Rheumatology 2015;54:20–28

RHEUMATOLOGY doi:10.1093/rheumatology/keu237
Advance Access publication 14 August 2014

Review
Psoriatic arthritis: current therapy and future
approaches
DoQuyen Huynh1 and Arthur Kavanaugh2

Abstract

Downloaded from http://rheumatology.oxfordjournals.org/ at Universidad Nacional Autonoma de Mexico on August 19, 2015
PsA is a systemic inflammatory condition that affects 20–30% of patients with psoriasis. It is characterized
by potential involvement of diverse tissues, including peripheral and axial joints, enthesitis, dactylitis
and skin and nail disease. The degree of involvement in each domain can vary over time in individual
patients and can differ substantially between PsA patients. The clinical heterogeneity along with the
varying extent of severity and activity can pose significant challenges to treatment. Although some studies
had suggested immunopathophysiological similarities between PsA and RA, more recently important
R EV I E W

distinctions have been defined. Similarly, although some immunomodulatory therapies have proved ef-
fective for both PsA and RA, recent data suggest distinct responses to certain targeted therapies. Herein,
current DMARDs and biologic agents as well as the potential role of emerging therapeutics will be
reviewed.
Key words: psoriatic arthritis, tumour necrosis factor inhibitors, disease-modifying anti-rheumatic drug, treat-
ment, review, ustekinumab, apremilast, IL-17 inhibitor, rituximab, methotrexate.

Clinical features and diagnosis reactants, such as ESR or CRP, however, many patients
with active disease will have normal levels. The majority
PsA is a chronic inflammatory arthritis that occurs in pa- of PsA patients are seronegative, in that serum tests for
tients with psoriasis. Recent studies have suggested that RF and ACPA are negative; however, there is a greater
20–30% of patients with psoriasis may have PsA [1]. Skin prevalence of RF/ACPA positivity among PsA patients
manifestations precede the arthritis in >80% of PsA compared with the general population [3]. The older
patients, at times by a decade or more. In addition to Moll and Wright criteria to classify PsA have been largely
synovitis, other manifestations common in PsA include supplanted by the Classification of Psoriatic Arthritis
enthesitis, dactylitis and anterior uveitis or iritis. (CASPAR) classification criteria, which have been shown
Gastrointestinal involvement with a resemblance to IBD to have high sensitivity and specificity in diverse
is common, although not always clinically apparent. The settings [4].
peak age at onset of PsA is between 30 and 50 years of
age. There is equal distribution between men and women Treatment guidelines and paradigms
with the exception of axial disease, which favours men
3:1. There are significant genetic associations common The clinical heterogeneity of PsA poses a challenge to
to psoriasis and PsA, some of which overlap with other clinicians in selecting the most appropriate treatments.
autoimmune conditions [2]. To help address this, international groups such as the
The diagnosis of PsA is clinical as there are no pathog- Group for Research and Assessment of Psoriasis and
nomonic, serological, imaging or other diagnostic tests. Psoriatic arthritis (GRAPPA) and the European League
Some patients may have elevations in acute phase Against Rheumatism (EULAR) have published treatment
recommendations [5, 6], as have some individual coun-
tries. The GRAPPA recommendations consider five do-
1
Division of Rheumatology and 2Division of Rheumatology, Allergy and mains of involvement (peripheral arthritis, skin and nail
Immunology, University of California, San Diego, La Jolla, CA, USA. involvement, enthesitis, dactylitis and axial arthritis) and
Submitted 3 December 2013; revised version accepted 9 April 2014. use a grid approach to account for various levels of dis-
Correspondence to: DoQuyen Huynh, Division of Rheumatology, ease activity and severity. The EULAR recommendations
University of California, San Diego, Fellow 9444 Medical Center Drive,
Suite 0943, La Jolla, CA 92093-0943, USA. E-mail: d4huynh@ucsd.edu employ an algorithmic approach that focuses mainly on
or doquyen9@gmail.com musculoskeletal manifestations, specifically peripheral

! The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

arthritis; manifestations such as dactylitis, enthesitis and
skin and nail involvement were to be considered separ-
ately. With PsA research proceeding apace, inclusion of
newer therapies into clinical guidelines requires ongoing
modification and updating.
Other therapeutic concepts are also being explored in
PsA. Central to any assessment of the efficacy of thera-
pies are the outcome measures used to quantify disease
activity across various domains of disease, both in clinical
studies and in the clinic. As many of the outcome meas-
ures used in PsA are borrowed from other conditions,
such as assessment of peripheral synovitis as has long
been done for RA, there has been substantial effort in
devising and validating PsA-specific outcome measures
[7, 8]. A recent review of the various outcomes measures
has been performed [9];. where there is no single univer-
sally accepted measure, in practice, minimal disease ac-
tivity has become to be considered an acceptable target
for treatment.
Newer treatment paradigms, some of which have also
been developed in some rheumatic and other diseases,
are also being assessed in PsA. Further, there has been
growing interest in the concept of treat to target in PsA. In
RA, data have shown that regular assessments of disease
activity and alteration of therapies aimed at achieving the
lowest levels of disease activity possible are associated
with optimal benefits in clinical response, joint damage
and functional ability. The Tight Control of Psoriatic
Arthritis (TICOPA) study addressed this, with PsA patients
randomized 1:1 to receive either (i) standard of care with
changes in medication and dose escalation to be deter-
mined by a physician every 12 weeks or (ii) a 4-week
follow-up with dose escalation and medication changes
as outlined by a protocol aimed at minimal disease activity
[10]. PsA patients under tight control achieved signifi-
cantly better clinical outcomes in ACR 20%, 50% and
70% responses (ACR20/50/70) of 62%, 51% and 38%
at 48 weeks compared with 45%, 25% and 17% in the
standard care group [11]. Overall skin improvement as
measured by the Psoriasis Area and Severity Index 75
(PASI75) was reached in 59% of the tight control group
compared with only 33% in the standard care group.
However, there were more adverse effects noted in the
tight control group. Further analysis may elucidate the
risk/benefit considerations of treat to target in PsA.
