main topic Wien Med Wochenschr DOI 10.1007/s10354-014-0300-2
Biological agents in psoriatic arthritis Roland Kocijan · Christian Muschitz · Jürgen Rech
Received: 12 June 2014 / Accepted: 6 August 2014 © Springer-Verlag Wien 2014
Summary Anti-tumor necrosis factors (TNFs) are effective drugs for the treatment of psoriatic arthritis (PsA) regarding reduction of pain and inflammation, enthesitis, dactylitis, as well as psoriatic skin and nail disease. Moreover, radiographic progression in PsA is decelerated. The efficacy of anti-TNFs seems to be independent of synthetic disease-modifying anti-rheumatic drugs, suggesting only a minor role of combination therapy in PsA. Anti-TNFs are generally well tolerated in patients with PsA. Adverse events are similar to those reported in patients with rheumatoid arthritis. Ustekinumab, a recently approved IL-12/IL-23-antibody is another promising biological agent in the treatment of PsA. Keywords Psoriatic arthritis · Biological agents · Anti-TNFs
Biologikatherapie bei Psoriasisarthritis Zusammenfassung TNF-Blocker sind effektive Medikamente zur Behandlung der PsA. Dies spiegelt sich in Reduktion von Schmerz, Entzündung, Daktylitis sowie Haut- und Nagelpsoriasis wider. Darüberhinaus wird die radiographische Progression verlangsamt. Die Wirksamkeit der TNF-Blocker scheint unabhängig von syntheti-
R. Kocijan, MD () · C. Muschitz, MD Medical Department II, St. Vincent Hospital, Academic Teaching Hospital of Medical University of Vienna, The VINFORCE Study Group, Stumpergasse 13, 1060 Vienna, Austria e-mail: [email protected] J. Rech, MD Department of Internal Medicine 3 and Institute of Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
13
schen DMARDs zu sein. Die Kombinationstherapie ist daher in der Behandlung der PsA von geringer Bedeutung. Ustekinumab, ein kürzlich zugelassener IL-12/IL23-Antikörper zeigte in bisherigen Studien zufriedenstellende Ergebnisse. Schlüsselwörter Psoriasisarthritis · Biologika · Anti-TNFs Psoriatic arthritis (PsA) is a chronic inflammatory joint disorder leading to bone erosion and joint destruction. PsA is associated with nail disease, dactylitis, enthesitis, spondylitis, and uveitis [1]. Usually skin psoriasis is present many years before the onset of arthritis [2]. The exact pathophysiology of PsA is currently unknown. However, genetic predisposition and environmental factors, including viral and bacterial infections, are suggested to cause PsA [3]. According to the recommendations of the European League Against Rheumatism (EULAR) for the management of PsA, nonsteroidal anti-inflammatory drugs are recommended as first-line therapy in PsA. In patients with active disease, synthetic disease-modifying antirheumatic drugs (DMARDs) should be initiated at an early stage of the disease to prevent joint damage. In addition, local injections of steroids are considered as adjunctive therapy in PsA [4]. Due to the potential risk of psoriasis flare, systemic corticosteroids are not typically recommended for the chronic use in the treatment of psoriasis and are only advisable in discrete circumstances with a low level of evidence (D) [5]. However, methotrexate (MTX), which is known to be a first-line treatment DMARD for rheumatoid arthritis (RA), seems to be less effective in PsA, as shown in previous studies. A Cochrane analysis showed that parenteral high-dose MTX and salazopyrin are the only synthetic DMARDs with well-demonstrated efficacy in the treatment of PsA [6]. MTX, when compared with placebo, suggests that
Biological agents in psoriatic arthritis
1
main topic
low-dose oral MTX does not improve synovitis in active PsA [7]. Therefore, there is currently no sufficient evidence for MTX as standard therapy in PsA [7]. Moreover, synthetic DMARDs such as MTX are known to be insufficient in the treatment of enthesitis and axial disease [4]. Consequently, a treatment with anti-tumor necrosis factor (TNF) alpha should be started, if the patient fails the treatment target low disease activity after 3–6 months of DMARD therapy or if the patient suffers from enthesitis, dactylitis, or predominantly axial disease or very active disease with structural damage, extra-articular manifestations, or extensive skin involvement [4]. The most important EULAR recommendations for biologics in PSA are summarized in Table 1. These are also in accordance with the recommendations of the Austrian Society for Rheumatology (Österreichische Gesellschaft für Rheumatologie, ÖGR), suggesting the initiation of biologics in PsA in case of insufficient response to synthetic DMARDs, including MTX, leflunomid, cyclosporin A, and sulfasalazin. Biologics are indicated for active and radiological progressive PsA (Fig. 1) [8]. According to the treat-to-target concept in RA, the EULAR recommendations for PsA suggest a switch to a second anti-TNF in
