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Psoriatic arthritis 2
Clinical management of psoriatic arthritis
Filip Van den Bosch, Laura Coates

Psoriatic arthritis, or the broader term psoriatic disease, refers to an inflammatory disorder that affects multiple Lancet 2018; 391: 2285–94
organs, including the skin and joints, and that also has related extra-articular manifestations and can have See Editorial page 2185
comorbidities. Patients with psoriatic disease have a substantial clinical burden. Early identification leading to This is the second in a Series of
timely diagnosis and treatment is crucial to prevent long-term structural damage and disability and the associated two papers about psoriatic
arthritis
socioeconomic consequences. The increase in therapeutic options, such as disease-modifying anti-rheumatic
drugs, both biological and targeted synthetic, has revolutionised the treatment of skin and joint disease, and has Department of Rheumatology,
Ghent University Hospital,
prompted clinicians to use the full clinical picture of an individual patient to make rational treatment decisions. Ghent, Belgium
Current research is also focused on treatment strategies, including treat to target, early remission-induction, (F Van den Bosch MD); VIB
and tapering. Center for Inflammation
Research, Unit for Molecular
Immunology and
Introduction 6 months, more than 1 year, and more than 2 years were Inflammation, Department of
Over the past two decades, it has become evident associated with worse outcomes, including poor function, Internal Medicine, Ghent
that psoriatic arthritis, traditionally defined as an erosive disease, arthritis mutilans, and poor quality of University, Ghent, Belgium
(F Van den Bosch); and Nuffield
inflammatory arthritis that is associated with psoriasis life.3 Furthermore, an analysis of data from the Swedish
Department of Orthopaedics,
and usually seronegative for rheumatoid factor, repre­ Early Psoriatic Arthritis registry, including 197 patients Rheumatology, and
sents a considerable diagnostic and therapeutic with 5 years of follow-up, showed that shorter symptom Musculoskeletal Sciences,
challenge for the treating physician. The advent of duration at diagnosis was predictive of minimal disease University of Oxford, Oxford,
UK (L Coates MBChB)
highly effective biological treatments for the disease activity (MDA; a potential goal of therapy) being achieved.4
Correspondence to:
has brought new perspectives regarding the control of Despite this knowledge, a considerable diagnostic delay
Dr Filip Van den Bosch,
signs and symptoms, improvement of quality of life, in patients with psoriatic arthritis remains. In a national Department of Rheumatology,
progression of structural damage, and prevention of clinical audit of inflammatory arthritis done by the British Ghent University Hospital,
disability. Consequently, the goal of treatment has Society for Rheumatology,5 data on all new referrals were 9000 Ghent, Belgium
filip.vandenbosch@ugent.be
evolved from merely the reduction of pain and stiffness collected for 21 months, and an analysis of 1016 patients
to the achievement of remission of joint and skin with psoriatic arthritis showed that these patients had
disease. At the same time, several new challenges have significantly longer delays in initial presentation to the
developed, such as screening for psoriatic arthritis general practitioner (8·9 vs 6·6 weeks), time to referral to
in general practices and dermatology departments; a rheumatology clinic (5·4 vs 4·0 weeks), and time to final
improving diagnosis, classification, and management diagnosis (28·6 vs 21·6 weeks) compared with patients
at an early stage of disease; and applying existing with rheumatoid arthritis, despite adjustment for age,
and novel therapies in rational and evidence-based sex, ethnicity, and social status.
treatment strategies. In this Series paper, we focus on
these aspects of the clinical management of psoriatic
arthritis. Search strategy and selection criteria
We did a review of the literature between November, 2017,
Early diagnosis, screening, and referral and January, 2018. We searched, without language
The evidence base supporting the importance of early restrictions, the MEDLINE and PubMed bibliographical
diagnosis of psoriatic arthritis has grown over the past database and the Cochrane Library for randomised
7 years. The earliest evidence came from the database of a controlled trials (including long-term extensions), strategy
clinic in Toronto, which showed that patients presenting trials, and observational studies, using the search terms
to a specialist clinic with duration of symptoms of more “psoriatic arthritis”, “psoriasis”, “spondyloarthritis”,
than 2 years had an increased prevalence of clinical joint “treatment”, and “treatment strategy”. Intervention was
damage progression compared with that of patients who defined as the use of any disease-modifying anti-rheumatic
presented with a disease duration of less than 2 years.1 drug. To ensure that the most up-to-date information was
Using a clinical database of a longitudinal cohort of included, we also reviewed abstracts presented at the
patients treated in Bath, UK, Tillett and colleagues showed annual conferences of the European League Against
that duration of symptoms of more than 1 year before Rheumatism (June, 2017) and the American College of
diagnosis was significantly predictive of poorer physical Rheumatology (November, 2017). References from
function more than 10 years later, despite active treatment.2 included studies were screened to identify additional
This finding was confirmed in another cross-sectional manuscripts of potential interest.
