Assessing the effectiveness of synthetic and biologic disease-modifying antirheumatic drugs in psoriatic arthritis – a systematic review

Figures & data

Table 1 Selection criteria for trials in review

Inclusion criteria	Exclusion criteria
Randomized controlled trial against placebo or two agents against each other, which for synthetic DMARDs lasted at least 12 weeks	All other study designs including cross-sectional observational, case series/cohort/registry, open-label
Primary outcome is related to clinical assessment of locomotor system (eg, symptoms, joint score/DAS, HAQ)	All other clinical outcomes (including skin, eyes, CVS, depression/psych/quality of life) and nonclinical outcomes (eg, imaging, biomarkers)
Primary intervention is a systemic disease-modifying agent, either DMARD or biologic	All other therapeutic agents including: • Local treatment (eg, IA steroids, IA yttrium, brachytherapy, IA biologics/DMARDs, botulinum) • Other drugs (nonsteroidal anti-inflammatory drugs) • Complementary therapy (eg, primrose oil) • Other immunotherapy (eg, leishmania or mycobacterial antigens) • Physiotherapy (including balneotherapy, interferential) or education • Surgery
Patients in study met diagnostic criteria for PsA, including criteria from CASPAR,^Citation26 Moll and Wright,^Citation1 and others unique to the trials	Some or all patients in the study did not meet PsA criteria and had other forms of spondyloarthritis

Abbreviations: PsA, psoriatic arthritis; DMARDs, disease-modifying agents; CVS, cardiovascular system; DAS, Disease activity score; HAQ, Health Assessment Questionnaire; IA, intra-articular.

Figure 1 Search strategy.

Table 2 Details of trials included

Reference	Year	Cases	Initial assessment		Disease duration	Age	Sex	Main analysis	Primary Outcome	Groups	Control	Treatment	Quality
			Joints	ESR CRP	Years	Years	M/F	Weeks		Number			Allocation	Double-blind	Analyzed for bias
Synthetic DMARDs
Willkens et al^Citation31	1984	37	3SJ/3TJ	–	11	45	15/22	12	None	2	Plac	MTX	Randomisation schedule	Yes	Yes
Palit et al^Citation32	1990	53	–	–	7	46	27/26	12	None	2	Plac	IM gold	Unstated	Yes	No
Farr et al^Citation33	1990	30	3SJ/3TJ	Both	7	46	16/14	24	None	2	Plac	SZP	Unstated	Yes	No
Fraser et al^Citation34	1993	39	3TJ	–	10	51	21/18	24	None	2	Plac	SZP	Unstated	Yes	No
Clegg et al^Citation35	1996	221	3SJ/3TJ	–	12	50	170/51	36	PsARC	2	Plac	SZP	Unstated	Yes	No
Combe et al^Citation36	1996	117	TJ1/SJ1	–	14	49	58/59	24	None	2	Plac	SZP	Unstated	Yes	No
Salvarani et al^Citation37	2001	99	3SJ/3TJ	–	2	48	62/37	24	Less pain	3	Control	Ciclosporin, SZP	Unstated	Yes	No
Kaltwasser et al^Citation38	2004	186	3SJ/3TJ	–	11	48	112/74	24	PsARC	2	Plac	Leflunomide	Randomisation schedule	Yes	No
Fraser et al^Citation39	2005	72	3TJ	–	3	47	26/46	52	FewerTJ	3	MTX	Ciclosporin, MTX	Unstated	Yes	No
Scarpa et al^Citation40	2008	35	–	–	<1	26	18/17	12	None	2	Control	MTX	Unstated	No	No
Kingsley et al^Citation41	2012	221	TJ1/SJ1	–	1	49	124/97	26	PsARC	2	Plac	MTX	Random number table	Yes	Yes
Schett et al^Citation42	2012	204	3SJ/3TJ	–	8	50	107/97	12	ACR20	3	Plac	Apremilast	Unstated	Yes	No
Kavanaugh^Citation43	2014	504	3SJ/3TJ	–	7	50	149/355	16	ACR20	3	Plac	Apremilast	Unstated	Yes	No
Biologic DMARDs
Mease et al^Citation44	2000	60	3SJ/3TJ	–	9	45	34/26	12	PsARC	2	Plac	Etanercept	Block	Yes	No
Mease et al^Citation45	2004	205	3SJ/3TJ	–	9	47	105/100	12	ACR20	2	Plac	Etanercept	Unstated	Yes	No
Antoni et al^Citation46	2005	104	5TJ/5SJ	Both	11	46	60/44	16	ACR20	2	Plac	Infliximab	Unstated	Yes	No
Antoni et al^Citation47	2005	200	5TJ/5SJ	CRP	8	47	122/78	14	ACR20	2	Plac	Infliximab	Dynamic algorithm	Yes	No
Mease et al^Citation48	2005	313	3SJ/3TJ	–	9	49	174/139	12	ACR20	2	Plac	Adalimumab	Unstated	Yes	No
Genovese et al^Citation49	2007	100	3SJ/3TJ	–	7	49	54/46	12	ACR20	2	Plac	Adalimumab	Interactive voice	Yes	No
Gottlieb et al^Citation50	2009	146	3SJ/3TJ	CRP	6	49	82/64	12	ACR20	2	Plac	Ustekinumab	Interactive voice	Yes	No
Kavanaugh et al^Citation51	2009	405	3SJ/3TJ	–	7	47	244/161	14	ACR20	3	Plac	Golimumab	Interactive voice	Yes	No
Mease et al^Citation52	2011	170	3SJ/3TJ	–	8	51	91/79	24	ACR20	4	Plac	Abatacept	Unstated	Yes	No
Baranauskaite et al^Citation53	2012	110	5SJ/5TJ	Both	3	41	60/50	16	ACR20	2	MTX	Infliximab/MTX	Unstated	Yes	Yes
McInnes et al^Citation54	2013	615	5TJ/5SJ	CRP	4	48	–	24	ACR20	3	Plac	Ustekinumab	Dynamic central	Yes	No
McInnes et al^Citation55	2013	42	3SJ/3TJ	–	6	47	15/27	6	ACR20	2	Plac	Secukinumab	Unstated	Yes	No
Mease et al^Citation56	2013	409	3SJ/3TJ	ESR	8	47	183/226	12	ACR20	3	Plac	Certolizumab	Interactive voice	Yes	No
Mease et al^Citation57	2014	168	3SJ/3TJ	–	9	52	61/107	12	ACR20	3	Plac	Brodalumab	Permuted block	Yes	No
Ritchlin et al^Citation58	2014	312	5TJ/5SJ	CRP	5	48	148/164	24	ACR20	3	Plac	Ustekinumab	Dynamic central	Yes	No