case of lack of efficacy. To date, a preference for a special anti-TNF is not recommended [4]. Currently, six biologics (certolizumab, etanercept, adalimumab, infliximab, golimumab, and ustekinumab) are available for the treatment for PsA. Numerous studies potentially demonstrate positive effects for anti-TNFs regarding PsA-associated enthesitis, dactylitis, skin psoriasis, psoriatic nail disease, and inhibition of radiographic progression [5, 9, 10]. Reduced disease activity in patients with PsA receiving anti-TNFs in clinical practice was also reflected by a prospective registry [11]. Moreover, PsA patients treated with anti-TNFs demonstrated less progression of radiographic damage after 1–2 and 3–4 years, respectively, when compared with patients treated with MTX. Consequently, treatment with TNF blockers had a better radiographic outcome compared with treatment with synthetic DMARDs [12]. Later, we discuss adalimumab and certolizumab in detail. Adalimumab is the most prescribed biological DMARD. Certolizumab was recently (2013) approved for PsA by the European Medicines Agency. In a 24-week, randomized, placebo-controlled trial, the efficacy and safety of adalimumab, a human mono-
Table 1 EULAR recommendations for biologics in psoriatic arthritis. (modified by Gossec et al. [4]) 1.
TNF-alpha inhibitors should be commenced in patients with active arthritis and an inadequate response and at least one synthetic DMARD (e.g., MTX)
2.
TNF-alpha inhibitors may be considered in patients with active enthesitis and/or dactylitis and an insufficient response to NSAIDs or local GCs
3.
TNF-alpha inhibitors should be considered in patients with active, mainly axial disease and insufficient response to NSAIDs
4.
TNF-alpha inhibitors may be considered for very active patients (many swollen joints, structural damage, extensive skin involvement and extra articular manifestations), naive for DMARD treatment
TNF tumor necrosis factor, DMARDs disease-modifying anti-rheumatic drugs, MTX methotrexate, NSAIDs nonsteroidal anti-inflammatory drugs, GC glucocorticoids
Fig. 1 High-resolution peripheral quantitative computed tomography (HR-pQCT) scan of the distal radius (a) and the metacarpophalangeal joints (MCPs) (b). Erosive psoriatic arthritis with bone erosion at the radius and MCP 3
2 Biological agents in psoriatic arthritis
13
main topic
clonal antibody against TNF-alpha, was evaluated in patients with PsA. At week 12 and 24, the American College of Rheumatology 20 % response (ACR-20) for the adalimumab group was more than 50 %. Also, significantly better results with respect to ACR-50 and ACR-70 responses were found for adalimumab compared with controls at both time points. Interestingly, no differences were found between response rates in patients receiving adalimumab with and without MTX combination therapy. Moreover, adalimumab treatment inhibited structural damage on radiographs and reduced the extent of skin psoriasis measured by Psoriasis Area and Severity Index (PASI-75). Disability improved significantly among patients treated with TNF inhibitor. Adalimumab was well tolerated in patients with PsA, and the adverse events were comparable to those previously reported in RA [13]. In an open-label extension trial, the efficacy of long-term adalimumab treatment (2 years) in PsA was evaluated. Adalimumab inhibited structural changes throughout 48 weeks and more than 2 years of therapy in patients who received TNF inhibition [14]. Response to ACR-50 and ACR-70 criteria increased slightly after 2 years of adalimumab treatment. Improvements in skin psoriasis were constant in week 48 and after 2 years. No additional safety concerns were reported for patients with PsA receiving adalimumab for 2 years [15]. Certolizumab pegol, a