Lastly, another concept that has received considerable
interest in RA and will be also assessed in PsA is whether
therapies such as biologic agents might be withdrawn
for PsA patients achieving treatment goals, with clinical
response being maintained.
Common conventional treatment agents
NSAIDs and corticosteroids
NSAIDs and corticosteroids are often prescribed as part
of the management of inflammatory joint diseases, includ-
ing PsA. While concerns had been raised about their
safety, a recent Cochrane review evaluating the safety of
NSAIDs and paracetamol in inflammatory arthritides
www.rheumatology.oxfordjournals.org
Psoriatic arthritis: treatment
suggested that overall NSAIDs may be used safely with
MTX without an increased risk of toxic adverse events or
liver, renal or pulmonary dysfunction [12]. Also, a placebo-
controlled study of nimesulide, a selective cyclooxygen-
ase 2 (COX-2) inhibitor, did result in improved signs and
symptoms of PsA and, contrary to prior suggestions,
NSAID use did not worsen skin disease [13].
Systemic and IA steroids are commonly used for PsA,
although again there are limited data confirming their util-
ity specifically in PsA [14, 15]. Nevertheless, it should be
noted that between 40% and 50% of patients in clinical
trials are or have previously been on oral steroids. One
small study compared the use of early IA steroid injection
Downloaded from http://rheumatology.oxfordjournals.org/ at Universidad Nacional Autonoma de Mexico on August 19, 2015
vs conservative management with NSAIDs in early PsA
patients presenting with oligoarticular disease. In this
study, patients also received SSZ if synovitis persisted
or if polyarticular disease occurred. By week 52, 81% of
patients on the IA steroid achieved complete response,
defined by the absence of synovitis, compared with only
51% in the conservative group. It should be noted that
SSZ was started in a greater percentage of the steroid
group (45%) as compared with the conservative group
(14%) and the study contained a mixture of patients with
oligoarticular arthritis, of whom few had an established
diagnosis of PsA [16].
SSZ
Among DMARDs, SSZ has one of the larger bodies of
evidence specifically in PsA. In a placebo-controlled trial
of 221 PsA patients there was improvement in peripheral
arthritis in 59% of SSZ-treated patients compared with
47% of controls; however, the overall effect size was
small [17]. Similarly a smaller double-blind randomized
controlled trial (RCT) suggested that the use of SSZ pro-
vided improvement in functional outcomes and to a lesser
degree skin disease [18]. Unfortunately there is no docu-
mented benefit of SSZ with regard to inhibition of joint
damage as assessed by radiographic progression [19].
LEF
LEF, an inhibitor of pyrimidine synthesis, was studied in a
multinational double-blind RCT called the Treatment of
PsA Study (TOPAS) [20]. Overall, 58.9% of the LEF-trea-
ted patients were clinical responders, compared with
29.7% of placebo controls. LEF was superior to placebo
in functional status scores, CRP reduction and 75% im-
provement in the PASI75. In a small retrospective study of
patients who were considered non-responders to MTX,
patients who received a combination of LEF and MTX
had improvements in their 28-joint DAS (DAS28) and
EULAR response criteria compared with those receiving
MTX monotherapy [21, 22]. The combination of MTX and
LEF can be associated with elevated liver function tests
and requires careful monitoring [23].
CSA and tacrolimus
CSA and tacrolimus inhibit calcineurin, resulting in the in-
hibition of T lymphocyte activation. CSA has been shown
to be effective in improving both skin and joint
21
DoQuyen Huynh and Arthur Kavanaugh

involvement in a number of clinical studies in psoriasis
and PsA [24]. CSA has also been shown to be effective
in combination with MTX and TNF inhibitor (TNFi). A
double-blind RCT that compared combination
CSA + MTX with MTX or placebo in PsA showed signifi-
cant improvement in CRP, PASI, swollen joint count and
US-defined synovitis with combination CSA + MTX [25].
Combinations of CSA with TNFi have also shown positive
results in an open label prospective study of 160 patients
receiving monotherapy CSA, monotherapy adalimumab
(ADA) or combination CSA + ADA. PsA patients on com-
bination CSA + ADA had statistically significant improve-
ments in Psoriatic Arthritis Response Criteria (PsARC),
Administration (FDA) for use in PsA: infliximab, etanercept,
ADA, golimumab and, most recently, certolizumab pegol
(Table 1) [38–48]. Overall, efficacy among the agents ap-
pears comparable, although there have not been head-to-
head trials. An indirect comparison reviewing data from
RCTs of the first four approved TNFis, and focusing on
changes in skin, peripheral joint and axial involvement,
suggested that there were no significant differences be-
tween the TNFis in PsA [49, 50]. Studies of certolizumab
pegol, the most recently approved agent, included pa-
tients who had previously been treated with other TNFis,
and showed efficacy comparable to TNFi-naive patients

Downloaded from http://rheumatology.oxfordjournals.org/ at Universidad Nacional Autonoma de Mexico on August 19, 2015
[46]. This suggests that TNFi switching may be viable in
ACR50 and HAQ assessments at 12 months compared PsA, as has been established in RA. Data supporting this
with those on monotherapy [26], although there was little concept also come from registries. In the Norwegian
difference in PASI outcomes between the groups. The DMARD (NOR-DMARD) registry, the durability of
popularity of CSA use has been tempered by the need
for close monitoring due to concerns about renal toxicity
and hypertension, especially at doses >3 mg/kg/day.