Note: – Represents no data available.

Abbreviations: ACR20, American College of Rheumatology 20 percent responders; CRP, C-reactive protein; DMARDs, disease-modifying agents; ESR, erythrocyte sedimentation rate; F, female; IM, intra-muscular; M, male; MTX, methotrexate; Plac, placebo; SZP, sulfasalazine; SJ, swollen joints; TJ, tender joints; PsARC, psoriatic arthritis response criteria.

Figure 2 Relative risks of American College of Rheumatology 20 percent responders.

Notes: *First arm of this study: ciclosporin. ^#Second arm of this study: sulfazalazine.

Table 3 Responses of American College of Rheumatology 20 percent responders for different drugs (including published abstracts)

Drug	Trials	Risk ratio	95% confidence intervals
Sulfasalazine^Citation37	1	1.23	0.67, 2.28
Ciclosporin^Citation37	1	1.25	0.69, 2.28
Clazakizumab^Citation64	1	1.26	0.72, 2.18
Leflunomide^Citation38	1	1.81	1.10, 2.96
Methotrexate^Citation41	1	1.82	0.97, 3.40
Ustekinumab^Citation50,Citation54,Citation58	3	2.06	1.64, 2.59
Apremilast^Citation42,Citation43,Citation59^–^Citation61	5	2.10	1.75, 2.51
Brodalimumab^Citation57	1	2.16	1.13, 4.13
Certolizumab^Citation56	1	2.39	1.72, 3.32
Abatacept^Citation52	1	2.49	1.23, 5.04
Secukinumab^Citation55,Citation62,Citation63	3	2.97	2.27, 3.88
Adalimumab^Citation48,Citation49	2	3.41	2.10, 5.54
Infliximab^Citation46,Citation47,Citation53	3	3.51	0.88, 13.98
Etanercept^Citation44,Citation45	2	4.15	2.71, 6.36
Golimumab^Citation51	1	5.73	3.10, 10.57

