Horizon Scanning Centre January Apremilast for psoriatic arthritis SUMMARY NIHR HSC ID: 3716

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1 Horizon Scanning Centre January 2013 Apremilast for psoriatic arthritis SUMMARY NIHR HSC ID: 3716 This briefing is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes or commissioning without additional information. Apremilast is intended to be used for the treatment of psoriatic arthritis (PsA). If licensed, apremilast will become the first available phosphodiesterase 4 (PDE-4) inhibitor for the treatment of PsA and may provide an additional treatment option for this patient group. Apremilast is an oral small-molecule inhibitor of PDE4. PDE4 inhibition elevates intracellular cyclic adenosine monophosphate levels, which in turn down-regulates the inflammatory response by modulating the expression of inflammatory cytokines such as tumour necrosis factor-α (TNF-α) and interleukin-23 (IL-23), and antiinflammatory cytokines such as IL-10; pro-inflammatory and antiinflammatory mediators implicated in psoriasis and PsA. The prevalence of psoriasis in the UK population is estimated at between 1.5-3%. The prevalence of inflammatory arthritis in people with psoriasis is estimated at 30%, with a prevalence of 50% recorded in some population studies. It is estimated that there are 60,353 people in England with PsA; however experts estimate that the true population prevalence of PsA maybe up to 1%. PsA can significantly affect the ability to work and to carry out daily tasks, and can have a substantial impact on quality of life; work disability and unemployment are high in those with PsA. People with PsA have a 60% higher risk of mortality and their life expectancy is estimated to be reduced by approximately 3 years. Guidelines recommend treatment of PsA with one or two conventional disease-modifying anti-rheumatic drugs (DMARDS) before proceeding to TNF inhibitors. Other treatment options include analgesics, corticosteroids and non-steroidal anti-inflammatory drugs. Apremilast is currently in phase III clinical trials comparing its effect on reducing arthritis against treatment with placebo. The first trial is expected to complete in September This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health. NIHR Horizon Scanning Centre, University of Birmingham nihrhsc@contacts.bham.ac.uk Web:

2 TARGET GROUP Psoriatic arthritis (PsA): active patients with inadequate response, contraindication, or intolerance to disease-modifying anti-rheumatic drugs (DMARDs) and/or tumour necrosis factor (TNF) inhibitor. TECHNOLOGY DESCRIPTION Apremilast (CC 10004) is an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4). PDE4 inhibition elevates intracellular cyclic adenosine monophosphate levels, which in turn down-regulates the inflammatory response by modulating the expression of inflammatory cytokines such as TNF-α and interleukin-23 (IL-23), and increases anti-inflammatory cytokines such as IL-10; proinflammatory and anti-inflammatory mediators implicated in psoriasis and PsA 1. Apremilast is intended for the treatment of PsA with inadequate response, contraindication, or intolerance to DMARDs and/or TNF inhibitors. It is administered orally at 20mg or 30mg twice daily. Apremilast is in phase III clinical trials for ankylosing spondylitis and psoriasis. It is also in phase II clinical trials for rheumatoid arthritis and Behcet's syndrome. INNOVATION and/or ADVANTAGES If licensed, apremilast will become the first available PDE-4 inhibitor for the treatment of PsA and may provide an additional treatment option for this patient group. DEVELOPER Celgene. AVAILABILITY, LAUNCH OR MARKETING In phase III clinical trials. PATIENT GROUP BACKGROUND PsA is a chronic inflammatory joint disease associated with psoriasis of the skin or nails. The diagnosis of PsA tends to occur within 10 years of diagnosis with psoriasis and leads to stiffness, pain, swelling and tenderness of the joints and surrounding ligaments and tendons 2. The most commonly affected areas include the small joints of the hands and feet, but it may also involve other larger joints such as hips, knees and spine 3. PsA has a chronic relapsing course, characterised by flares and remissions, which may be life-long 4. Although the cause of psoriasis and its associated arthritis is not fully understood, evidence suggests that it is a T-cell mediated disease, most likely auto-immune in origin, with a strong genetic component 5. 2