PEGylated FC-free anti-TNF, was also evaluated for the treatment of PsA in the “RAPIDPsA study.” In this double-blind, placebo-controlled phase 3 trial, the primary end point was the treatment response ACR-20 after 12 weeks of therapy. Significantly, patients receiving certolizumab more often achieved the primary end point when compared with controls. Significant differences were found after 1 week (ACR-20) and 4 weeks (ACR-50 and ACR-70), respectively, and continued to week 24. Moreover, PASI improved significantly after week 24, and approximately 60 % of patients reached PASI-75 response. Concomitant DMARD use and prior anti-TNF exposure did not influence response to certolizumab [16]. Interestingly, comparing the anti-TNFs approved in PsA (adalimumab, etanercept, infliximab, and golimumab; certolizumab not included in this analysis) in patients with PsA did not show significant differences in ACR-50 response after 24 weeks of treatment [17]. Moreover, the treatment recommendations for PsA suggest that anti-TNFs (etanercept, infliximab, and adalimumab—certolizumab and golimumab not included in this analysis) are equally effective for the treatment of peripheral arthritis, the inhibition of radiographic progression, and the improvement of skin disease (level of evidence A) [5]. Adverse effects of anti-TNFs, in general, are an increased risk of infections, including reactivation of tuberculosis, anemia, and skin reactions at the injection site. Moreover, a slightly increased risk for lymphoma was discussed. Ustekinumab, a new IL-12/IL-23-antibody approved for the treatment of plaque psoriasis and PsA, showed
13
promising data regarding reduction of joint diseases activity as well as improvement of quality of life in patients with PsA [18]. Additionally, in a recently published multicenter, randomized, double-blind, and placebo-controlled phase 3 trial (PSUMMIT I und PSUMMIT II), ustekinumab therapy demonstrated significantly less radiographic progression of joint damage in patients with active PsA [19].
Future perspectives Apremilast, an oral phosphodiesterase-4 inhibitor, showed significant improvements in disease activity, skin psoriasis, and physical function as well as an acceptable safety profile in a placebo-controlled trial on patients with PsA [20]. Apremilast is approved in the USA, and the application for approval has been submitted for Europe. A novel concept in the treatment of PsA is secukinumab, a fully human, anti-interleukin IL-17A monoclonal antibody, suggesting some clinical benefits, including quality-of-life improvements. However, larger clinical trials of secukinumab in PsA are needed to evaluate the safety and efficacy of IL-17A inhibitor [21]. Abatacept, a selective T-cell costimulation modulator well established for the therapy of RA, may be an effective therapy option also for PsA, as reported in a phase 2 trial [22]. The efficacy and safety of subcutaneous abatacept in PsA are currently under research in a phase 3 randomized, placebo-controlled study (ASTRAEA) [23]. Conflict of interest The authors state no conflict of interest.
References 1. Veale DJ. Psoriatic arthritis: recent progress in pathophysiology and drug development. Arthritis Res Ther. 2013;15:224. 2. Cassell S, Kavanaugh A. Psoriatic arthritis: pathogenesis and novel immunomodulatory approaches to treatment. J Immune Based Ther Vaccines. 2005;3:6. 3. Vasey FB. Etiology and pathogenesis of psoriatic arthritis. In: Gerber LH, Espinoza LR, editors. Psoriatic arthritis. Orlando: Grune & Stratton; 1985. pp. 45–57. 4. Gossec L, Smolen JS, Gaujoux-Viala C, et al. European League Against Rheumatism recommendations for the management of psoriatic arthritis with pharmacological therapies. Ann Rheum Dis. 2012;71:4–12. 5. Ritchlin CT, Kavanaugh A, Gladman DD, et al. Treatment recommendations for psoriatic arthritis. Ann Rheum Dis. 2009;68:1387–94. 6. Jones G, Crotty M, Brooks P. Interventions for psoriatic arthritis. Cochrane Database Syst Rev. 2000;(3):CD000212. 7. Kingsley GH, Kowalczyk A, Taylor H, et al. A randomized placebo-controlled trial of methotrexate in psoriatic arthritis. Rheumatology (Oxford). 2012;51:1368–77. 8. http://www.Rheuma2000.at. 9. Mease PJ, Goffe BS, Metz J, et al. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet. 2000;356:385–90.