TaylorWGladmanDHelliwellPCASPAR Study GroupClassification criteria for psoriatic arthritis: development of new criteria from a large international studyArthritis Rheum2006542665267316871531

 PubMed Web of Science ®Google Scholar

MollJMWrightVPsoriatic arthritisSemin Arthritis Rheum1973355784581554

 PubMedGoogle Scholar

WillkensRFWilliamsHJWardJRRandomized, double-blind, placebo controlled trial of low-dose pulse methotrexate in psoriatic arthritisArthritis Rheum1984273763816712754

 PubMed Web of Science ®Google Scholar

PalitJHillJCapellHAA multicentre double-blind comparison of auranofin, intramuscular gold thiomalate and placebo in patients with psoriatic arthritisBr J Rheumatol1990292802832116206

 PubMedGoogle Scholar

FarrMKitasGDWaterhouseLJubbRFelix-DaviesDBaconPASulphasalazine in psoriatic arthritis: a double-blind placebo-controlled studyBr J Rheumatol19902946491968355

 PubMedGoogle Scholar

FraserSMHopkinsRHunterJANeumannVCapellHABirdHASulphasalazine in the management of psoriatic arthritisBr J Rheumatol1993329239258104656

 PubMedGoogle Scholar

CleggDORedaDJMejiasEComparison of sulfasalazine and placebo in the treatment of psoriatic arthritis. A Department of Veterans Affairs Cooperative StudyArthritis Rheum199639201320208961906

 PubMed Web of Science ®Google Scholar

CombeBGoupillePKuntzJLTebibJLiotéFBregeonCSulphasalazine in psoriatic arthritis: a randomized, multicentre, placebo-controlled studyBr J Rheumatol1996356646688670601

 PubMedGoogle Scholar

SalvaraniCMacchioniPOlivieriIA comparison of cyclosporine, sulfasalazine, and symptomatic therapy in the treatment of psoriatic arthritisJ Rheumatol2001282274228211669169

 PubMed Web of Science ®Google Scholar

KaltwasserJPNashPGladmanDTreatment of Psoriatic Arthritis Study GroupEfficacy and safety of leflunomide in the treatment of psoriatic arthritis and psoriasis: a multinational, double-blind, randomized, placebo-controlled clinical trialArthritis Rheum2004501939195015188371

 PubMed Web of Science ®Google Scholar

FraserADvan KuijkAWWesthovensRA randomised, double blind, placebo controlled, multicentre trial of combination therapy with methotrexate plus ciclosporin in patients with active psoriatic arthritisAnn Rheum Dis20056485986415528283

 PubMed Web of Science ®Google Scholar

ScarpaRPelusoRAttenoMThe effectiveness of a traditional therapeutical approach in early psoriatic arthritis: results of a pilot randomised 6-month trial with methotrexateClin Rheumatol20082782382618030515

 PubMed Web of Science ®Google Scholar

KingsleyGHKowalczykATaylorHA randomized placebo-controlled trial of methotrexate in psoriatic arthritisRheumatology2012511368137722344575

 PubMed Web of Science ®Google Scholar

SchettGWollenhauptJPappKOral apremilast in the treatment of active psoriatic arthritis: results of a multicenter, randomized, double-blind, placebo-controlled studyArthritis Rheum2012643156316722806399

 PubMed Web of Science ®Google Scholar

KavanaughAMeasePJGomez-ReinoJJTreatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitorAnn Rheum Dis2014731020102624595547

 PubMed Web of Science ®Google Scholar

MeasePJGoffeBSMetzJVanderStoepAFinckBBurgeDJEtanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trialLancet200035638539010972371

 PubMed Web of Science ®Google Scholar

MeasePJKivitzAJBurchFXEtanercept treatment of psoriatic arthritis: safety, efficacy, and effect on disease progressionArthritis Rheum2004502264227215248226

 PubMed Web of Science ®Google Scholar

AntoniCEKavanaughAKirkhamBSustained benefits of infliximab therapy for dermatologic and articular manifestations of psoriatic arthritis: results from the infliximab multinational psoriatic arthritis controlled trial (IMPACT)Arthritis Rheum2005521227123615818699