3 NHS or GOVERNMENT PRIORITY AREA This topic is relevant to: The Musculoskeletal Services Framework (2006). CLINICAL NEED and BURDEN OF DISEASE The prevalence of psoriasis in the UK population is estimated at between 1.5-3% 1,2. The prevalence of inflammatory arthritis in people with psoriasis is estimated at 30% 1, with a prevalence of 50% recorded in some population studies 6. It is estimated that there are 60,353 people in England with PsA 7 ; however experts estimate that the true population prevalence of PsA maybe up to 1% a. An estimated 5-10% of people with psoriasis and 25-40% of people with PsA have severe arthritis with progressive joint lesions 8. PsA has an equal gender distribution and characteristically develops in those aged years. A review of the experience of PsA patients treated with DMARDs reported that over 70% of patients discontinued due to a lack of efficacy or adverse events (from 35% with methotrexate to 94% with hydroxychloroqine) 9. Approximately 2.4% of people with PsA are potentially eligible to receive treatment with biologics 7 ; however approximately 25% of patients discontinue their first anti-tnf treatment within the first year (9.5% discontinue due to inefficacy and 10.0% due to adverse events) 10, and 30% of patients do not respond to anti-tnf treatment b. Structural joint damage has been shown radiologically in up to 47% of people with PsA at a median interval of 2 years from disease onset 11. PsA can significantly affect the ability to work and to carry out daily tasks, and can have a substantial impact on quality of life; work disability and unemployment are high in those with PsA 1,12. Health-related quality of life measures and physical function are similar to rheumatoid arthritis 13. Direct health costs for PsA are considerable and correlate with impaired physical function 14. Several comorbid conditions are also associated with PsA, including psychological and cardiovascular diseases, and their management has a major impact on the economic burden associated with PsA 5. People with PsA have a 60% higher risk of mortality 1 and their life expectancy is estimated to be reduced by approximately 3 years 15. In , there were 6,805 hospital admissions for PsA (ICD10 L40.5) in England and Wales, resulting in 4,582 bed days and 6,948 finished consultant episodes 16. PATIENT PATHWAY RELEVANT GUIDANCE NICE Guidance NICE technology appraisal. Golimumab for the treatment of psoriatic arthritis (TA220). April NICE technology appraisal. Etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis (TA199). August Other Guidance European League Against Rheumatism. European League Against Rheumatism recommendations for the management of psoriatic arthritis with pharmacological therapies a Expert personal communication. b Expert personal communication. 3

4 Scottish Intercollegiate Guidelines Network. Diagnosis and management of psoriasis and psoriatic arthritis in adults Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. Treatment recommendations for psoriatic arthritis British Society of Rheumatology. Guideline for anti-tnf-a therapy in psoriatic arthritis EXISTING COMPARATORS and TREATMENTS The clinical management of PsA aims to suppress joint, tendon and entheseal inflammation 4, and reduce functional limitations and joint damage. Treatments include a range of physical therapy and pharmacological treatments. Guidelines recommend treatment with 1 or 2 conventional DMARDS before proceeding to TNF inhibitors 18,20. Treatment options include 1,3,17 : Non-biologic therapies Analgesics. Corticosteroids limited role in PsA 5. Non-steroidal anti-inflammatory drugs (NSAIDs). DMARDs, including methotrexate (MTX) 21,6, sulfasalazine, leflunomide, gold