TABLE 1 Summary of results of clinical trials of TNFis in
PsA
MTX
MTX is widely accepted as a cornerstone therapy in PsA,
Patients meeting
as reflected in both the GRAPPA and EULAR treatment reponse criteria, %
recommendations [27–29]. Despite its popularity there is a Study
paucity of studies assessing MTX use in PsA, and results Agent/trial size ACR20 PASI75
have been disparate. The MTX in PsA trial randomized
221 PsA patients to placebo or 15 mg of MTX weekly for Etanercept [38, 39]
Week 12 205 59 38
6 months [30]. The overall results suggested significant
Week 24 55 40
efficacy for MTX only in the physician global assessment
Week 48 169 64 40
and PASI, and the primary outcomes were not achieved. Infliximab/IMPACT [40, 47, 48]
However, a number of factors in study design may have Week 14 200 58 64
contributed to these results, including a high dropout rate, Week 24 54 60
a relatively low dose of MTX and inclusion of PsA patients Week 54 173 59 50
with less severe disease. Indeed, when analysis was re- Week 98 104 62 64
stricted to polyarticular patients, MTX was effective. ADA/ADEPT [41, 42]
A recent systematic analysis reviewed the five RCTs in Week 12 315 58 49
the medical literature and about a dozen other observa- Week 24 57 59
Week 48 245 59 59
tional studies [31]. Although disparate results were re-
Week 104 57 58
ported in the individual studies, in general it appeared Golimumab/GO-REVEAL [43–45]
that trials using weekly doses of MTX of 515 mg achieved 50 mg
clinical benefit, whereas those using smaller doses did Week 14 405 51 40
not. Further support for the efficacy of MTX comes from Week 24 52 56
the open-label RESPOND [32] study, in which 115 treat- Week 52 360 67 62
ment-naive PsA patients were randomized to receive Week 104 335 67 86
combination MTX + infliximab or MTX monotherapy at a 100 mg
dose of 15 mg. At 16 weeks, 86% of patients received Week 14 45 58
Week 24 61 66
an ACR20 response rate with combination therapy, as
Week 52 360 71 68
did 66% of patients on MTX monotherapy. Overall, des-
Week 104 335 70 86
pite the paucity of evidence, MTX remains a mainstay of Certolizumab/ 409
drug therapy in PsA. rapid-PsA [46]
200 mg
TNF inhibitors Week 12 58 47
Week 24 138 64 62
The introduction of biologic therapies with anti-TNFis has 400 mg
greatly improved the clinician’s ability to treat all of the Week 12 51 47
various manifestations of PsA. The clinical efficacy of Week 24 135 56 61
TNFis exceeds that of traditional DMARDs and TNFis
have been shown to significantly inhibit joint damage as TNFis: tumour necrosis factor inhibitors; ADA: adalimumab;
assessed by radiographic progression [33–37]. Currently ACR20: 20% response to ACR criteria; PASI75: Psoriasis
five TNFis are approved by the US Food and Drug Area and Severity Index 75.

22 www.rheumatology.oxfordjournals.org

remaining on a second TNFi was less than that for the
first TNFi course, but suggested that some patients will
respond to TNFi switching [52]. Similarly in DANBIO
(a nationwide registry of biologic therapies in Denmark),
retention rates on a second or even a third TNFi sug-
gest that switching TNFis can result in clinical
improvement [52].
Factors such as cost and patients’ concerns regarding
side effects over the long term have raised the question of
whether treatments might be tapered or even withdrawn
in patients achieving low levels of disease activity. In RA,
studies have suggested that such a strategy might be
viable for a subset of patients, particularly those with ear-
lier disease who achieve very low levels of disease activity
on treatment. In PsA, to date there has been only one
prospective case–control study addressing this. Dose re-
duction of ADA to 40 mg every 4 weeks was done in a
population that included 76 PsA patients who had ob-
tained clinical remission [53]. At the 28-week follow-up,
88.6% of PsA patients remained in clinical remission;
interestingly, only 17.6% of the RA patients in the study
remained in remission. Other studies addressing dose re-
duction and withdrawal are currently under way and may
help define the patient characteristics that predict suc-
cess on lower doses of specific agents.
Newer therapies and agents
Despite advances in therapy, there remain patients who
fail to respond to classic DMARDs and TNFis or who have
loss of efficacy over time. Driven in part by this unmet
clinical need, newer classes and targets of therapy have
emerged. This has also been facilitated by studies further
advancing our understanding of the immunopathophysiol-
ogy of disease (Figs. 1 and 2). For example, one study
suggested a potentially key role for IL-23 in arthritides
characterized by enthesitis, including PsA [54]. Thus, in
an animal model of enthesitis, a specific subset T cell
residing in the enthesis, distinct from Th17 cells, pos-
sessed the ability to respond to IL-23, leading to up-
regulation of other inflammatory mediators, including
IL-6, IL-17 and IL-22. Of note, this model had a resemb-
lance to human disease, with enthesitis and entheseal
new bone formation as well as inflammation in the aortic
root and valve.
Ustekinumab: IL-12/IL-23 inhibitor
Ustekinumab is a human mAb directed against the p40
subunit common to IL-12 and IL-23 that has received
regulatory approval for psoriasis and PsA. In P-SUMMIT
I, 615 PsA patients with no prior TNFi exposure were ran-
domized 1:1:1 to receive placebo vs 45 mg or 90 mg of
ustekinumab. ACR20/50/70 and PASI 75 responses were
examined at 24 weeks. In the 90 mg ustekinumab group
the ACR20/50/70 and PASI75 were 49.5%/27.9%/14.2%
and 62.4%, whereas control responses were 22.8%/
8.7%/2.4% and 11%, respectively. There were also sig-
nificant improvements in the enthesitis, dactylitis and
function as measured by the HAQ. Responses were main-
tained up to 108 weeks [55, 56]. In P-SUMMIT II, PsA
www.rheumatology.oxfordjournals.org
Psoriatic arthritis: treatment
FIG. 1 Proposed immunopathogenesis in the skin
Downloaded from http://rheumatology.oxfordjournals.org/ at Universidad Nacional Autonoma de Mexico on August 19, 2015
Dendritic and T helper (Th17, Th1) cells secrete varying
implicated cytokines that further increase and recruit
leucocyte activation and ultimately systemic inflammation.
DC: dendritic cell.
patients who had previously received treatment with
TNFis were included. Of note, the magnitude of clinical
response was less than in TNF-naive patients [57].
Analysis of radiographic data from the combined
P-SUMMIT I and II databases showed inhibition of radio-
graphic progression [58]. In the studies, ustekinumab was
generally safe and well tolerated.