Biological agents in psoriatic arthritis
3
main topic 10. Kavanaugh A, McInnes I, Mease P, et al. Golimumab, a new human tumor necrosis factor alpha antibody, administered every four weeks as a subcutaneous injection in psoriatic arthritis: twenty-four-week efficacy and safety results of a randomized, placebo-controlled study. Arthritis Rheum. 2009;60:976–86. 11. Glintborg B, Østergaard M, Dreyer L, et al. Treatment response, drug survival, and predictors thereof in 764 patients with psoriatic arthritis treated with anti-tumor necrosis factor α therapy: results from the nationwide Danish DANBIO registry. Arthritis Rheum. 2011;63:382–90. 12. Eder L, Thavaneswaran A, Chandran V, et al. Tumour necrosis factor α blockers are more effective than methotrexate in the inhibition of radiographic joint damage progression among patients with psoriatic arthritis. Ann Rheum Dis. 2014;73:1007–11. 13. Mease PJ, Gladman DD, Ritchlin CT, et al. Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: results of a double-blind, randomized, placebo-controlled trial. Arthritis Rheum. 2005;52:3279–89. 14. Gladman DD, Mease PJ, Ritchlin CT, et al. Adalimumab for long-term treatment of psoriatic arthritis: forty-eight week data from the adalimumab effectiveness in psoriatic arthritis trial. Arthritis Rheum. 2007;56:476–88. 15. Mease PJ, Ory P, Sharp JT, et al. Adalimumab for long-term treatment of psoriatic arthritis: 2-year data from the Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT). Ann Rheum Dis. 2009;68:702–9. 16. Mease PJ, Fleischmann R, Deodhar AA, et al. Effect of certolizumab pegol on signs and symptoms in patients with psoriatic arthritis: 24-week results of a Phase 3 doubleblind randomised placebo-controlled study (RAPID-PsA). Ann Rheum Dis. 2014;73:48–55.
4 Biological agents in psoriatic arthritis
17. Fénix-Caballero S, Alegre-del Rey EJ, Castaño-Lara R, et al. Direct and indirect comparison of the efficacy and safety of adalimumab, etanercept, infliximab and golimumab in psoriatic arthritis. J Clin Pharm Ther. 2013;38:286–93. 18. Gottlieb A, Narang K. Ustekinumab in the treatment of psoriatic arthritis: latest findings and clinical potential. Ther Adv Musculoskelet Dis. 2013;5:277–85. 19. Kavanaugh A, Ritchlin C, Rahman P, et al. Ustekinumab, an anti-IL-12/23 p40 monoclonal antibody, inhibits radiographic progression in patients with active psoriatic arthritis: results of an integrated analysis of radiographic data from the phase 3, multicentre, randomised, double-blind, placebo-controlled PSUMMIT-1 and PSUMMIT-2 trials. Ann Rheum Dis. 2014;73:1000–6. 20. Kavanaugh A, Mease PJ, Gomez-Reino JJ, et al. Treatment of psoriatic arthritis in a phase 3 randomised, placebocontrolled trial with apremilast, an oral phosphodiesterase 4 inhibitor. Ann Rheum Dis. 2014;73:1020–6. 21. McInnes IB, Sieper J, Braun J, et al. Efficacy and safety of secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe psoriatic arthritis: a 24-week, randomised, double-blind, placebo-controlled, phase II proof-of-concept trial. Ann Rheum Dis. 2014;73:349–56. 22. Mease P, Genovese MC, Gladstein G, et al. Abatacept in the treatment of patients with psoriatic arthritis: results of a sixmonth, multicenter, randomized, double-blind, placebocontrolled, phase II trial. Arthritis Rheum. 2011;63:939–48. 23. http://clinicaltrials.gov/show/NCT01860976.