salts (very rarely used), and anti-malarials (very rarely used). Usually administered within three months of diagnosis to stabilise joint function, either as monotherapy or in combination with biologic agents. Biologic therapies TNF-α inhibitors such as etanercept, infliximab, adalimumab and golimumab. EFFICACY and SAFETY Trial Sponsor Status Source of information Location Design Participants Schedule Follow-up Primary outcome PALACE-1, NCT , CC PSA-002; apremilast vs placebo; phase III. Celgene Corporation. Ongoing. Abstract 22, trial registry 23, manufacturer. EU (incl UK), USA, Canada and other countries. Randomised, placebo-controlled. n=504; aged 18 years; PsA; 3 swollen and 3 tender joints; inadequately treated by DMARDs; therapeutic failure on <3 agents for PsA or 1 TNF inhibitor; concurrent treatment with MTX, leflunomide, or sulfasalazine allowed; stable dose of NSAIDs, opiates and low dose oral corticosteroids allowed. Randomised to apremilast 20mg, 30mg or placebo, orally twice daily for 24 weeks. Patients on placebo who do not have at least 20% improvement in swollen and tender joint counts at week 16 cross over to apremilast 20mg or 30mg. Active treatment for up to 4.5 years; follow-up of 4 weeks for safety and efficacy. ACR 20 c at week 16. c ACR: American College of Rheumatology criteria comprises a core set of six outcome variables for the assessment of clinically important improvement: tender joint count, swollen joint count, patient and physician global assessments, pain, disability, and an acute-phase reactant (erythrocyte sedimentation rate [ESR] or C-reactive protein level [CRP]). ACR 20 represents 20% improvement in tender and swollen joint counts and 20% improvement in 3 of the 5 remaining ACR core set measures. 4

5 Secondary outcomes Key results Adverse effects (AEs) Expected reporting date Adverse effects (AEs), HAQ-DI d, physical function domain score of SF-36 e, PsARC f, VAS g, MASES h, dactylitis severity score, CDAI i, DAS28 j, FACIT-Fatigue k, EULAR l response, ACR 50, ACR 70, plasma biomarkers. For apremilast 20mg, 30mg and placebo respectively (p value vs placebo): Primary endpoint, ACR 20 at week 16: All subjects (n=504), 31.3% (p<0.05), 41.0% (p<0.0001) and 19.4%; apremilast alone subset (n=172), 31.5% (p<0.05), 50.8% (p<0.0001) and 10.5%; apremilast with DMARDS subset (n=317), 31.2% (NS m ), 35.0% (NS) and 24.1%; biologic naïve subset (n=363), 31.2% (NS), 43.3% (p<0.05) and 23.7%; biologic naïve, apremilast alone subset (n=89), 24.1% (NS), 58.8% (p<0.05) and 11.5%; biologic naïve, apremilast with DMARDS subset (n=274), 33.3% (NS), 37.2 (NS) and 27.2%. Secondary endpoints: ACR 50, 15.3% (p<0.05), 19.9% (p<0.0001) and 4.2%; ACR 70, 5.5% (p<0.05), 11.2% (p<0.0001) and 0.6%; mean HAQ-DI change, (p<0.05), (p<0.05) and ; mean DAS-28 change, 0.66 (p<0.05), 0.91 (p<0.0001) and 0.20; good or moderate EULAR response, 45.4% (p<0.05), 51.6% (p<0.0001) and 29.1%; mean SF- 36 physical function change, 3.50 (p<0.05), 5.06 (p<0.0001) and For apremilast 20mg, 30mg and placebo respectively, AEs in 5% of treatment group: diarrhoea, 11.3%,19.0% and 2.4%; nausea, 9.5%, 18.5% and 6.5%; headache, 10.1%, 10.7% and 4.8%; and upper respiratory tract infection, 6.0%, 4.2% and 3.6%. Serious AEs, 8, 9 and 7 subjects. Study completion date reported as Sept Trial PALACE-2, NCT , CC PSA-003, ; apremilast vs placebo; phase III. PALACE-3, NCT , CC PSA-004, ; apremilast vs placebo; phase III. PALACE-4, NCT , CC PSA-005, ; apremilast vs placebo; phase III. Sponsor Celgene Corporation. Celgene Corporation. Celgene Corporation. Status Ongoing. Ongoing. Ongoing. Source of information Trial registry 24, manufacturer. Trial registry 25, manufacturer. Trial registry 26, manufacturer. Location EU (incl UK), USA, Canada, Russia, South Africa and Taiwan. EU (incl UK), USA, Canada, Australia, Korea and Russia. EU (incl UK), USA, Canada, Australia and Russia. Design Randomised, placebocontrolled. Randomised, placebocontrolled. Randomised, placebocontrolled. d HAQ-DI: Health Assessment Questionnaire for Rheumatoid Arthritis. e SF-36: Short Form 