IL-17 inhibitors
IL-17, an inflammatory cytokine secreted by Th17 T cells
and other cells, has been identified in psoriatic plaques
and inflamed entheses. Currently there are three IL-17 in-
hibitors in advanced phase clinical trials, including secu-
kinumab, ixekizumab and brodalumab. Secukinumab and
ixekizumab are mAbs against IL-17A, while brodalumab is
a mAb directed against the IL-17 receptor A (IL-17RA).
Data for these agents have shown very robust improve-
ments in skin psoriasis. For example, in a phase IIb RCT of
secukinumab at 150 and 75 mg, there was PASI75 im-
provement of 81% and 57% of the patients, respectively,
compared with 9% for placebo at 12 weeks [59]. A dose-
finding randomized study of ixekizumab also showed sig-
nificant PASI improvement in >77% of patients compared
with 8% for placebo [60]. These authors also mention a
significant reduction in joint pain assessed by a visual
analogue scale (VAS) in 12 patients who also carried the
diagnosis of PsA. Similar to secukinumab and ixekizumab,
a phase II dose-finding trial of brodalumab showed early
improvement in PASI75 at 12 weeks compared with pla-
cebo (70 mg, 45%; 140 mg, 85.9%; 210 mg, 86.3%;
280 mg, 76%; placebo, 16%) [61].
In PsA, a small (n = 24) double-blind RCT of secukinu-
mab has demonstrated significant improvement in the
HAQ disability index (HAQ-DI) and CRP; however, the pri-
mary endpoint of ACR20 improvement was not met [62].
23
DoQuyen Huynh and Arthur Kavanaugh
FIG. 2 Proposed immunopathogenesis in PsA
Local cytokines IL-17, IL-6 and IL-23 further increase in-
flammation in joint and entheseal complex. Localized in-
flammation leads to activation of osteoclasts and erosion
formation. The presence of novel resident entheseal T
cells expressing RORgt receptors respond to IL-23 acti-
vation and further secrete IL-22 and enhance IL-6. IL-22
may activate local osteoblast cells leading to bony prolif-
eration characteristically seen in PsA. OC: osteoclast; OB:
osteoblast; RORgt: RAR-related orphan receptor; RANK:
receptor activator of nuclear factor kappa B.
Interestingly, in RA, IL-17 inhibitors have also been stu-
died, and clinical responses appeared to be modest com-
pared with therapies with other mechanisms of action.
Brodalumab has been studied in PsA as well [63]. Doses
of 140 mg and 280 mg given subcutaneously resulted in
ACR20 responses at 12 weeks of 36.8% and 39.3%, re-
spectively, compared with 18.2% for placebo. Additional
longer-term studies will be necessary to define the effect
of IL-17 inhibitors on the various manifestations of PsA.
Apremilast: phosphodiesterase inhibitor
Elevated levels of cyclic adenosine monophosphate
(cAMP) down-regulate pro-inflammatory cytokines such
as IL-12, IL-23, TNF-a and IFN-g (Fig. 3). Phosphodiester-
ase enzymes that degrade cAMP, e.g. phosphodiesterase
enzyme 4 (PDE4), have become a potential therapeutic
target. The PDE4 inhibitor apremilast has been assessed
in several studies in PsA patients. In a phase II study,
apremilast at a dose of 20 mg or 40 mg twice daily
24
FIG. 3 Mechanism of action of apremilast and tofacitinib
Downloaded from http://rheumatology.oxfordjournals.org/ at Universidad Nacional Autonoma de Mexico on August 19, 2015
Apremilast: In immune cells, Toll-like receptor 4 (TLR4)
activation leads to downstream signalling that activates
nuclear factor kappa B (NFkB, which increases tran-
scription of pro-inflammatory mediators such as IL-23 and
TNF-a. Simultaneously G protein coupled receptors
(GPCRs) activate adenylyl cyclase (AC), leading to ele-
vated levels of cyclic adenosine monophosphate (cAMP).
In cells such as monocytes, cAMP is degraded by
phosphodiesterase enzyme 4 (PDE4). Apremilast inhibits
PDE4, which leads to elevated levels of cAMP. High levels
of cAMP activate protein kinase A (pKa), leading to
phosphorylation of cAMP-responsive element binding
transcriptions factors such as cAMP-responsive element
binding protein (CREB), which can bind to promoter se-
quences of anti-inflammatory genes such as IL-10. Both
TLR4 and GPCR downstream signalling require shared
co-factors such as CREB binding protein (CBP) and p300.
Greater activation of the anti-inflammatory pathway by
apremilast may further decrease pro-inflammatory sig-
nalling by recruiting important co-factors needed in acti-
vation. Tofacitinib: Janus kinase (JAK) activation-specific
cytokines such as IL-6 lead to phosphorylation of the
signal transducer and activator of transcription (STAT)
pathway, which mediates transcription of pro-inflamma-
tory cytokines. Tofacitinib blocks JAK activity and therein
suppresses STAT signalling. IRAK: interleukin receptor-
associated kinase; TRAF6: tumour necrosis factor recep-
tor-associated factor 6; STAT3: signal transducer and
activator of transcription 3.
demonstrated significant ACR20 responses of 43.5%
and 35.8%, respectively, compared with 11.8% for pla-
cebo controls at week 12 [64]. Results from phase III trials,
dubbed PALACE 1, 2, 3 and 4, have also recently been
reported. In PALACE 1, 504 patients were randomized
1:1:1 to receive placebo, apremilast 20 mg twice a day
or apremilast 30 mg twice a day [65]. At 16 weeks, 31%
and 40% of apremilast 20 and apremilast 30 mg patients,
respectively, achieved ACR20, compared with only 19%
on placebo. Long-term follow-up to week 52 in PALACE 4
revealed persistence of benefit, with 58% of patients
meeting ACR20, although fewer patients met ACR50 or
www.rheumatology.oxfordjournals.org

70 and benefit to the skin was modest [66]. Overall, apre-
milast appeared to be well tolerated with minimal effects
on any laboratory parameters.