study, which showed that delays in diagnosis of more than

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For NICE guidelines on the
assessment and management
of psoriasis see https://www.
nice.org.uk/guidance/cg153
2286 www.thelancet.com Vol 391 June 2, 2018
An important opportunity for screening and referral
arises from the fact that most patients with psoriatic
arthritis present with psoriasis before developing
musculoskeletal symptoms. One of the strongest bio­
markers for the subsequent development of psoriatic
arthritis is the presence of psoriasis. Data from the UK
Clinical Practice Research Datalink database showed
that 92·8% of patients had psoriasis either before their
diagnosis of psoriatic arthritis or within the same
calendar year, whereas only 7·1% received a diagnosis of
psoriatic arthritis first. Most cases of psoriatic arthritis
occurred synchronously with a diagnosis of psoriasis, or
within 10 years of the onset of psoriasis.5 This finding
might be a slight overestimate due to coding issues in
the data; however, similar results were found in the
Bath longitudinal dataset,6 providing external validity.
According to the only published prospective study on
psoriatic arthritis development, in patients with psori­
asis followed up for 8 years, the incidence of psoriatic
arthritis was 2·7% per year (95% CI 2·1–3·6) and the
development of psoriatic arthritis was predicted by
severe psoriasis, nail involvement, uveitis, and a low
educational level.7
Patients with psoriasis are often unaware of the risk of
developing arthritis, which can lead to further delays in
diagnosis. In some cases, a period of preclinical disease
might be identifiable, but established clinical disease
can also go unidentified for some time.8 A period
of increasing musculoskeletal and fatigue symptoms
occurring before the development of psoriatic arthritis
has been shown.9 In addition to delays in diagnosis
in primary care, many patients in psoriasis clinics
have undiagnosed psoriatic arthritis.10 As patients with
psoriasis will frequently have contact with a health
professional—either a dermatologist or primary care
physician—about their condition before the development
of arthritis, there is an opportunity for patient education
and screening to identify cases of psoriatic arthritis.
The reasons why psoriatic arthritis sometimes
re­mains unidentified are not clear, but might include
insufficient musculoskeletal expertise among primary
care physicians and dermatologists.
A simple questionnaire-based screening method to
identify psoriatic arthritis in people with psoriasis has
the potential to enable earlier treatment of this disabling
disease and to prevent unnecessary suffering. Multiple
patient-completed screening questionnaires are available,
although research has shown that their specificity can be
low despite their reasonable sensitivity.11 Other musculo­
skeletal complaints, such as osteoarthritis and gout, can
also be identified using the same questionnaires, with
such conditions often representing a higher proportion
of newly identified cases than that of psoriatic arthritis. A
few studies have directly compared these questionnaires
and found no significant differences in their performance
in terms of sensitivity, specificity, and positive predictive
value. The National Institute for Health and Care
Excellence in the UK recommends the use of the
Psoriasis Epidemiology Screening Tool,12 as this
questionnaire is the quickest and easiest to complete,
comprising only five questions.
As there is no gold-standard diagnostic test for
psoriatic arthritis, the diagnostic process relies on
various pieces of evidence to establish the likelihood of
a patient having the disease. Most patients with psoriasis
and inflammatory arthritis are likely to have psoriatic
arthritis, but there are many cases in which disease
presentation is ambiguous, making diagnosis chal­
lenging. In rheumatology clinics, psoriatic arthritis
must be distinguished from other inflammatory
arthritides. In patients with known psoriasis, the key
issue is to identify whether the patient has inflammatory
joint disease or whether musculoskeletal pain is due to
another process. The diagnosis of psoriatic arthritis—
particularly in the early stages of the disease—is difficult
in many cases, and there has been little research in this
area. Data from the Swedish Early Psoriatic Arthritis
registry suggested different distributions of inflamed
joints in women compared with men with early psoriatic
arthritis (mean symptom duration 11 months): the
predominant pattern in women was polyarthritis,
whereas men more often had monoarthritis or
oligoarthritis and had a higher prevalence of axial
disease (isolated or in combination with peripheral joint
inflammation).4 Although patients most frequently
develop psoriasis before or simultaneously with the
development of arthritis, a minority of patients develop
arthritis before skin disease, which can cause diagnostic
uncertainty.