36-Item Health Survey. f PsARC: Psoriatic arthritis response criteria (based on measures of tender and swollen joint counts, and physician's and patient s global assessment of disease activity). g VAS: Visual analog scale for pain. h MASES: Maastricht Ankylosing Spondylitis Entheses Score. i CDAI : Clinical Disease Activity Index. j DAS28: Disease Activity Score is a measure of disease activity in rheumatoid arthritis and assesses the number of tender and swollen joints (out of the 28 commonly affected), the ESR or CRP, and the patient s global assessment of health'. k FACIT-Fatigue: Functional Assessment of Chronic Illness Therapy-Fatigue. l EULAR response: European League Against Rheumatism Response criteria. m NS: Not statistically significant. 5

6 Participants Schedule Follow-up Primary outcome Secondary outcomes Expected reporting date Trial Sponsor Status Source of information Location Design Participants n=495 (planned); aged 18 years; PsA; 3 swollen and 3 tender joints; inadequately treated by DMARDs; therapeutic failure on <3 agents for PsA or 1 TNF inhibitor; concurrent treatment with MTX, leflunomide, or sulfasalazine allowed; stable dose of NSAIDs, opiates and low dose oral corticosteroids allowed. Randomised to apremilast 20mg, 30mg, or placebo, orally twice daily for 24 weeks. Patients on placebo who do not have at least 20% improvement in swollen and tender joint counts at week 16 cross over to apremilast 20mg or 30mg. Active treatment for up to 4.5 years; follow-up period of 4 weeks for safety and efficacy. n=495 (planned); aged 18 years; PsA; 3 swollen and 3 tender joints; at least one 2cm psoriasis lesion; inadequately treated by DMARDs; therapeutic failure on <3 agents for PsA or 1 TNF inhibitor; concurrent treatment with MTX, leflunomide, or sulfasalazine allowed; stable dose of NSAIDs, opiates and low dose oral corticosteroids allowed. Randomised to apremilast 20mg, 30mg, or placebo, orally twice daily for 24 weeks. Patients on placebo who do not have at least 20% improvement in swollen and tender joint counts at week 16 cross over to apremilast 20mg or 30mg. Active treatment for up to 4.5 years; follow-up period of 4 weeks for safety and efficacy. n=495 (planned); aged 18 years; PsA; 3 swollen and 3 tender joints; at least one 2cm psoriasis lesion; no prior treatment with DMARDs; no prior treatment with MTX, leflunomide, or sulfasalazine; stable dose of NSAIDs, opiates and oral corticosteroids allowed. Randomised to apremilast 20mg, 30mg, or placebo, twice daily. Patients on placebo who do not have at least 20% improvement in swollen and tender joint counts at week 16 cross over to apremilast 20mg or 30mg. Active treatment for up to 5 years; follow-up period of 4 weeks for safety and efficacy. ACR 20 at week 16. ACR 20 at week 16. ACR 20 at week 16. Adverse effects (AEs), HAQ-DI, physical function domain score of SF-36, PsARC, VAS, MASES, dactylitis severity score, CDAI, DAS28, FACIT- Fatigue, EULAR response, ACR 20, ACR 50, ACR 70, plasma levels of biomarkers. Study completion date reported as Nov Adverse effects (AEs), HAQ-DI, physical function domain score of SF-36, PsARC, VAS, MASES, dactylitis severity score, CDAI, DAS28, FACIT- Fatigue, EULAR response, ACR 20, ACR 50, ACR 70, PASI-75 n in participants with 3% psoriasis body surface area. Study completion date reported as Dec NCT , CC PsA-001; apremilast vs placebo; phase II. Celgene Corporation. Published. Publication 27, trial registry 28, manufacturer. Adverse effects (AEs), HAQ-DI, physical function domain score of SF-36, PsARC, VAS, MASES, dactylitis severity score, CDAI, DAS28, FACIT- Fatigue, ACR 20, ACR 50, ACR 70. Study completion date reported as Aug EU (incl UK) and Canada. Randomised, placebo-controlled. n=204; aged 18 years; PsA; 3 swollen and 3 tender joints; negative for rheumatoid factor; stable dose of MTX, oral corticosteroids, or NSAIDs allowed; no other systemic therapy within 28 days of randomisation. n PASI: Psoriasis Area and Severity Index (PASI-75 or PASI-50 is a 75% or 50% reduction in the score, respectively). 6

