Comment
Psoriatic arthritis: novel targets add to a therapeutic
renaissance
Psoriasis is the most common chronic auto­
inflammatory skin disease, affecting 2–3% of the
world’s population, of whom 10–30% have psoriatic
arthritis.1 As a result of better elucidation of crucial
pathogenic inflammatory pathways and the advent of
biologic disease-modifying anti-rheumatic therapies,
the treatment of psoriatic arthritis has undergone a
renaissance.2
Interleukin 23 is a heterodimeric cytokine that
consists of a p40 subunit, which is shared with
interleukin 12, and a unique p19 subunit. It is
produced by T cells, dendritic cells, and macrophages
in response to mechanical stress, the microbiota, and
abnormalities in HLA B27 protein folding, inducing
differentiation and maintenance of T-helper-17 cells.3
The interleukin 23–interleukin 17 pathway has an
important role in the pathogenesis of psoriasis and
psoriatic arthritis. It acts at the crossroads of innate
and adaptive immunity, driving local entheseal
inflammation via interleukin 23-responsive γδ T cells,
which are a rich source of interleukin 17, interleukin 22,
and tumour necrosis factor. In turn, secretion of these
factors leads to secondary synovitis, osteitis, bone
destruction, and bone hyperproliferation, typical of
psoriatic arthritis, and epidermal proliferation and
inflammation, typical of psoriasis.4
Previous studies5,6 have established the efficacy
and safety of the interleukin 12 and interleukin 23
inhibitor ustekinumab in the treatment of psoriasis
and psoriatic arthritis. Guselkumab, a humanised
IgG1 monoclonal antibody that targets the unique
p19 subunit of interleukin 23, allows sparing of the
interleukin 12–T-helper-1 axis, which is important for
defence against intracellular pathogens via interferon
γ production. Guselkumab has shown good efficacy
and safety in previous studies7 of psoriasis, both
when compared with placebo and with adalimumab,
and is now approved by the US Food and Drug
Administration and the European Medicines Agency
for this indication.
In The Lancet, Atul Deodhar and colleagues8
report the first-ever multicentre, randomised,
placebo-controlled, phase 2a trial of the efficacy
www.thelancet.com Vol 391 June 2, 2018 2187
and safety of guselkumab in patients with active
psoriatic arthritis, which was defined as more
than three swollen and tender joints, elevated
C-reactive protein, at least 3% body surface rash,
and an inadequate response to traditional disease-
modifying anti-rheumatic therapies or one previous
Science Photo Library
tumour necrosis factor inhibitor (limited to 20% of
patients). The primary endpoint was the proportion
of patients with at least 20% improvement in signs
and symptoms of psoriatic arthritis according to See Articles page 2213
American College of Rheumatology (ACR) criteria at
week 24. Patients were randomly assigned to receive
100 mg guselkumab (n=100) or placebo (n=49) via
subcutaneous injection at baseline, week 4, and
then every 8 weeks up to 24 weeks, at which point
all patients received guselkumab up to 56 weeks.
Rescue to ustekinumab was offered to patients with
less than 5% improvement in number of swollen
and tender joints at week 16. The included patients
had long-standing active skin and joint disease, as
evidenced by a mean disease duration of 7 years, a
mean of 11 swollen joints, and a mean Psoriasis Area
and Severity Index (PASI) score of 10 at baseline.
Moreover, 66 (44%) of 149 patients were on
methotrexate at baseline, 107 (72%) had pre-existing
enthesitis, and 81 (54%) had pre-existing dactylitis.
58 (58%) of 100 patients in the guselkumab
group attained the primary endpoint compared
with nine (18%) of 49 patients in the placebo
group (p<0·0001), with the results not affected by
concomitant methotrexate use or tumour necrosis
factor inhibitor exposure (although few participants
had previously received anti-tumour necrosis factor
α drugs). 23 (23%) patients in the guselkumab group
achieved minimal disease activity compared with
one (2%) patient on placebo (p=0·0010). Significant
benefit with guselkumab was observed by 4 weeks of
treatment (the first assessment point). The proportion
of patients with at least 20% or 50% improvement in
signs and symptoms of psoriatic arthritis according to
ACR criteria had plateaued by 20 weeks, whereas the
proportion with at least 70% improvement according
to ACR criteria had not plateaued by 24 weeks.