By contrast with diagnosis, classification is the process
of defining homogeneous cases for the purpose of
researching a condition. Classification criteria are
designed such that the same information is used in the
same way in every research study to ensure homogeneity
of the population being studied. It is inevitable that the
classification criteria will not completely agree with
physician diagnosis, but this disagreement can be
measured in terms of the false-positive and false-negative
rates.
Historically, there have been several classification
criteria for psoriatic arthritis. The first to be widely used
were the Moll and Wright criteria, which defined psoriatic
arthritis as an inflammatory arthritis (peripheral arthritis,
sacroiliitis, or spondylitis) occurring in the presence
of psoriasis, usually with an absence of rheumatoid
factor on serological tests. These criteria were probably
designed to maximise sensitivity, but it is possible that
Moll and Wright also used the presence or absence of
other features of psoriatic disease to make the diagnosis
in the clinic. Many modifications to the criteria, as well as
new classification criteria, have been proposed over
subsequent years,13 and researchers have therefore
proposed a large study to compare existing criteria and
develop new definitive ones.14

The Classification of Psoriatic Arthritis (CASPAR)
criteria15 were published in 2006 as the culmination of a
6-year project involving international rheuma­tologists,
dermatologists, and methodologists. The study recruited
more than 500 patients with psoriatic arthritis and
500 control participants with other forms of
inflammatory arthritis, and used two different statistical
techniques to derive new data-driven criteria for the
classification of psoriatic arthritis. The fundamental
CASPAR criterion is the presence of inflammatory
articular disease (joint, spine, or entheseal), with typical
features such as psoriasis (current, or personal or family
history), psoriatic nail dystrophy, absence of rheumatoid
factor, dactylitis (current or personal history), and
radiological evidence of new juxta-articular bone
formation providing additional points to yield a
definitive classification.15 The CASPAR study pre­
dominantly recruited patients with established disease,
with less than 10% of participants having had recent
onset of symptoms (duration <2 years). However, the
criteria have been tested in early-arthritis clinics with
reasonable sensitivity and specificity. Several studies
have suggested a slightly lower sensitivity in new
referrals compared with patients with a longer disease
duration due to most new referrals not showing the
typical new bone formation on radiological images, but
specificity remains high.16–18 In the Leiden Early Arthritis
cohort,18 the CASPAR criteria had a high sensitivity of
88·7% and clearly outperformed other peripheral
spondyloarthritis criteria while maintaining a specificity
of more than 95%. Even compared with other spondylo­
arthritides, the specificity of the criteria for diagnosing
psoriatic arthritis remained high, although that analysis
was done on data from patients presenting with
predominant peripheral arthritis symptoms.18
Therapeutic options in psoriatic arthritis
Conventional synthetic disease-modifying
anti-rheumatic drugs
The use of conventional synthetic disease-modifying anti-
rheumatic drugs (csDMARDs) for psoriatic arthritis has
historically followed the same treatment schedules
proposed for rheumatoid arthritis. In peripheral psoriatic
arthritis, some efficacy has been shown for sulfasalazine,
methotrexate, leflunomide, and ciclosporin. However,
clinical trials in psoriatic arthritis were often non-
controlled, used varying classification and improvement
criteria (making comparison between trials difficult), and
included only small numbers of patients with psoriatic
arthritis. Leflunomide was the only csDMARD for which
efficacy was shown in a double-blind, placebo-controlled
study in patients with psoriatic arthritis.19 In the placebo-
controlled Methotrexate In Psoriatic Arthritis (MIPA)
study,20 methotrexate showed no significant effects on
arthritis. This finding was unexpected because most
rheumatologists use methotrexate as the first-line
csDMARD treatment for psoriatic arthritis in daily
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practice, and this approach is also part of the European
League Against Rheumatism (EULAR) treatment recom­
mendations. The result might have been affected by
certain limitations of the MIPA study, namely the relatively
low target dose and the low proportion of patients who
completed the trial. Methotrexate appeared to be more
effective in the polyarthritis subgroup in the MIPA study.20
This is one of the few published drug trials to include
patients with psoriatic arthritis who have oligoarthritis, in
whom outcome measures may be less sensitive to change
because of lower baseline disease activity. Sulfasalazine
has been tested in several studies, including a placebo-
controlled study in 1996.21 However, in individual
randomised controlled trials, significant efficacy of
sulfasalazine for psoriatic arthritis was not consistently
shown.21 A Cochrane meta-analysis of six studies did find
that pooled indices for sulfasalazine were statistically
better than those of the placebo, with a small effect size.22
Data regarding the effect of csDMARDs on radiological
joint damage are scarce. When past patient cohorts
treated with methotrexate were compared, a more recent
patient group showed better efficacy in terms of both
signs and symptoms and the retardation of structural
damage.23 Although it cannot be formally proven, these
observed effects could be the consequences of a higher
weekly dose of methotrexate and earlier initiation of
csDMARD treatment in the more recent patient group.23
For other psoriatic arthritis manifestations, such as
enthesitis, dactylitis, and spondylitis, the efficacy of
csDMARDs has not been confirmed, and these drugs are
thus not included in the Group for Research and
Assessment of Psoriasis and Psoriatic Arthritis
(GRAPPA) treatment guidelines for these specific
lesions.