Abatacept: CTLA-4 inhibitor
T cells appear to play an important role in the pathogen-
esis in PsA. T cell activation is dependent on both specific
antigen presentation and co-stimulation. CTLA-4 inhibits
CD28 interactions with CD80 and CD86 and thereby
down-regulates T cell activation. Abatacept, a fusion pro-
tein composed of the extracellular domain of CTLA-4
linked to an IgG1 Fc portion, has proven efficacy in nu-
merous studies in patients with RA [67, 68]. In PsA, the
results of a randomized double-blind placebo-controlled
trial evaluating varying doses over a 6-month period have
been reported [69]. The results suggest abatacept-treated
patients, particularly those at a dose of 10 mg/kg, had a
significantly higher percentage of ACR20 responses (48%)
compared with placebo (19%). Trends toward improve-
ment in erosion, osteitis and synovitis as seen on MRI
and general improvement in physical function and quality
of life were observed. Unfortunately, the skin response
was inconsistent and patients previously exposed to
TNFis had a less robust response than TNFi-naive pa-
tients. Further studies evaluating the potential efficacy of
abatacept in PsA are currently ongoing.
Tocilizumab: IL-6 inhibitor
Tocilizumab, a humanized mAb to the IL-6 receptor, has
been approved for RA and it is being studied in PsA. Of
note, a randomized trial of tocilizumab in AS showed no
clinical efficacy despite a decrease in CRP [70]. In a case
report of two patients with PsA, there was a reduction in
CRP levels but no benefit in skin or joint symptoms, which
were alleviated subsequently with the use of anti-TNFis
[71]. Currently there is only one documented case report
of tocilizumab improving tender joint count, swollen joint
count and patient global VAS in an atypical PsA patient
that had loss of efficacy on TNFis [72].
Janus kinase (JAK) inhibitors
Another target of drug therapy are the JAK molecules:
JAK1, JAK2, JAK3 and TYK2. These intracellular mol-
ecules are important in signal transduction of cytokines
such as IL-2, IL-12 and IL-6 (Fig. 3). Tofacitinib was FDA
approved in late 2012 for the treatment of RA. Of note, it
has been shown to be effective in phase II trials of mod-
erate to severe psoriasis at doses of 5 and 15 mg twice
daily at 12 weeks of therapy [73]. Further studies in PsA
are under way.
Rituximab: CD20 inhibitor
Rituximab (RTX), a chimeric mAb directed against
CD20, has been shown to be effective and is approved
for use in RA. Recently an open-label trial of RTX in 26
patients who had either AS or PsA showed modest im-
provement in 11 of 26 patients (47.8%) as measured by
the BASDAI [74]. Of note, 23 of the 26 patients had pre-
vious exposure to TNFis. Of the 11 patients, 7 had axial
www.rheumatology.oxfordjournals.org
Psoriatic arthritis: treatment
disease while the remaining 4 had peripheral disease.
Other open-label studies also suggest quite modest im-
provement in PsA patients treated with RTX, although
some improvement may be due to concomitant steroid
use [75, 76].
Conclusion
PsA is a chronic inflammatory condition with significant
heterogeneity in clinical manifestations, including skin
and nail psoriasis, enthesitis, dactylitis, axial arthritis and
peripheral arthritis. Among DMARDs, MTX is most com-
monly used, despite a paucity of high-quality studies sup-
Downloaded from http://rheumatology.oxfordjournals.org/ at Universidad Nacional Autonoma de Mexico on August 19, 2015
porting its use. LEF, ciclosporin and SSZ are all
efficacious for arthritis and psoriasis to varying degrees
in some PsA patients. Unarguably, the class of anti-
TNFis has established itself as most effective for all the
various manifestations of PsA, and in fact could be con-
sidered the standard of care, particularly in patients with
severe, active disease. There remain unanswered ques-
tions concerning established therapies in PsA. Prominent
among these is whether TNFi and DMARD combinations,
especially with MTX, might be synergistic in PsA as they
are in RA. To date, all trials of TNFis in PsA have allowed
MTX, but have required active disease as an eligibility cri-
terion. Such a study design obviates the ability to assess
the additive or synergistic benefit of TNFi and MTX. As
noted, there is great interest in newer treatment
approaches, such as treat to target, and possibly tapering
or discontinuing therapy in patients achieving treatment
goals. Finally, pharmacoeconomic assessments specific
to PsA will help establish the value of currently available
agents and optimize their use.
Success with established therapies has helped drive
interest in newer therapies. Among the newer agents,
the greatest amount of data to date are for the IL-12/
IL-23 inhibitor ustekinumab. This agent may have its
main role in PsA patients in whom skin manifestations
are particularly active or severe. On the horizon it appears
that apremilast may offer an effective option for PsA, par-
ticularly for patients with more moderate disease activity
and in whom safety concerns might impact the choice of
other treatments. There has been interest in the effects in
PsA of therapies already approved for use in RA.
Interestingly, some therapies effective in RA, such as
RTX, seem not to be very effective in PsA. Abatacept
has some efficacy in PsA, but that too appears to be
less than its efficacy in RA. This suggests that whereas
these disease states both respond to TNFis, differences in
their immunopathogenesis may be revealed by distinct
responsiveness to other targeted therapies. In that
regard, although there are limited data currently available,
it might be argued that the efficacy of IL-17 inhibition in
the arthritis of PsA seems to be notably less than the re-
sponse of skin psoriasis. Currently the treatment outlook
in PsA appears optimistic, with numerous studies under
way. Undoubtedly these studies will allow the introduction
of additional agents and novel treatment strategies, and
ultimately help optimize the care of patients with this im-
portant condition.
25
DoQuyen Huynh and Arthur Kavanaugh
Rheumatology key messages
. PsA is a chronic inflammatory disease treated by
the use of DMARDs and TNF inhibitors.
. Newer agents to treat PsA show promise and clin-
ical trials of agents with different mechanisms of
activity are under way.
Disclosure statement: A.K. has conducted clinical re-
search activities for AbbVie, Amgen, Janssen, UCB,
Pfizer, Roche and Sanofi. The other author has declared
no conflicts of interest.
References
1 Ceponis A, Kavanaugh A. Use of methotrexate in patients
with psoriatic arthritis. Clin Exp Rheumatol 2010;28(Suppl
61):s132–7.