7 Schedule Follow-up Primary outcome Secondary outcomes Key results Randomised to apremilast 20mg twice daily, 40mg once daily, or placebo. Patients on placebo were re-randomised at week 12 to apremilast 20mg twice daily or 40mg once daily. Active treatment for 24 weeks, follow up for 4 weeks. ACR 20 at week 12. AEs, PsARC, DAS, PASI score, maximal ACR, ACR 50, ACR 70, time to ACR 20/50/70, time to PASI-50, dactylitis severity score, proportion without enthesitis, time to relapse of psoriasis, time to relapse of PsA, proportion of subjects who relapse, Quality of Life assessment scores, change in synovitis and change in inflammatory markers in synovial tissue. For apremilast 20mg (n=69), 40mg (n=67) and placebo (n=68), respectively, at week 12 (p value vs placebo): ACR 20 response, 43.5% (p<0.001), 35.8% (p=0.002) and 11.8%; ACR 50 response, 17.4% (p=0.012), 13.4% (p=0.056) and 2.9%; ACR 70 response, not significant; PsARC, 52.5% (p-value not reported), 50.7% (p-value not reported) and 22.1%. For apremilast 20mg (n=40), 40mg (n=46), placebo/apremilast 20mg (n=20) and placebo/apremilast 40mg (n=20), respectively, at week 24 ACR 20 response, 42.5%, 43.5%, 40.0% and 45.0%; ACR 50 response, 22.5%, 23.9%, 15.0% and 20.0%; ACR 70 response, 17.5%, 13.0%, 5.0% and 15.0%. Adverse effects (AEs) Analysis of MTX use showed no significant difference in ACR 20 response. 1 AE was reported in 84.3% of patients in placebo-controlled phase and 68.3% of patients in treatment-extension phase. AEs in 10% of any treatment group: For apremilast 20mg (n=69), 40mg (n=67) and placebo (n=68), respectively, during placebo-controlled phase: 1 AE, 85.5%, 86.6% and 80.9%; diarrhoea, 20.3%, 26.9% and 8.8%; headache, 18.8%, 22.4% and 16.2%; nausea,17.4%, 22.4% and 17.6%; fatigue, 7.2%, 16.4% and 8.8%; nasopharyngitis, 11.6%, 11.9% and 17.6%; dizziness, 4.3%, 10.4% and 4.4%; upper abdominal pain, 10.1%, 6.0% and 4.4%. For apremilast 20mg (n=40), 40mg (n=46), placebo/apremilast 20mg (n=20) and placebo/apremilast 40mg (n=20), respectively, during treatment-extension phase: 1 AE, 72.5%, 65.2%, 55.0% and 80.0%; nasopharyngitis,17.5%, 15.2%, 15.0% and 30.0%; nausea, 2.5%, 8.7%, 5.0% and 25.0%; diarrhoea, 5.0%, 6.5%, 0% and 20.0%; headache,12.5%, 4.3%, 5.0% and 0%; urinary tract infection, 2.5%, 0%, 0% and 10.0%. For apremilast 20mg (n=37), 40mg (n=42), placebo/apremilast 20mg (n=17) and placebo/apremilast 40mg (n=20), respectively, during follow up: 1 AE, 24.3%, 26.2%, 35.3% and 40.0%; nasopharyngitis,2.7%, 4.8%, 5.9% and 10.0%; psoriatic arthropathy, 5.4%, 0%, 17.6% and 15.0%; psoriasis, 5.4%, 7.1%, 11.8% and 0%. ESTIMATED COST and IMPACT COST The cost of apremilast is not yet known. The cost of selected comparator treatments (TNF inhibitors) for PsA are summarised below: 7

8 Drug Dose Annual cost 6 Adalimumab 40mg SC o every 2 weeks. 9,295 Etanercept 25mg SC twice weekly, or 50mg once weekly. 9,295 Infliximab 5mg/kg IV p at week 0, 2 and 6, then every 8 weeks. 13,428 for first year q. 10,910 for subsequent years. Golimumab 50mg SC once monthly. 9,295 IMPACT - SPECULATIVE Impact on Patients and Carers Reduced mortality/increased length of survival Reduced symptoms or disability Other: No impact identified Impact on Services Increased use of existing services Decreased use of existing services: oral therapy. Re-organisation of existing services Need for new services Other: None identified Impact on Costs Increased drug treatment costs Reduced drug treatment costs Other increase in costs: Other reduction in costs: Other: uncertain unit cost compared to existing treatments None identified Other Issues Clinical uncertainty or other research question identified REFERENCES None identified 1 Schafer PH, Parton A, Gandhi AK et al. Apremilast, a camp phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis. British Journal of Pharmacoloy 2010;159(4): National Institute for Health and Clinical Excellence. Etanercept, infliximab and Adalimumab for the treatment of psoriatic arthritis (review). Technology appraisal TA199. London: NICE; August The Psoriasis Association. Psoriatic arthritis. May Accessed 17 October Kyle S, Chandler D, Griffiths CEM et al. Guideline for anti-tnf-a therapy in psoriatic arthritis. Rheumatology 2005;44: Griffiths CEM, Clark CM, Chalmers RJG et al. A systematic review of treatments for severe psoriasis. Health Technology Assessment 2000;4(40). 