 Comment
39 (40%) of 98 patients in the guselkumab group had
100% reduction in the PASI score (indicating complete
clearing of psoriasis) compared with three (6%) of
48 patients in the placebo group. No nail disease data
were presented.
The main strength of this study is that all of the
prespecified primary and secondary endpoints,
including those of signs, symptoms, resolution of
dactylitis and enthesitis, physical function, and quality
of life, were in favour of guselkumab. These benefits
were maintained to 12 months. Unfortunately,
numbers of patients rescued were too small to
meaningfully examine the switch to ustekinumab
compared with remaining on guselkumab.
Although this study comprised a reasonably small
number of patients who were followed up for a
relatively short period of time, no new safety signals
were observed compared with trials of guselkumab
in psoriasis, with the exception of neutropenia
(three [3%] of 100 patients in the guselkumab group
had grade 2 neutropenia and one [1%] had grade 3
neutropenia without associated sepsis). In particular,
no patient in either group had tuberculosis or any
other opportunistic infection (ie, candidiasis or zoster),
and no adverse effects of interest (ie, depression
and reactivation of inflammatory bowel disease)
were reported. Uveitis was not mentioned. Only
one injection-site reaction was reported (in the
placebo group), and six (5%) of the 128 patients who
had received guselkumab at 56 weeks had anti-drug
antibodies, without loss of clinical effect. None of
these patients had neutralising antibodies.
The study has several limitations. The sample size
was small, and few patients who had not responded
to anti-tumour necrosis factor α drugs or had disease
for less than 2 years before baseline were included.
However, larger phase 3 studies (NCT03158285,
NCT03162796) in patients with psoriatic arthritis,
including those who have not responded to tumour
necrosis factor inhibitors, are underway. The
study did not use an active comparator, such as a
tumour necrosis factor inhibitor, ustekinumab, or
an interleukin 17 inhibitor, although a head-to-
head comparison with an interleukin 17 inhibitor in
patients with psoriasis is ongoing (NCT03090100).
The authors did not do subgroup analyses for
type of psoriatic arthritis, such as axial disease or
2188 www.thelancet.com Vol 391 June 2, 2018
pauciarthropathy (less than five swollen joints),
which are common presentations in clinical practice.
Furthermore, they did not assess radiological
progression, which will form part of a longer phase 3
study (NCT03158285), and given the long half-life of
guselkumab, investigation of different dose regimens
and timings would have been interesting.
In summary, Deodhar and colleagues8 showed good
efficacy for guselkumab in all aspects of psoriatic
arthritis, with a manageable safety profile, and
thus have introduced an important new drug to the
therapeutic armamentarium. An additional benefit
might be the ability to treat the extra-articular
manifestation, inflammatory bowel disease, as
has been seen with interleukin 12–interleukin 23
inhibition.9 However, if interleukin 23 does have
a pivotal role in the pathogenesis of psoriasis and
psoriatic arthritis and control downstream production
of several cytokines, it is disappointing that the
excellent efficacy response for guselkumab was
equivalent but not numerically superior to existing
drugs, such as interleukin 17 inhibitors (although
these drugs have been tested in different patient
populations with different disease activities). Either
our measures are limited in their ability to show better
responses in patients with long-standing disease (a
regression to the mean) or, more likely, pathways
other than the interleukin 23–interleukin 17 pathway
are important in the pathogenesis of psoriatic
arthritis.
Peter Nash
University of Queensland, Brisbane, QLD 4006, Australia
drpnash@tpg.com.au
I have received funding for clinical trials and honoraria from Abbvie,
Bristol-Myers Squibb, Eli Lilly, Pfizer, Roche, and Sanofi, all outside the area
and product commented on here.
1 Scotti L, Franchi M, Marchesoni A, Corrao G. Prevalence and incidence of
psoriatic arthritis: a systematic review and meta-analysis.
Semin Arthritis Rheum 2018; published online Jan 6. DOI:10.1016/j.
semarthrit.2018.01.003.
2 Mease P. Psoriatic arthritis and spondyloarthritis assessment and
management update. Curr Opin Rheumatol 2013; 25: 287–96.