 PubMed Web of Science ®Google Scholar

AntoniCKruegerGGde VlamKIMPACT 2 Trial InvestigatorsInfliximab improves signs and symptoms of psoriatic arthritis: results of the IMPACT 2 trialAnn Rheum Dis2005641150115715677701

 PubMed Web of Science ®Google Scholar

MeasePJGladmanDDRitchlinCTAdalimumab Effectiveness in Psoriatic Arthritis Trial Study GroupAdalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: results of a double-blind, randomized, placebo-controlled trialArthritis Rheum2005523279328916200601

 PubMed Web of Science ®Google Scholar

GenoveseMCMeasePJThomsonGTSafety and efficacy of adalimumab in treatment of patients with psoriatic arthritis who had failed disease modifying antirheumatic drug therapyJ Rheumatol2007341040105017444593

 PubMed Web of Science ®Google Scholar

GottliebAMenterAMendelsohnAUstekinumab, a human interleukin 12/23 monoclonal antibody, for psoriatic arthritis: randomised, double-blind, placebo-controlled, crossover trialLancet200937363364019217154

 PubMed Web of Science ®Google Scholar

KavanaughAMcInnesIMeasePGolimumab, 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 studyArthritis Rheum20096097698619333944

 PubMed Web of Science ®Google Scholar

MeasePGenoveseMCGladsteinGAbatacept in the treatment of patients with psoriatic arthritis: results of a six-month, multicenter, randomized, double-blind, placebo-controlled, phase II trialArthritis Rheum20116393994821128258

 PubMed Web of Science ®Google Scholar

BaranauskaiteARaffayováHKungurovNVRESPOND investigatorsInfliximab plus methotrexate is superior to methotrexate alone in the treatment of psoriatic arthritis in methotrexate-naive patients: the RESPOND studyAnn Rheum Dis20127154154821994233

 PubMed Web of Science ®Google Scholar

McInnesIBKavanaughAGottliebABPSUMMIT 1 Study GroupEfficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trialLancet201338278078923769296

 PubMed Web of Science ®Google Scholar

McInnesIBSieperJBraunJEfficacy 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 trialAnn Rheum Dis20147334935623361084

 PubMed Web of Science ®Google Scholar

MeasePJFleischmannRDeodharAAEffect of certolizumab pegol on signs and symptoms in patients with psoriatic arthritis: 24-week results of a phase 3 double-blind randomised placebo-controlled study (RAPID-PsA)Ann Rheum Dis201473485523942868

 PubMed Web of Science ®Google Scholar

MeasePJGenoveseMCGreenwaldMWBrodalumab, an anti-IL17RA monoclonal antibody, in psoriatic arthritisN Engl J Med20143702295230624918373

 PubMed Web of Science ®Google Scholar

RitchlinCRahmanPKavanaughAPSUMMIT 2 Study GroupEfficacy 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 trialAnn Rheum Dis20147399099924482301

 PubMed Web of Science ®Google Scholar

MeasePGottliebABBermanAA phase IIb, randomized, double-blind, placebo-controlled, dose-ranging, multicenter study to evaluate the efficacy and safety of clazakizumab, an anti-IL-6 monoclonal antibody, in adults with active psoriatic arthritisArthritis Rheum201466S423

 Web of Science ®Google Scholar

CutoloMMyersonGEFleischmannRMLong-term (52-week) results of a phase 3, randomized, controlled trial of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis (PALACE 2)Arthritis Rheum201365S346S347

 Google Scholar

WellsAFEdwardsCJAdebajoAOApremilast in the treatment of DMARD-naive psoriatic arthritis patients: results of a phase 3 randomized, controlled trial (PALACE 4)Arthritis Rheum201365S3320S3321

 Google Scholar

MeasePMcInnesIBKirkhamBSecukinumab, a Human anti-interleukin-17A monoclonal antibodyArthritis Rheum201466S423S424

 Web of Science ®Google Scholar

McInnesIBMeasePJKirkhamBSecukinumab, a human anti-interleukin-17A monoclonal Antibody, improves active psoriatic arthritis: 24 week efficacy and safety data from a phase 3 randomised multicentre, double-blind, placebo-controlled study using subcutaneousArthritis Rheum2014662539

 Web of Science ®Google Scholar