13
Biological agents in psoriatic arthritis Roland Kocijan · Christian Muschitz · Jürgen Rech
Received: 12 June 2014 / Accepted: 6 August 2014 © Springer-Verlag Wien 2014
Summary Anti-tumor necrosis factors (TNFs) are effective drugs for the treatment of psoriatic arthritis (PsA) regarding reduction of pain and inflammation, enthesitis, dactylitis, as well as psoriatic skin and nail disease. Moreover, radiographic progression in PsA is decelerated. The efficacy of anti-TNFs seems to be independent of synthetic disease-modifying anti-rheumatic drugs, suggesting only a minor role of combination therapy in PsA. Anti-TNFs are generally well tolerated in patients with PsA. Adverse events are similar to those reported in patients with rheumatoid arthritis. Ustekinumab, a recently approved IL-12/IL-23-antibody is another promising biological agent in the treatment of PsA. Keywords Psoriatic arthritis · Biological agents · Anti-TNFs
Biologikatherapie bei Psoriasisarthritis Zusammenfassung TNF-Blocker sind effektive Medikamente zur Behandlung der PsA. Dies spiegelt sich in Reduktion von Schmerz, Entzündung, Daktylitis sowie Haut- und Nagelpsoriasis wider. Darüberhinaus wird die radiographische Progression verlangsamt. Die Wirksamkeit der TNF-Blocker scheint unabhängig von syntheti-
R. Kocijan, MD () · C. Muschitz, MD Medical Department II, St. Vincent Hospital, Academic Teaching Hospital of Medical University of Vienna, The VINFORCE Study Group, Stumpergasse 13, 1060 Vienna, Austria e-mail: [email protected] J. Rech, MD Department of Internal Medicine 3 and Institute of Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
13
schen DMARDs zu sein. Die Kombinationstherapie ist daher in der Behandlung der PsA von geringer Bedeutung. Ustekinumab, ein kürzlich zugelassener IL-12/IL23-Antikörper zeigte in bisherigen Studien zufriedenstellende Ergebnisse. Schlüsselwörter Psoriasisarthritis · Biologika · Anti-TNFs Psoriatic arthritis (PsA) is a chronic inflammatory joint disorder leading to bone erosion and joint destruction. PsA is associated with nail disease, dactylitis, enthesitis, spondylitis, and uveitis [1]. Usually skin psoriasis is present many years before the onset of arthritis [2]. The exact pathophysiology of PsA is currently unknown. However, genetic predisposition and environmental factors, including viral and bacterial infections, are suggested to cause PsA [3]. According to the recommendations of the European League Against Rheumatism (EULAR) for the management of PsA, nonsteroidal anti-inflammatory drugs are recommended as first-line therapy in PsA. In patients with active disease, synthetic disease-modifying antirheumatic drugs (DMARDs) should be initiated at an early stage of the disease to prevent joint damage. In addition, local injections of steroids are considered as adjunctive therapy in PsA [4]. Due to the potential risk of psoriasis flare, systemic corticosteroids are not typically recommended for the chronic use in the treatment of psoriasis and are only advisable in discrete circumstances with a low level of evidence (D) [5]. However, methotrexate (MTX), which is known to be a first-line treatment DMARD for rheumatoid arthritis (RA), seems to be less effective in PsA, as shown in previous studies. A Cochrane analysis showed that parenteral high-dose MTX and salazopyrin are the only synthetic DMARDs with well-demonstrated efficacy in the treatment of PsA [6]. MTX, when compared with placebo, suggests that
Biological agents in psoriatic arthritis
1
main topic
low-dose oral MTX does not improve synovitis in active PsA [7]. Therefore, there is currently no sufficient evidence for MTX as standard therapy in PsA [7]. Moreover, synthetic DMARDs such as MTX are known to be insufficient in the treatment of enthesitis and axial disease [4]. Consequently, a treatment with anti-tumor necrosis factor (TNF) alpha should be started, if the patient fails the treatment target low disease activity after 3–6 months of DMARD therapy or if the patient suffers from enthesitis, dactylitis, or predominantly axial disease or very active disease with structural damage, extra-articular manifestations, or extensive skin involvement [4]. The most important EULAR recommendations for biologics in PSA are summarized in Table 1. These are also in accordance with the recommendations of the Austrian Society for Rheumatology (Österreichische Gesellschaft für Rheumatologie, ÖGR), suggesting the initiation of biologics in PsA in case of insufficient response to synthetic DMARDs, including MTX, leflunomid, cyclosporin A, and sulfasalazin. Biologics are indicated for active and radiological progressive PsA (Fig. 1) [8]. According to the treat-to-target concept in RA, the EULAR recommendations for PsA suggest a switch to a second anti-TNF in