2 Chandran V, Gladmann DD. Update on biomarkers in
psoriatic arthritis. Curr Rheumatol Rep 2010;12:288–94.
3 Vander CB, Hoffman IE, Zmierczak H et al. Anti-citrulli-
nated peptide antibodies may occur in patients with
psoriatic arthritis. Ann Rheum Dis 2005;64:1145–9.
4 Taylor W, Gladman D, Helliwell P et al. Classification cri-
teria for psoriatic arthritis; development of new criteria
from a large international study. Arthritis Rheum 2006;54:
2665–73.
5 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.
6 Ritchlin CT, Kavanaugh A, Gladman DD et al. Treatment
recommendations for psoriatic arthritis. Ann Rheum Dis
2009;68:1387–94.
7 Healy PJ, Helliwell PS. Measuring clinical enthesitis in
psoriatic arthritis: assessment of existing measures and
development of an instrument specific to psoriatic arth-
ritis. Arthritis Rheum 2008;59:686–91.
8 Palominos PE, Gaujoux-Viala C et al. Clinical outcomes in
psoriatic arthritis: a systematic literature review. Arthritis
Care Res 2012;64:397–406.
9 Wajed J, Helliwell P, Korendowych E et al. Disease as-
sessment in psoriatic spectrum: a modular approach for
use in routine clinical practice. Ann Rheum Dis 2014;73:
318–9.
10 Coates LC, Navarro-Coy N, Brown SR et al. The TICOPA
protocol (TIght COntrol of Psoriatic Arthritis): a rando-
mized controlled trial to compare intensive management
versus standard care in early psoriatic arthritis. BMC
Musculoskelet Disord 2012;21:101.
11 Coates LC, Moverly A, McParland L et al. Results of a
randomized control trial comparing tight control of psori-
atic arthritis (TICOPA) with standard of care: tight control
improves outcome. ACR meeting, San Diego, 2013.
Abstract 814.
12 Colebatch AN, Marks JL, van der Heijde DM, Edwards CJ.
Safety of nonsteroidal anti-inflammatory drugs and/or
paracetamol in people receiving methotrexate for inflam-
matory arthritis: a Cochrane systematic review. J
Rheumatol Suppl 2012;90:62–73.
26
13 Sarzi-Puttini P, Santandrea S, Boccassini L, Panni B,
Caruso I. The role of NSAIDs in psoriatic arthritis: evidence
from a controlled study with nimesulide. Clin Exp
Rheumatol 2001;19(Suppl 22):S17–20.
14 Brenner M, Molin S, Ruebsam K et al. Generalized pus-
tular psoriasis induced by systemic glucocorticosteroids:
four cases and recommendations for treatment. Br J
Dermatol 2009;161:964–6.
15 Eder L, Chandran V, Ueng J et al. Predictors of response
to intra-articular steroid injection in psoriatic arthritis.
Rheumatology 2010;49:1367–73.
16 Marzo-Ortega H, Green MJ, Keenan AM et al. A rando-
Downloaded from http://rheumatology.oxfordjournals.org/ at Universidad Nacional Autonoma de Mexico on August 19, 2015
mized controlled trial of early intervention with intra ar-
ticular corticosteroids followed by sulfasalazine versus
conservative treatment in early oligoarthritis. Arthritis Care
Res 2007;57:154–60.
17 Clegg DO, Reda DJ, Abdellatif M. Comparison of
sulfasalazine and placebo for the treatment of axial
and peripheral articular manifestations of the seronega-
tive spondyloarthopathies. Arthritis Rheum 1999;25:
1957–61.
18 Gupta AK, Grober JS, Hamilton TA. Sulfasalazine therapy
for psoriatic arthritis: a double blind, placebo controlled
trial. J Rheumatol 1995;22:894–8.
19 Rahman P, Gladman DD, Cook RJ, Zhou Y, Young G. The
use of sulfasalazine in psoriatic arthritis: a clinic experi-
ence. J Rheumatol 1998;25:1957–61.
20 Jaimes-Hernandez J, Melendez-Mercado CI, Mendoza-
Fuentes A et al. Efficacy of leflunomide 100 mg weekly
compared to low dose methotrexate in patients with active
rheumatoid arthritis: double blind, randomized clinical trial.
Rheumatol Clin 2012;8:243–9.
21 Behrens F, Finkenwirth C, Pavelka K et al. Leflunomide in
psoriatic arthritis: results from a large European pro-
spective observational study. Arthritis Care Res 2013;65:
464–70.
22 Sakellariou GT, Sayegh FE, Anastasilakis AD,
Kapetanos GA. Leflunomide addition in patients with ar-
ticular manifestations of psoriatic arthritis resistant to
methotrexate. Rheumatol Int 2013;33:2917–20.
23 Curtis JR, Beukelman T, Onofrei A et al. Elevated liver
enzyme tests among patients with rheumatoid arthritis or
psoriatic arthritis treated with methotrexate and or leflu-
nomide. Ann Rheum Dis 2012;69:43–7.
24 Salvarani C, Macchioni P, Olivieri I et al. A comparison of
cyclosporine, sulfasalazine, and symptomatic therapy in
the treatment of psoriatic arthritis. J Rheumatol 2001;28:
2274–82.
25 Fraser AD, van Kuijk AWR, Westhovens R et al. A rando-
mized double blind, placebo controlled, multicenter trial of
combination therapy with methotrexate plus cyclosporine
in patients with active psoriatic arthritis. Ann Rheum Dis
2005;64:859–64.
26 Karanikolas GN, Koukli EM, Katsalira A et al. Adalimumab
or cyclosporine as monotherapy and in combination in
severe psoriatic arthritis: results from a prospective 12-
month nonrandomized unblinded clinical trial. J
Rheumatol 2011;38:2466–74.
27 Chandran V, Schentag CT, Gladman DD. Reappraisal
of the effectiveness of methotrexate in psoriatic
www.rheumatology.oxfordjournals.org

arthritis: results from a longitudinal observational cohort. J
Rheumatol 2008;35:469–71.