3 Lories RJ, McInnes IB. Primed for inflammation: enthesis-resident T cells.
Nat Med 2012; 18: 1018–19.
4 Sherlock JP, Joyce-Shaikh B, Turner SP, et al. IL-23 induces
spondyloarthropathy by acting on ROR-γt+ CD3+CD4–CD8– entheseal
resident T cells. Nat Med 2012; 18: 1069–76.
5 Ritchlin C, Rahman P, Kavanaugh A, et al. Efficacy 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 trial. Ann Rheum Dis 2014; 73: 990–99.

6 Kimball AB, Papp KA, Wasfi Y, et al. Long-term efficacy of ustekinumab in
patients with moderate-to-severe psoriasis treated for up to 5 years in
the PHOENIX 1 study. J Eur Acad Dermatol Venereol 2013; 27: 1535–45.
7 Nakamura M, Lee K, Jeon C, et al. Guselkumab for the treatment of
psoriasis: a review of phase III trials. Dermatol Ther 2017; 7: 281–92.
Hip arthroscopy: an evidence-based approach
It started with the knee, then the shoulder, then the
ankle, and now it is the hips’ turn. Instead of open
surgery, arthroscopic surgery of the hip joint can be
used to repair structural damage. Arthroscopic surgery is
considered to be less invasive than an open procedure,
and the intact tissues are minimally exposed and not
traumatised. This approach can lead to quicker recovery
and early return to function and activity, with fewer
complications.1 For the hip, arthroscopy spares the
cutting of the ligamentum teres and reduces damage
to the capsular structures by avoiding dislocation.
The literature has also supported the idea of hip
arthroscopy as a less invasive method of repairing the
damage caused by femoroacetabular impingement.2,3
Femoroacetabular impingement, originally described by
Ganz and colleagues,4 is abnormal bony morphology of
the femoral head–neck junction, rim of the acetabulum,
or both. This abnormal bone results in impingement
and decreased space within the joint, causing damage to
the intra-articular structures.
Although numerous case series and cohort
studies have shown that arthroscopic treatment of
femoroacetabular impingement-related intra-articular
damage reduces symptoms and returns patients to
activity with high patient satisfaction, no phase 1 trials
had been done.2,3,5–7 The results from the UK FASHIoN
study, reported in The Lancet by Damian Griffin
and colleagues,8 provide this needed evidence. Griffin
and colleagues compare hip arthroscopy with a
structured physical therapy programme (personalised
hip therapy) for the treatment of hip symptoms due
to femoroacetabular impingement in 348 patients.
12 months after randomisation, hip arthroscopy
resulted in superior clinical benefit compared with
conservative treatment (mean difference in Inter­
national Hip Outcome Tool score 6·8, 95% CI 1·7–12·0;
p=0·0093).
Although this patient sample might seem small, the
authors should be commended on completing this
www.thelancet.com Vol 391 June 2, 2018 2189
Comment
8 Deodhar A, Gottlieb AB, Boehncke W-H, et al. Efficacy and safety of
guselkumab in patients with active psoriatic arthritis: a randomised,
double-blind, placebo-controlled, phase 2 study. Lancet 2018; 391: 2213–24.
9 Neurath MF. IL-23: a master regulator in Crohn disease. Nat Med 2007;
13: 26–28.
study with this number of patients. Today’s health- See Articles page 2225
care consumers tend to have abundant knowledge
about their medical issues. Patients often come to
the office asking for a specific treatment. There is also
variability between the surgeons’ training background
and experience. These factors make randomised trials
difficult to complete; not only is it challenging to recruit
patients, but the expense of these types of studies
makes them nearly impossible to do in orthopaedics.
UK FASHIoN is not the only phase 1 study of hip
arthroscopy. As the Article mentions, a recent study9 in
a military population showed no difference between hip
arthroscopy and conservative care; however, there was
a large crossover rate and power was limited in some
analyses. The study by Griffin and colleagues is the first to
establish the efficacy of hip arthroscopy versus physical
therapy in the medical literature. The authors randomly
assigned more than 50% of the available patients and
provided a conservative treatment protocol, which
included an assessment, injections, education, and
exercise. Although the conservative protocol produced
inferior outcomes, there were no differences in general
health measures. The patients in the conservative group
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