case of lack of efficacy. To date, a preference for a special anti-TNF is not recommended [4]. Currently, six biologics (certolizumab, etanercept, adalimumab, infliximab, golimumab, and ustekinumab) are available for the treatment for PsA. Numerous studies potentially demonstrate positive effects for anti-TNFs regarding PsA-associated enthesitis, dactylitis, skin psoriasis, psoriatic nail disease, and inhibition of radiographic progression [5, 9, 10]. Reduced disease activity in patients with PsA receiving anti-TNFs in clinical practice was also reflected by a prospective registry [11]. Moreover, PsA patients treated with anti-TNFs demonstrated less progression of radiographic damage after 1–2 and 3–4 years, respectively, when compared with patients treated with MTX. Consequently, treatment with TNF blockers had a better radiographic outcome compared with treatment with synthetic DMARDs [12]. Later, we discuss adalimumab and certolizumab in detail. Adalimumab is the most prescribed biological DMARD. Certolizumab was recently (2013) approved for PsA by the European Medicines Agency. In a 24-week, randomized, placebo-controlled trial, the efficacy and safety of adalimumab, a human mono-
Table 1 EULAR recommendations for biologics in psoriatic arthritis. (modified by Gossec et al. [4]) 1.
TNF-alpha inhibitors should be commenced in patients with active arthritis and an inadequate response and at least one synthetic DMARD (e.g., MTX)
2.
TNF-alpha inhibitors may be considered in patients with active enthesitis and/or dactylitis and an insufficient response to NSAIDs or local GCs
3.
TNF-alpha inhibitors should be considered in patients with active, mainly axial disease and insufficient response to NSAIDs
4.
TNF-alpha inhibitors may be considered for very active patients (many swollen joints, structural damage, extensive skin involvement and extra articular manifestations), naive for DMARD treatment
TNF tumor necrosis factor, DMARDs disease-modifying anti-rheumatic drugs, MTX methotrexate, NSAIDs nonsteroidal anti-inflammatory drugs, GC glucocorticoids
Fig. 1 High-resolution peripheral quantitative computed tomography (HR-pQCT) scan of the distal radius (a) and the metacarpophalangeal joints (MCPs) (b). Erosive psoriatic arthritis with bone erosion at the radius and MCP 3
2 Biological agents in psoriatic arthritis
13
main topic
clonal antibody against TNF-alpha, was evaluated in patients with PsA. At week 12 and 24, the American College of Rheumatology 20 % response (ACR-20) for the adalimumab group was more than 50 %. Also, significantly better results with respect to ACR-50 and ACR-70 responses were found for adalimumab compared with controls at both time points. Interestingly, no differences were found between response rates in patients receiving adalimumab with and without MTX combination therapy. Moreover, adalimumab treatment inhibited structural damage on radiographs and reduced the extent of skin psoriasis measured by Psoriasis Area and Severity Index (PASI-75). Disability improved significantly among patients treated with TNF inhibitor. Adalimumab was well tolerated in patients with PsA, and the adverse events were comparable to those previously reported in RA [13]. In an open-label extension trial, the efficacy of long-term adalimumab treatment (2 years) in PsA was evaluated. Adalimumab inhibited structural changes throughout 48 weeks and more than 2 years of therapy in patients who received TNF inhibition [14]. Response to ACR-50 and ACR-70 criteria increased slightly after 2 years of adalimumab treatment. Improvements in skin psoriasis were constant in week 48 and after 2 years. No additional safety concerns were reported for patients with PsA receiving adalimumab for 2 years [15]. Certolizumab pegol, a PEGylated FC-free