6 National Institute for Health Research Horizon Scanning Centre. Ustekinumab (Stelara) for psoriatic arthritis with structural joint damage. Birmingham: NIHR HSC; September National Institute for Health and Clinical Excellence. Costing statement: Psoriatic arthritis golimumab. London: NICE; April o SC: Subcutaneously. p IV: Intravenously. q Based on an adult weight of between 65 and 80kg. 8

9 8 National Institute for Health Research Horizon Scanning Centre. Certolizumab pegol (Cimzia) for psoriatic arthritis second line. Birmingham: NIHR HSC; September National Institute for Health and Clinical Excellence. Technology Assessment Report For NICE MTA. Etanercept, Infliximab and Adalimumab for the Treatment of Psoriatic Arthritis. December Saad AA, Ashcroft DM, Watson KD et al. Persistence with anti-tumour necrosis factor therapies in patients with psoriatic arthritis: observational study from the British Society of Rheumatology Biologics Register. Arthritis Research and Therapy 2009;11(2):R52 11 Kane D, Stafford L Bresnihan B et al. A prospective, clinical and radiological study of early psoriatic arthritis: an early synovitis clinic experience. Rheumatology (Oxford) 2003;42(12): Tillett W, de-vries C and McHugh NJ. Work disability in psoriatic arthritis: a systematic review. Rheumatology (Oxford) 2012;51(2): Rosen CF, Mussani F, Chandran V et al. Patients with psoriatic arthritis have worse quality of life than those with psoriasis alone. Rheumatology (Oxford) 2012;51(3): Poole CD, Lebmeier M, Ara R et al. Estimation of health care costs as a function of disease severity in people with psoriatic arthritis in the UK. Rheumatology (Oxford) 2010;49(10): Woolacott N, Bravo Vergel Y, Hawkins N et al. Etanercept and infliximab for the treatment of psoriatic arthritis: a systematic review and economic evaluation. Health Technology Assessment 2006;10:(31). 16 NHS. Hospital episode statistics. NHS England HES data National Institute for Health and Clinical Excellence. Golimumab for the treatment of psoriatic arthritis. Technology appraisal TA220. London: NICE; April Gossec L, Smolen JS, Gaujoux-Viala C et al. European League Against Rheumatism recommendations for the management of psoriatic arthritis with pharmacological therapies. Annals of Rheumatic Disease 2012;71(1): Scottish Intercollegiate Guidelines Network. Diagnosis and management of psoriasis and psoriatic arthritis in adults. National clinical guideline 121. Edinburgh: SIGN; October Ritchlin CT, Kavanaugh A, Gladman DD et al. Treatment recommendations for psoriatic arthritis. Annals of Rheumatic Disease 2009;68(9): National Institute for Health Research Horizon Scanning Centre. Secukinumab for active and progressive psoriatic arthritis. Birmingham: NIHR HSC; November Kavanaugh A, Mease PJ, Gomez-Reino JJ et al. Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis: results of a phase 3, randomised, controlled trial. American College of Rhematology Annual Meeting, Washington DC, USA. November Abstract L13. Oral presentation ClinicalTrials.gov. Efficacy and safety study of apremilast to treat active psoriatic arthritis (PALACE-1). Accessed 5 December ClinicalTrials.gov. PALACE 2: Efficacy and safety study of apremilast to treat active psoriatic arthritis. Accessed 5 December ClinicalTrials.gov. PALACE 3: Efficacy and safety study of apremilast to treat active psoriatic arthritis Accessed 5 December ClinicalTrials.gov. Efficacy and safety study of apremilast to treat active psoriatic arthritis (PsA) (PALACE4) Accessed 5 December Schett G, Wollenhaupt J, Papp K et al. Oral apremilast in the treatment of active psoriatic arthritis: results of a multicenter, randomized, double-blind, placebo-controlled study. Arthritis and Rheumatism 2012;64(10): ClinicalTrials.gov. Phase II Study With CC in Psoriatic Arthritis. Accessed 6 December