28 Scarpa R, Peluso R, Atteno M et al. The effectiveness of a
traditional therapeutic approach in early psoriatic arthritis:
results of a pilot randomized 6month trial with metho-
trexate. Clin Rheumatol 2008;27:823–6.
29 Ritchlin CT, Kavanaugh A, Gladman DD et al. Treatment
recommendations for psoriatic arthritis. Ann Rheum Dis
2009;68:1387–94.
30 Kingsley GH, Kowalczyk A, Taylor H et al. A randomized
placebo-controlled trial of methotrexate in psoriatic arth-
ritis. Rheumatology 2012;51:1368–77.
31 Ceponis A, Kavanaugh A. Use of methotrexate in patients
with psoriatic arthritis. Clin Exp Rheumatol 2010;28(Suppl
61):S132–7.
32 Baranauskaite A, Raffayova H, Kungurov NV et al.
Infliximab plus methotrexate is superior to methotrexate
alone in the treatment of psoriatic arthritis in methotrex-
ate-naive patients: the RESPOND study. Ann Rheum Dis
2012;71:541–8.
33 Ceponis A, Kavanaugh A. Treatment of psoriatic arthritis
with biological agents. Semin Cutan Med Surg 2010;29:
56–62.
34 Boehncke WH, Prinz J, Gottlieb A. Biologic therapies for
psoriasis. A systematic review. J Rheumatol 2006;33:
1147–51.
35 Salvarani C, Pipitone N, Catanoso M et al. Adalimumab in
psoriatic arthritis. J Rheumatol 2012;39(Suppl 89):77–81.
36 Spadaro A, Lubrano E, Ferrara NM, Scarpa R. Etanercept
in psoriatic arthritis. J Rheumatol 2012;39(Suppl 89):74–6.
37 Cantini F, Niccoli L, Nannini C, Kaloudi O, Cassara E.
Infliximab in psoriatic arthritis. J Rheumatol 2012;39(Suppl
89):71–3.
38 Mease PJ, Goffe BS, Metz J et al. Etanercept treatment of
psoriatic arthritis and psoriasis: a randomized trial. Lancet
2000;356:385–90.
39 Mease PJ, Kivitz AJ, Burch FX et al. Continued inhibition of
radiographic progression in patients with psoriatic arthritis
following 2 years of treatment with etanercept. J
Rheumatol 2006;33:712–21.
40 Antoni C, Kavanaugh A, van der Heijde D et al. Two-year
efficacy and safety of infliximab treatment in patients with
active psoriatic arthritis: findings of the Infliximab multi-
national psoriatic arthritis controlled trial (IMPACT). J
Rheumatol 2008;35:869–76.
41 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.
42 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, rando-
mized, placebo-controlled trial. Arthritis Rheum 2005;52:
3279–89.
43 Kavanaugh A, McInnes I, Mease P et al. Golimumab, a
new human tumor necrosis factor alpha antibody, ad-
ministered 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.
www.rheumatology.oxfordjournals.org
Psoriatic arthritis: treatment
44 Kavanaugh A, van der Heijde D, McInnes I et al.
Golimumab in psoriatic arthritis: one-year clinical efficacy,
radiographic, and safety results from a randomized, pla-
cebo-controlled trial. Arthritis Rheum 2012;64:2504–17.
45 Kavanaugh A, McInnes I, Mease P et al. Clinical efficacy,
radiographic and safety findings through 2 years of goli-
mumab treatment in patients with active psoriatic arthritis:
results from a long-term extension of the randomized
placebo-controlled GO-REVEAL study. Ann Rheum Dis
2013;72:1777–85.
46 Mease PJ, Fleischmann R, Deadhar AA et al. Effect of
certolizumab pegol on signs and symptoms in patients
with psoriatic arthritis: 24 week results of a phase 3
Downloaded from http://rheumatology.oxfordjournals.org/ at Universidad Nacional Autonoma de Mexico on August 19, 2015
double-blind randomized placebo controlled study
(RAPID-PsA). Ann Rheum Dis 2014;73:233–7.
47 Antoni C, Krueger GG, de Vlam K et al. Infliximab improves
signs and symptoms of psoriatic arthritis: results of the
IMPACT 2 trial. Ann Rheum Dis 2005;64:1150–7.
48 Kavanaugh A, Krueger GG, Beutler A et al. Infliximab
maintains a high degree of clinical response in patients
with active psoriatic arthritis through 1 year of treatment:
results from the IMPACT2 trial. Ann Rheum Dis 2007;66:
498–505.
49 Atteno M, Peluso R, Costa L et al. Comparison of effect-
iveness and safety of infliximab, etanercept and adalimu-
mab in psoriatic arthritis patients who experienced an
inadequate response to previous disease-modifying anti-
rheumatic drugs. Clin Rheumatol 2010;29:399–403.
50 Thorlund K, Druyts E, Avina-Zubieta JA, Mills EJ. Anti-
tumor necrosis factor (TNF) drugs for the treatment of
psoriatic arthritis: an indirect comparison meta-analysis.
Biologics 2012;6:417–27.
51 Fagerli K, Lie E, van der Heijde D et al. Switching
between TNF inhibitors in psoriatic arthritis: data
from the NOR-DMARD study. Ann Rheum Dis 2013;72:
1840–4.
52 Glintborg B, Ostergaard M, Krogh NS et al. Clinical re-
sponse, drug survival, and predictors thereof among 548
patients with psoriatic arthritis who switched tumor ne-
crosis factor a inhibitor therapy: results from the Danish
Nationwide DANBIO registry. Arthritis Rheum 2013;65:
1213–23.
53 Cantini F, Niccoli L, Cassara E, Kaloudi O, Nannini C.
Sustained maintenance of clinical remission after adali-
mumab dose reduction in patients with early psoriatic
arthritis: a long term follow up study. Biologics 2012;6:
201–6.
54 Sherlock P, Joyce-Shaikh B, Turner S et al. IL-23 induces
spondylarthropathy by acting on ROR-gt+
CD3+CD4 CD8 entheseal resident T cells. Nat Med
2012;18:1069–77.