anti-TNF, was also evaluated for the treatment of PsA in the “RAPIDPsA study.” In this double-blind, placebo-controlled phase 3 trial, the primary end point was the treatment response ACR-20 after 12 weeks of therapy. Significantly, patients receiving certolizumab more often achieved the primary end point when compared with controls. Significant differences were found after 1 week (ACR-20) and 4 weeks (ACR-50 and ACR-70), respectively, and continued to week 24. Moreover, PASI improved significantly after week 24, and approximately 60 % of patients reached PASI-75 response. Concomitant DMARD use and prior anti-TNF exposure did not influence response to certolizumab [16]. Interestingly, comparing the anti-TNFs approved in PsA (adalimumab, etanercept, infliximab, and golimumab; certolizumab not included in this analysis) in patients with PsA did not show significant differences in ACR-50 response after 24 weeks of treatment [17]. Moreover, the treatment recommendations for PsA suggest that anti-TNFs (etanercept, infliximab, and adalimumab—certolizumab and golimumab not included in this analysis) are equally effective for the treatment of peripheral arthritis, the inhibition of radiographic progression, and the improvement of skin disease (level of evidence A) [5]. Adverse effects of anti-TNFs, in general, are an increased risk of infections, including reactivation of tuberculosis, anemia, and skin reactions at the injection site. Moreover, a slightly increased risk for lymphoma was discussed. Ustekinumab, a new IL-12/IL-23-antibody approved for the treatment of plaque psoriasis and PsA, showed
13
promising data regarding reduction of joint diseases activity as well as improvement of quality of life in patients with PsA [18]. Additionally, in a recently published multicenter, randomized, double-blind, and placebo-controlled phase 3 trial (PSUMMIT I und PSUMMIT II), ustekinumab therapy demonstrated significantly less radiographic progression of joint damage in patients with active PsA [19].
Future perspectives Apremilast, an oral phosphodiesterase-4 inhibitor, showed significant improvements in disease activity, skin psoriasis, and physical function as well as an acceptable safety profile in a placebo-controlled trial on patients with PsA [20]. Apremilast is approved in the USA, and the application for approval has been submitted for Europe. A novel concept in the treatment of PsA is secukinumab, a fully human, anti-interleukin IL-17A monoclonal antibody, suggesting some clinical benefits, including quality-of-life improvements. However, larger clinical trials of secukinumab in PsA are needed to evaluate the safety and efficacy of IL-17A inhibitor [21]. Abatacept, a selective T-cell costimulation modulator well established for the therapy of RA, may be an effective therapy option also for PsA, as reported in a phase 2 trial [22]. The efficacy and safety of subcutaneous abatacept in PsA are currently under research in a phase 3 randomized, placebo-controlled study (ASTRAEA) [23]. Conflict of interest The authors state no conflict of interest.
References 1. Veale DJ. Psoriatic arthritis: recent progress in pathophysiology and drug development. Arthritis Res Ther. 2013;15:224. 2. Cassell S, Kavanaugh A. Psoriatic arthritis: pathogenesis and novel immunomodulatory approaches to treatment. J Immune Based Ther Vaccines. 2005;3:6. 3. Vasey FB. Etiology and pathogenesis of psoriatic arthritis. In: Gerber LH, Espinoza LR, editors. Psoriatic arthritis. Orlando: Grune & Stratton; 1985. pp. 45–57. 4. Gossec L, Smolen JS, Gaujoux-Viala C, et al. European League Against Rheumatism recommendations for the management of psoriatic arthritis with pharmacological therapies. Ann Rheum Dis. 2012;71:4–12. 5. Ritchlin CT, Kavanaugh A, Gladman DD, et al. Treatment recommendations for psoriatic arthritis. Ann Rheum Dis. 2009;68:1387–94. 6. Jones G, Crotty M, Brooks P. Interventions for psoriatic arthritis. Cochrane Database Syst Rev. 2000;(3):CD000212. 7. Kingsley GH, Kowalczyk A, Taylor H, et al. A randomized placebo-controlled trial of methotrexate in psoriatic arthritis. Rheumatology (Oxford). 2012;51:1368–77. 8. http://www.Rheuma2000.at. 9. Mease PJ, Goffe BS, Metz J, et al. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet. 2000;356:385–90.