Biological disease-modifying anti-rheumatic drugs
Data on the development and approval statuses of
biological disease-modifying anti-rheumatic drugs
(bDMARDs) are summarised in the table. Tumour
necrosis factor (TNF) inhibitors (etanercept, infliximab,
adalimumab, golimumab, and certolizumab pegol)
have shown consistent efficacy in short-term and long-
term studies of patients with active psoriatic arthritis,
and are currently approved for the treatment of
moderate to severe psoriatic arthritis.24–28 In all studies
of these TNF inhibitors, continuation of previous
csDMARD treatment (usually methotrexate) was
permitted but not obligatory. Notably, the size of the
response in patients receiving TNF inhibitor was
similar with or without concomitant csDMARDs;
however, the data do not allow for a conclusion on
whether, for a patient with newly diagnosed psoriatic
arthritis, there would be an advantage of receiving
combination therapy as opposed to monotherapy
consisting of either the csDMARD or the TNF inhibi­tor
alone. An ongoing trial (NCT02376790) testing
methotrexate alone versus etanercept alone versus
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p19 subunit) that enables the expansion of Th17 cells—

Psoriatic Psoriasis Ankylosing Inflammatory bowel
arthritis spondylitis disease or by blocking the activity of the primary cytokine
produced by these cells, interleukin 17. Ustekinumab
bDMARDs
is a monoclonal antibody with high affinity for the
Etanercept EMA, FDA EMA, FDA EMA, FDA PoC (for CD) failed
p40 subunits of interleukin 12 and interleukin 23, and
Infliximab EMA, FDA EMA, FDA EMA, FDA EMA, FDA
is efficacious for the treatment of peripheral psoriatic
Adalimumab EMA, FDA EMA, FDA EMA, FDA EMA, FDA
arthritis, including enthesitis and dactylitis.37,38 The
Golimumab EMA, FDA .. EMA, FDA EMA (for UC), FDA (for UC)
antibody also has very good efficacy in the skin,
Certolizumab pegol EMA, FDA Phase 3 EMA, FDA FDA (for CD)
with superiority versus etanercept in a head-to-head
Ustekinumab EMA, FDA EMA, FDA Phase 3 failed EMA (for CD), FDA (for CD)
trial for psoriatic skin disease.39 Notably, although
Secukinumab EMA, FDA EMA, FDA EMA, FDA PoC (for CD) failed initial beneficial effects were observed in an open-label
Ixekizumab EMA, FDA EMA, FDA Phase 3 .. pilot study investigating ustekinumab in ankylosing
Brodalumab Phase 2 EMA, FDA .. .. spondylitis,40 a large phase 3 trial programme
Guselkumab Phase 2 EMA, FDA .. .. (NCT02437162, NCT02438787) in axial spondyloarthritis
Abatacept EMA, FDA Phase 2 PoC failed PoC (for CD and UC) failed did not reach its primary endpoint, thereby prompting
tsDMARDs questions about the efficacy of the drug in axial
Apremilast EMA, FDA EMA, FDA Phase 3 failed Phase 2 (for UC) manifestations of psoriatic arthritis.
Tofacitinib FDA Phase 3 Phase 2 Phase 2 failed Currently, there are two monoclonal antibodies
Data were retrieved from ClinicalTrials.gov on April 6, 2018. bDMARD=biological disease-modifying anti-rheumatic targeting interleukin 17A: secukinumab and ixekizumab.
drug. EMA=approved for use by the European Medicines Agency. FDA=approved for use by the US Food and Drug Both antibodies have been approved for the treatment of
Administration. PoC=proof-of-concept study. CD=Crohn’s disease. UC=ulcerative colitis. tsDMARD=targeted synthetic
psoriatic arthritis on the basis of large phase 3 trials,
disease-modifying anti-rheumatic drug.