55 McInnes I, Kavanaugh A, Gottlieb A et al. Ustekinumab in
patients with active psoriatic arthritis: results of the phase
3, multicenter, double-blind, placebo-controlled
PSUMMIT I study. Ann Rheum Dis 2012;71(Suppl):
S107–48.
56 McInnes IB, Kavanaugh A, Gottlieb AB et al. Efficacy and
safety of ustekinumab in patients with active psoriatic
arthritis: 1 year results of the phase 3 multicentre, double
blind, placebo-controlled PSUMMIT 1 trial. Lancet 2013;
382:780–9.
27
DoQuyen Huynh and Arthur Kavanaugh
57 Kavanaugh A, Puig L, Gottlieb A et al. Efficacy and safety
of ustekinumab in patients with active psoriatic arthritis: 2
year results from a phase 3, multicenter, double-blind,
placebo-controlled study. ACR meeting, San Diego, 2013.
Abstract L10.
58 McInnes I, Ritchlin C, Rahman P. Ustekinumab is effective
in inhibiting radiographic progression in patients with
active psoriatic arthritis: integrated data analysis of two
phase 3, randomized, placebo-controlled studies. ACR
meeting, San Diego, 2013. Abstract 1695.
59 Papp KA, Langley RG, Sigurgeirsson MA et al. Efficacy
and safety of secukinumab in the treatment of moderate-
to-severe plaque psoriasis: a randomized, double-blind,
placebo-controlled phase II does-ranging study. Br J
Dermatol 2013;168:412–21.
60 Leonardi C, Matheson R, Zachariae C et al. Anti-interleu-
kin-17 monoclonal antibody ixekizumab in chronic plaque
45. psoriasis. N Engl J Med 2012;366:1190–9.
61 Papp K, Leonardi C, Menter A et al. Brodalumab, an anti-
interleukin-17-receptor antibody for psoriasis. N Engl J
Med 2012;366:1181–9.
62 McInnes IB, Sieper J, Braun J et al. Efficacy and safety of
secukinumab, a fully human anti-interleukin-17A mono-
clonal antibody, in patients with moderate-to-severe
psoriatic arthritis: a 24-week, randomized, double blind,
placebo controlled, phase II proof of concept trial. Ann
Rheum Dis 2014;73:349–56.
63 Genovese M, Mease P, Greenwald M et al. Clinical re-
sponse to brodalumab, an anti-interleukin-17 receptor
antibody, in subjects with psoriatic arthritis. ACR meeting,
San Diego, 2013. Abstract 817.
64 Schett G, Wollenhautpt J, Papp K et al. Oral apremilast in
the treatment of active psoriatic arthritis: results of a
multicenter, randomized, double-blind, placebo-con-
trolled study. Arthritis Rheum 2012;64:3156–67.
65 Kavanaugh A, Mease PJ, Adebajo AO et al. Long term (52
week) results of a phase 3, randomized controlled trial of
apremilast, an oral phosphodiesterase 4 inhibitor, in pa-
tients with psoriatic arthritis. Ann Rheum Dis 2013;
72(Suppl 3):163.
66 Wells A, Edwards CJ, Adebajo A et al. Apremilast in the
treatment of DMARD naı̈ve psoriatic arthritis patients: re-
sults of a phase 3 randomized controlled trial (PALACE 4).
ACR meeting, San Diego, 2013. Abstract L4.
67 Westhovens R, Kremer J, Moreland L et al. Safety and
efficacy of the selective costimulation modulator
28
abatacept in patients with rheumatoid arthritis receiving
background methotrexate: a 5 year extended phase IIB
study. J Rheumatol 2009;36:736–42.
68 Schiff M, Weinblatt ME, Valente R et al. Head-to-head
comparison of subcutaneous abatacept versus adalimu-
mab for rheumatoid arthritis: two-year efficacy and
safety findings from AMPLE trial. Ann Rheum Dis 2014;73:
86–94.
69 Mease P, Genovese MC, Gladstein G et al. Abatacept in
the treatment of patients with psoriatic arthritis: results of
a six-month, multicenter, randomized double-blind pla-
cebo controlled, phase II trial. Arthritis Rheum 2011;63:
939–48.
Downloaded from http://rheumatology.oxfordjournals.org/ at Universidad Nacional Autonoma de Mexico on August 19, 2015
70 Sieper J, Porter-Brown B, Thompson L, Harari O,
Dougados MJ. Tocilizumab (TCZ) is not effective for
the treatment of ankylosing spondylitis (AS): results of
phase II international, multicenter, randomized, double-
blind, placebo-controlled trial. Ann Rheum Dis 2012;
1(Suppl 3):110.
71 Ogata A, Umegaki N, Katavama I, Kumanogo A, Tanaka T.
Psoriatic arthritis in two patients with an inadequate re-
sponse to treatment with tocilizumab. Joint Bone Spine
2012;79:85–7.
72 Hughes M, Chinoy H. Successful use of tocilizumab in a
patient with psoriatic arthritis. Rheumatology 2013;52:
1728–9.
73 Mamolo C, Harness J, Tan H, Menter A. Tofacitinib (CP-
690,550), an oral Janus kinase inhibitor, improves patient-
reported outcomes in phase 2b, randomized, double-
blind, placebo-controlled study in patients with moderate-
to-severe psoriasis. J Eur Acad Dermatol Venereol 2013;
28:192–203.
74 Wendling D, Dougados M, Berenbaum F et al. A nation-
wide series: data from the AIR registry of the French
Society of Rheumatology. J Rheumatol 2012;39:2327–31.
75 Mease P, Kavanaugh A, Genovese M et al. Rituximab in
psoriatic arthritis provides modest clinical improvement
and reduces expression of inflammatory biomarkers in
skin lesions [abstract]. Arthritis Rheum 2010;62(Suppl):
S818.
76 Song IH, Heldmann F, Rudwaleit M et al. Different re-
sponse to rituximab in tumor necrosis factor blocker-naive
patients with active ankylosing spondylitis and in patients
in whom tumor necrosis factor blockers have failed: a
twenty-four week clinical trial. Arthritis Rheum 2012;62:
1290–7.
www.rheumatology.oxfordjournals.org