Biological agents in psoriatic arthritis
3
main topic 10. Kavanaugh A, McInnes I, Mease P, et al. Golimumab, a new human tumor necrosis factor alpha antibody, administered every four weeks as a subcutaneous injection in psoriatic arthritis: twenty-four-week efficacy and safety results of a randomized, placebo-controlled study. Arthritis Rheum. 2009;60:976–86. 11. Glintborg B, Østergaard M, Dreyer L, et al. Treatment response, drug survival, and predictors thereof in 764 patients with psoriatic arthritis treated with anti-tumor necrosis factor α therapy: results from the nationwide Danish DANBIO registry. Arthritis Rheum. 2011;63:382–90. 12. Eder L, Thavaneswaran A, Chandran V, et al. Tumour necrosis factor α blockers are more effective than methotrexate in the inhibition of radiographic joint damage progression among patients with psoriatic arthritis. Ann Rheum Dis. 2014;73:1007–11. 13. Mease PJ, Gladman DD, Ritchlin CT, et al. Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: results of a double-blind, randomized, placebo-controlled trial. Arthritis Rheum. 2005;52:3279–89. 14. Gladman DD, Mease PJ, Ritchlin CT, et al. Adalimumab for long-term treatment of psoriatic arthritis: forty-eight week data from the adalimumab effectiveness in psoriatic arthritis trial. Arthritis Rheum. 2007;56:476–88. 15. Mease PJ, Ory P, Sharp JT, et al. Adalimumab for long-term treatment of psoriatic arthritis: 2-year data from the Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT). Ann Rheum Dis. 2009;68:702–9. 16. Mease PJ, Fleischmann R, Deodhar AA, et al. Effect of certolizumab pegol on signs and symptoms in patients with psoriatic arthritis: 24-week results of a Phase 3 doubleblind randomised placebo-controlled study (RAPID-PsA). Ann Rheum Dis. 2014;73:48–55.
4 Biological agents in psoriatic arthritis
17. Fénix-Caballero S, Alegre-del Rey EJ, Castaño-Lara R, et al. Direct and indirect comparison of the efficacy and safety of adalimumab, etanercept, infliximab and golimumab in psoriatic arthritis. J Clin Pharm Ther. 2013;38:286–93. 18. Gottlieb A, Narang K. Ustekinumab in the treatment of psoriatic arthritis: latest findings and clinical potential. Ther Adv Musculoskelet Dis. 2013;5:277–85. 19. Kavanaugh A, Ritchlin C, Rahman P, et al. Ustekinumab, an anti-IL-12/23 p40 monoclonal antibody, inhibits radiographic progression in patients with active psoriatic arthritis: results of an integrated analysis of radiographic data from the phase 3, multicentre, randomised, double-blind, placebo-controlled PSUMMIT-1 and PSUMMIT-2 trials. Ann Rheum Dis. 2014;73:1000–6. 20. Kavanaugh A, Mease PJ, Gomez-Reino JJ, et al. Treatment of psoriatic arthritis in a phase 3 randomised, placebocontrolled trial with apremilast, an oral phosphodiesterase 4 inhibitor. Ann Rheum Dis. 2014;73:1020–6. 21. McInnes IB, Sieper J, Braun J, et al. Efficacy and safety of secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe psoriatic arthritis: a 24-week, randomised, double-blind, placebo-controlled, phase II proof-of-concept trial. Ann Rheum Dis. 2014;73:349–56. 22. Mease P, Genovese MC, Gladstein G, et al. Abatacept in the treatment of patients with psoriatic arthritis: results of a sixmonth, multicenter, randomized, double-blind, placebocontrolled, phase II trial. Arthritis Rheum. 2011;63:939–48. 23. http://clinicaltrials.gov/show/NCT01860976.
13