which have shown efficacy of these antibodies for
Table: Current development and approval statuses of drugs for psoriatic arthritis and related disorders the treatment of arthritis, enthesitis, and dactylitis.41–44
Secukinumab is also approved for the treatment of active
methotrexate and etanercept combined could provide ankylosing spondylitis, supporting its use in cases of
additional data later in 2018. inflammatory spondylitis in psoriatic arthritis. In phase 3
There is convincing evidence that TNF inhibitors can trial programmes of skin psoriasis, blockade of
halt structural damage in peripheral psoriatic arthritis, interleukin 17A resulted in high PASI skin responses
as shown by stable scores for erosion and joint (PASI 75 to PASI 100),45 with superior efficacy over
narrowing based on radiographs of the hands and feet, ustekinumab46 and etanercept47 in head-to-head trials. It
in contrast to further progression observed in the remains to be shown whether broader interleukin 17
placebo group. Although the pivotal phase 3 studies24–28 blockade—eg, with bimekizumab, a monoclonal anti­
of TNF inhibitors in psoriatic arthritis have used body that neutralises human interleukin 17A and
different instruments to assess enthesitis (thereby interleukin 17F—could lead to even greater clinical
making comparison difficult), there is clinical responses in the skin and joints.48 Another approach to
consensus29,30 that all of these agents can treat refractory targeting multiple cytokines of the interleukin 17 family is
inflammation at the enthesis and that they are to block the interleukin 17 receptor. Brodalumab, a
efficacious for the treatment of dactylitis. Regarding human monoclonal antibody against interleukin 17
axial disease, all TNF inhibitors have shown efficacy in receptor A, has been approved for the treatment of skin
ankylosing spondylitis.31–35 Finally, remarkable efficacy psoriasis, and phase 2 data suggest a beneficial effect in
of all TNF inhibitors has been observed for skin and nail psoriatic arthritis.49
manifestations of psoriatic arthritis, but with a New data are emerging regarding the treatment
somewhat lower proportion of patients showing a efficacy of selective interleukin 23 inhibitors. Gusel­
Psoriasis Area and Severity Index (PASI) 75 skin kumab and risankizumab are monoclonal antibodies
response with the standard etanercept dose than with that target the p19 subunit of interleukin 23, and as
monoclonal antibodies targeting TNF. such have no biological effect on interleukin 12. These
Although TNF inhibitors have substantially improved antibodies showed clear efficacy in the treatment of
outcomes in psoriatic arthritis, some patients have not skin psoriasis, with superiority versus adalimumab and
adequately benefited, have not had a sustained ustekinumab.50–53 In the current issue of The Lancet,
response, or have had side-effects. Therefore, biological Atul Deodhar and colleagues54 describe the efficacy of
treatments with a different mode of action have been an guselkumab in patients with psoriatic arthritis in a
unmet need. There is now ample evidence that phase 2a trial. Statistically significant improvements in
T-helper-17 (Th17) cells, which are effector cells in all major arthritis efficacy outcomes were reported
inflammation and tissue damage, have an important compared with placebo. Regarding risankizumab, there
role in the pathophysiology of psoriatic disease.36 The are currently only abstract data available, but these data
Th17 axis can be targeted by inhibiting interleukin 23— indicate significantly improved joint symptoms in
an upstream cytokine (consisting of a p40 subunit and a psoriatic arthritis.55

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In a phase 3 clinical trial,56 abatacept—a selective T-cell
co-stimulation modulator modelled on the extracellular
domain of human cytotoxic T-lymphocyte-associated
antigen 4—was shown to elicit a moderate response in
patients with psoriatic arthritis, with slightly better
efficacy in patients naive to TNF inhibitors than in those
who had been exposed to TNF inhibitors. These findings
led to the approval of abatacept for the treatment of active
psoriatic arthritis.
Targeted synthetic disease-modifying anti-rheumatic
drugs
With the approval of apremilast—a phosphodiesterase 4
inhibitor—for the treatment of active psoriatic arthritis,
the new treatment category of targeted synthetic disease-
modifying anti-rheumatic drugs (tsDMARDs) was added
to the therapeutic armamentarium. Apremilast treatment
resulted in moderate improvement of joint and skin
symptoms, albeit not within the range of the responses
achieved by inhibitors of TNF or interleukin 17. The
major advantage of apremilast is its reassuring safety
profile.57
Tofacitinib, an oral JAK inhibitor that preferentially
inhibits signalling through JAK3 and JAK1, is one of the
most recent drugs to become available for the treatment of
psoriatic arthritis, having been approved by the US Food
and Drug Administration in December, 2017. The approval
of tofacitinib for this indication was based on a phase 3
programme that included patients naive to TNF inhibitors58
and patients who had had inadequate responses to TNF
inhibitors.59 In TNF inhibitor-naive patients, the efficacy of
tofacitinib in terms of joint and skin responses was similar
to that of adalimumab.58 Significant improvements were
also observed in patients with inadequate responses to
TNF inhibitors.59 Other JAK inhibitors with different
selectivity are being investigated in phase 2–3 studies
(NCT03104374, NCT03101670).
