 68: 1387–94. Kavanaugh AF, Ritchlin CT, and GRAPPA Treatment Guideline Committee. Systematic review of treatments for psoriatic arthritis: an evidence based approach and basis for treatment guidelines. J Rheumatol 2006; 33: 1417–21. Saad AA, Ashcroft DM, Watson KD, Hyrich KL, Noyce PR, Symmons DP, and the British Society for Rheumatology Biologics Register. Persistence with anti-tumour necrosis factor therapies in patients with psoriatic arthritis: observational study from the British Society of Rheumatology Biologics Register. Arthritis Res Ther 2009; 11: R52.
www.thelancet.com Published online June 29, 2015 http://dx.doi.org/10.1016/S0140-6736(15)61170-9
Comment
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Langley RG, Elewski BE, Lebwohl M, et al. Secukinumab in plaque psoriasis—results of two phase 3 trials. N Engl J Med 2014; 371: 326–38. Griffiths CE, Reich K, Lebwohl M, et al, for the UNCOVER-2 UNCOVER-3 investigators. Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. Lancet 2015; published online June 10. http://dx.doi.org/10.1016/S0140-6736(15)60125-8. McInnes IB, Mease PJ, Kirkham B, et al, on behalf of the FUTURE 2 Study Group. Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2015; published online June 29. http://dx.doi.org/10.1016/S0140-6736(15)61134-5. Mease PJ, McInnes IB, Kirkham B, et al. Secukinumab, a human anti-interleukin-17A monoclonal antibody, improves active psoriatic arthritis and inhibits radiographic progression: efficacy and safety data from a phase 3 randomized, multicenter, double-blind, placebo-controlled study. Arthritis Rheum 2014; 66 (suppl): S423 (abstr 923).
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Ritchlin C, Rahman P, Kavanaugh A, et al. Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial. Ann Rheum Dis 2014; 73: 990–99. Coates LC, Moverley AR, McParland L, et al. Results of a randomised controlled trial comparing tight control of early psoriatic arthritis (TICOPA) with standard care: tight control improves outcome. Arthritis Rheum 2013; 65: S346.
www.thelancet.com Published online June 29, 2015 http://dx.doi.org/10.1016/S0140-6736(15)61170-9
3