Treatment strategies
Despite the expanding range of therapeutic options that
target different immunological pathways, no trials of
treatments to date have consistently achieved an ACR20
in more than 60% of patients. Therefore, the develop­
ment and testing of other treatment modalities or
strategies is necessary. There has been little research
into how therapies should be used in psoriatic arthritis.
Practising rheumatologists are challenged, on a daily
basis, with choosing the appropriate drug for each
patient, relying on treatment recommendations for
guidance. Two sets of recom­ mendations have been
published and were updated in 2015.29,30 The EULAR
recommendations provide a step-by-step algorithm-
based approach that focuses on peripheral joint
manifestations and incorporates adverse prognostic
factors and extra-articular manifestations as additional
factors that can support the decision of a physician to
potentially skip a certain treatment phase. The GRAPPA
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recommendations30 present a schematic that details the
different available treatment modalities for arthritis,
spondylitis, enthesitis, dactylitis, skin disease, nail
disease, and comorbidities. However, in the absence of
adequately powered head-to-head trials on the efficacies
of different bDMARDs and tsDMARDs in psoriatic
arthritis, the guidance necessarily remains vague, and
the choice between various biological or small-molecule
therapeutics will essentially be determined by long-term
safety and efficacy outcomes, thus favouring TNF
inhibitors because of their longer history of use in daily
practice. Only in specific subgroups, such as patients
with extensive skin disease, does it seem obvious to
choose agents blocking the Th17 pathway (which have
shown efficacy superior39,47 to that of TNF inhibitors in
terms of skin outcomes). Another possible differentiator
is the presence of active inflammatory bowel disease, for
which agents like etanercept60 or secukinumab61 have not
shown efficacy. However, the number of patients with
very extensive skin disease or with inflammatory bowel
disease is likely to be low in daily rheumatological
practice.
Treat to target
The concept of treat to target (ie, therapy escalation
driven by the aim of achieving a prespecified, objective,
disease-activity target) has been established in
rheumatoid arthritis in several randomised controlled
trials62,63 and its implementation in routine clinical
practice is now recommended. In psoriatic arthritis,
data strongly suggest a link between inflammation and
damage, with evidence that the number of actively
inflamed joints predicts future joint damage, both
clinical64 and radiographic,65 and that the presence of
active inflammation in a particular joint predicts
damage in that same joint.66 Given these data and the
success of the treat-to-target approach in rheumatoid
arthritis, the approach has been extrapolated to the
spondyloarthritides.
To date, only one strategic study has compared a therapy
steered towards a prespecified treatment target versus a
conventional non-steered approach in the spondylo­
arthritides. The Tight Control of Psoriatic Arthritis
(TICOPA) study recruited 206 patients with recent-onset
psoriatic arthritis, who were randomised on a 1:1 basis to
receive tight control or standard care.67 The odds of
achieving ACR20 (odds ratio 1·91, p=0·039), ACR50,
ACR70, and PASI 75 were all significantly higher for the
tight-control group than for the standard-care group.
Improvements were also seen in patient-reported out­
comes, including physical function (Health Assessment
Questionnaire), quality of life (Psoriatic Arthritis Quality-
Of-Life index), and (for those with axial disease) Bath
Ankylosing Spondylitis Disease Activity Index and Bath
Ankylosing Spondylitis Functional Index.
The treat-to-target recommendations for spondylo­
arthritides, determined by an international taskforce,
 Series
were updated in 2017 to encompass the data from the
TICOPA trial.68 The taskforce and the EULAR treatment
guidelines29 recommend that remission should be the
main target, with low disease activity as an alternative, but
no consensus on the measure to be used has been
reached. One of the key challenges in choosing a target is
the hetero­ geneity of disease presentation in psoriatic
arthritis and the need to ensure that any potential target
would work for most patients. Targets could be indi­
vidualised according to the clinical manifestations of
the disease, but validated measures of musculoskeletal
disease activity (arthritis, dactylitis, enthesitis, and
axial disease) should be included alongside a measure
of cutaneous manifestations for psoriatic arthritis
specifically.
The potential measures recommended were the
Disease Activity in Psoriatic Arthritis (DAPSA)
index69—which includes 68-joint and 66-joint counts,
patient pain visual analogue scale, patient global
disease activity visual analogue scale, and C-reactive
protein concentration—and the very low disease activity
(VLDA) and MDA criteria.70 DAPSA is the quickest to
use but only assesses articular disease and thus
provides a very limited assessment of psoriatic disease.
The VLDA and MDA criteria include assessments of
articular disease (68-joint and 66-joint counts),
enthesitis, skin disease (PASI or body surface area),
and patient-reported measures (visual analogue scales
for pain and global disease activity, and the health
assessment questionnaire for function).70 The MDA
and VLDA criteria are feasible to use, but are only a
binary measurement of state and do not measure the
degree of disease activity or response on a continuous
scale.
Several studies have examined the validity of these
measures, but more recent publications have compared
them head to head.71 In these studies, both DAPSA and
MDA or VLDA targets have been associated with a small
amount of residual disease and high quality of life.
However, the exclusion of a domain for psoriasis, as in the
DAPSA index, results in neglect of skin disease. The
residual skin disease seen in patients with remission
according to DAPSA is then associated with a reduced
quality of life in some cases.71 Additionally, given the
design of the DAPSA index, greater amounts of residual
disease in some domains can be seen while other domains
are relatively unaffected.
Management of early psoriatic arthritis
Given the strong observational evidence that a delay in
diagnosis is associated with several poor long-term
outcomes, it seems likely that early intervention with
effective therapy could improve patient outcomes. As
with most questions regarding therapeutic strategies
in psoriatic arthritis, the effects of early therapy have
not yet been directly addressed. Small studies have
investigated early methotrexate use in patients with
2290 www.thelancet.com Vol 391 June 2, 2018
psoriatic arthritis72 and golimumab use in patients with
mixed very-early peripheral spondyloarthritis (among
which 40% had concomitant skin or nail psoriasis).73
Another study that investigated early methotrexate use,
either alone or with infliximab infusion,74 showed a
significant difference between the two groups in terms
of the ACR20 at 16 weeks, but with high proportions of
patients achieving ACR20 responses in both groups.
These responses were much higher than those seen in
trials of methotrexate use in established psoriatic
arthritis,20,23 suggesting better outcomes of therapy given
in early disease, although one reason for this greater
response could be the open-label study design (ie,
awareness of receiving the active agent could have led to
a greater expectation of response). Thus, further research
is needed to address the effect of early versus delayed
therapy and to establish the optimal therapeutic regimen
for use in early psoriatic arthritis.
Studies of rheumatoid arthritis75 have investigated
different initial treatment strategies, comparing the so-
called step-up and step-down approaches and early
biologic therapy. Unfortunately, comparable literature in
psoriatic arthritis is very sparse. The potential benefits of
early combination treatment or aggressive treatment
strategies are unknown, and further research is needed.
In the absence of data, international recommendations29,30
for the management of psoriatic arthritis have been
based on the step-up approach to therapy, but with
caveats that treatment decisions should be individualised
and that more aggressive therapy should be considered
in those with poor prognostic markers.
The UK audit of inflammatory arthritis5 done between
2014 and 2015 analysed the management and outcomes
of 1016 patients with psoriatic arthritis compared with
matched rheumatoid arthritis controls. At baseline,
patients with psoriatic arthritis had similar or less-
severe disease activity, functional impairment, and
disease impact; however, they had significantly higher
scores for disease impact and poorer responses to
treatment (as measured by EULAR response criteria) by
the 3-month follow-up assessment compared with
control patients. Patients with psoriatic arthritis were
more likely to receive no DMARD therapy or single
DMARD therapy, whereas patients with rheumatoid
arthritis were more likely to receive double or triple
DMARD therapy at diagnosis.5 Although this approach
would be in line with current international treatment
recommendations,29,30 it does highlight the potential
risk of under-treatment in psoriatic arthritis. It is
also notable that poorer outcomes are seen earlier in
the course of the disease compared with rheumatoid
arthritis.
Treatment interruption and tapering
With the increasing availability of effective therapy,
remission is an attainable target. Given the considerable
costs of many of these medications, researchers and

clinicians have investigated the feasibility of tapering or
withdrawing therapies for patients in remission. To
date, such studies have been small, and it is difficult to
draw clear conclusions. When therapy was stopped
completely, 45–77% of patients had a flare in their
symptoms and disease activity levels despite being in
remission before cessation of therapy.76–78 Subsequent
studies have investigated dose reduction rather than
complete withdrawal. In a Spanish study, dose reduction
of etanercept and adalimumab for patients in remission
for at least a year showed sustained disease control with
the reduced dose for around 2 years, but was associated
with a cost reduction of more than €1 million in a cohort
of 144 patients.79 Subsequent studies have also shown
that the dosing interval of etanercept can be extended in
a substantial proportion (56–72%) of patients.80–82 In a
comparison of patients with psoriatic arthritis receiving
a full dose or a reduced dose of DMARDs, ultrasound-
assessed disease activity appeared to be the same in
both groups.83
Management of comorbidities
Our review has so far focused on the management of
musculoskeletal manifestations of psoriatic arthritis,
but there are several other systems involved in this
condition that should be taken into account when
planning therapy. Psoriasis is present in most patients
with psoriatic arthritis and should be addressed when
planning treatment. In cases with substantial skin
involvement, close collaboration with a dermatologist is
helpful to optimally manage skin and musculoskeletal
disease. Within the spectrum of spondyloarthritides,
extra-articular manifestations, such as inflammatory
bowel disease and uveitis, are also a risk. Close
communication with relevant specialists (eg, ophthal­
mologists and gastroenterologists) is crucial for the
optimal management of multiple related conditions.
This communication is particularly important for
therapy choice, as some treatments for psoriatic
arthritis could worsen comorbidities or extra-articular
spondylo­arthropathy manifestations (eg, interleukin 17
inhibitors can exacerbate disease in patients with active
inflammatory bowel disease), and some might also be
licensed therapies for the related condition (eg, TNF
inhibitors for inflammatory bowel disease and uveitis).
Beyond the spectrum of spondyloarthritides, other key
comorbidities in psoriatic arthritis, particularly those
relating to cardiovascular risk, represent a considerable
burden in patients. In a cohort of patients with psoriatic
arthritis, 44% had metabolic syndrome,84 which was
associated with severity of psoriatic arthritis disease.
Elements of metabolic syndrome can complicate the
selection of and affect the efficacy and safety of psoriatic
arthritis treatments, particularly steroids and DMARDs,
which might increase risk of cardiovascular disease,
hypertension, and liver abnormalities. Obesity is also
associated with psoriasis and psoriatic arthritis, with a
www.thelancet.com Vol 391 June 2, 2018 2291
Series
prevalence of around 45%,85 and can limit the tolerance
to therapies and increase the risk of progressive hepatic
fibrosis.86 Obesity is also associated with poorer clinical
outcomes in patients being treated for psoriatic
arthritis;87,88 weight loss of 5–10% of body mass can
increase the probability of achieving MDA compared
with weight loss of less than 5%.89
Conclusions and remaining questions
Clinical management of psoriatic arthritis has changed
markedly over the past decade. With the advent of
promising new therapeutic options came the need for
timely diagnosis and classification, and for research on
outcome parameters that can encompass the whole
spectrum of psoriatic disease. Despite the important
improvements that have been highlighted in this paper,
there is still a considerable research agenda. Many of the
unanswered questions relate to the need to individualise
treatment, which is particularly relevant in psori­ atic
arthritis because the disease is so heterogeneous in its
presentation. Most clinical trials have focused on
peripheral arthritis and recruited predominantly patients
with polyarticular disease. By contrast, few patients with
oligoarthritis have been recruited to these studies, and
the efficacy of treatments is therefore not well known
in this subgroup. Beyond peripheral arthritis, the
management of other domains affected by psoriatic
arthritis is a clear unmet need. The efficacies of new
therapies for enthesitis and dactylitis are often only
assessed as secondary outcomes in trials of peripheral
arthritis. The first studies addressing enthesitis as the
primary outcome are underway, but results are not yet
available. Rheumatologists should also be encouraged to
assess skin disease—not just arthritis—when making
therapeutic decisions. Finally, there is a need to study
not just classic extra-articular manifestations, but also
comorbidities such as cardiovascular disease, metabolic
syndrome, and depression, as these could all contribute
to the important global burden of disease.
Contributors
FVdB and LC contributed equally to this manuscript. Both authors did
the literature search, analysis and interpretation of data, and writing of
the manuscript, and read and approved the final submitted
manuscript.
Declaration of interests
FVdB has received grant funding from Abbvie, Janssen, and UCB, and
has received speaker or consultancy honoraria from Abbvie,
Bristol-Myers Squibb, Celgene, Lilly, Janssen, Merck, Novartis, Pfizer,
and UCB. LC has received grant funding from Abbvie, Celgene,
Janssen, Lilly, Novartis, and Pfizer, and has received honoraria from
Abbvie, Amgen, Celgene, Galapagos, Janssen, Lilly, Merck Sharp &
Dohme, Novartis, Pfizer, Prothena, Sun Pharma, and UCB, in addition
to non-financial support from Abbvie.
Acknowledgments
LC is funded by a National Institute for Health Research Clinician
Scientist award. The work was supported by the National Institute for
Health Research Oxford Biomedical Research Centre. The views
expressed are those of the author and not necessarily those of the UK
National Health Service, the National Institute for Health Research,
or the Department of Health.
 Series
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