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ARD Online First, published on December 7, 2015 as 10.1136/annrheumdis-2015-208337
Clinical and epidemiological research
EXTENDED REPORT
also making clear that safety aspects and contraindications need The recommendations are targeted at all appropriate stake-
to be considered in therapeutic decision-making. As an umbrella holders: (A) rst, physicians, aiming particularly at rheumatolo-
organisation of national rheumatological societies, EULAR gists, but also other physicians involved in the care of people
decided to put its primary emphasis on the musculoskeletal with PsA (irrespective of clinical presentation), including general
aspects of the disease.8 The EULAR recommendations were practitioners, dermatologists and other specialists; (B) people
based on the evidence available at that time4 and on the results with PsA who can use these recommendations for information
of the discussions and votes by an expert committee. However, on current therapies, treatment strategies and opportunities; and
as with most recommendations and especially in a rapidly evolv- (C) other stakeholders which include ofcials in governments,
ing eld such as PsA, it was anticipated that the 2012 recom- social security agencies and reimbursement agencies as well as
mendations would need updating within a few years. Indeed, hospital managers.
additional evidence on agents already approved at that time as
well as data on new compounds have become available since
RESULTS
2012 (S Ramiro, JS Smolen, S Landew, et al, Pharmacological
Overarching principles
treatment of psoriatic arthritis: a systematic literature review for
The Task Force designated some principles regarding the care of
the 2015 update of the EULAR Recommendations for the man-
patients with PsA of such generic nature as to be overarching
agement of psoriatic arthritis. Submitted to ARD 2015).9
(table 1).
Moreover, new trials have addressed therapeutic strategies10 and
The rst and third overarching principles remain unchanged
treat-to-target recommendations have been developed for PsA
compared with 2012. Of note, an optimal management of
since the publication of the EULAR PsA management recom-
patients with PsA also includes non-pharmacological strategies
mendations.11 12 All these developments prompted us to update
with patient education and regular exercising. In the second
the recommendations for the management of PsA with non-
overarching principle, the shared decision with the patient,
topical pharmacological therapies.
which refers to the necessity to discuss and record treatment
aims, management plans and reasons for the recommended
approaches with the patient, was expanded by adding consider-
METHODS
ing efcacy, safety and costs. All these aspects, including costs,
The EULAR standardised operating procedures were applied.13
need to be taken into account when making treatment decisions.
In June 2014, a Steering Group consisting of seven rheumatolo-
Indeed, while rheumatologists and patients cannot be held
gists, one fellow, one patient research partner and one health
responsible for costs of therapies, they need to bear in mind
professional dened the questions that were to be addressed
that cost considerations are part of evidence-based medicine
through an SLR. The SLR was performed between June 2014
approaches,17 especially also in the light of the advent of novel
and January 2015 and is published as an accompanying paper.14
targeted therapies and biosimilars (see below).
In parallel, a general review of treatment strategies, prognostic
In the fourth overarching principle, the reference to the treat-
factors and comorbidities was performed. In January 2015, the
ment target as remission has been deleted, since it is now dealt
Steering Group as well as the Task Force met to discuss the
with in Recommendation 1, but the necessity to abrogate
results of the literature review, aiming at aggregating the avail-
inammation, which may be seen as a surrogate wording for the
able information on disease management in PsA into practical
term remission, is still clearly stated.
recommendations. The Task Force consisted of 34 persons from
The fth overarching principle has been modied: formerly it
14 European countries: 27 rheumatologists, 3 people affected
dealt with the principle of treating to target, but this is now
with PsA, 2 health professionals, 1 dermatologist and 1 rheuma-
contained in Recommendation 1. This principle now mentions
tology fellow. This inclusive approach aimed at obtaining broad
the importance of considering comorbidities, which are frequent
consensus and applicability of the recommendations.
in PsA and need to be assessed and treated. In particular, cardio-
The process was evidence-based and consensus-based and
vascular diseases and metabolic syndrome appear more common
included, between June 2014 and February 2015, two expert
in patients with PsA than in controls.18 19
meetings, the SLR and extensive discussions. The recently pro-
posed nomenclature distinguishing csDMARDs, tsDMARDs,
bDMARDs, biologic original DMARDs and biosimilar Recommendations
DMARDs (bsDMARDs) was applied.3 Beyond the overarching principles, the process led to 10 recom-
Each recommendation from 2012 as well as those that were mendations on drug management and treatment strategies, pre-
newly developed based on the SLR were discussed in detail sented in table 1. Table 1 also provides the category of evidence,
and, where necessary, modied until acceptable to the Task grade of recommendation and level of agreement for each of
Force; at each step, a 67% majority was required for approval the bullet points.16 These recommendations also serve as the
or rejection of a particular recommendation. If a clear-cut basis for the algorithm provided in gure 1.
approval or rejection was not obtained, the wording was Importantly, the table and the gure synthesise the rationale
amended until it met the predetermined level of approval. behind the recommendations in an abbreviated way that may
Thus, each of the recommendations presented here has not fully reect all important aspects. Therefore the accompany-
received approval by at least two-thirds of the Task Force ing text, presented below, has to be regarded as integral to the
members. The Task Force members were provided with the recommendations; the multiple facets are contained within the
category of evidence and grade of recommendation for each text and not necessarily within the bullet points in the table
item.15 16 let alone the algorithm. Furthermore, in all cases the balance
After the nal meeting, an anonymised email-based voting on between efcacy and safety must be taken into account for an
the level of agreement was performed, using a 010 scale with a individual patient.
vote of 0 meaning total disagreement with a particular recom- 1. Treatment should be aimed at reaching the target of remis-
mendation and 10 meaning total agreement with it. The means sion or, alternatively, minimal/low disease activity, by regular
and SDs of scores from the whole group were calculated. monitoring and appropriate adjustment of therapy.
2 Gossec L, et al. Ann Rheum Dis 2015;0:112. doi:10.1136/annrheumdis-2015-208337
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Table 1 Updated EULAR recommendations for the management of PsA, with levels of evidence, grade of recommendations and level of
agreement
Level of agreement
Overarching principles (meanSD)
A. PsA is a heterogeneous and potentially severe disease, which may require multidisciplinary treatment 9.61.1
B. Treatment of patients with PsA should aim at the best care and must be based on a shared decision 9.21.7
between the patient and the rheumatologist, considering efficacy, safety and costs
C. Rheumatologists are the specialists who should primarily care for the musculoskeletal manifestations 9.50.8
of patients with PsA; in the presence of clinically significant skin involvement a rheumatologist and a
dermatologist should collaborate in diagnosis and management
D. The primary goal of treating patients with PsA is to maximise health-related quality of life, through 9.61.0
control of symptoms, prevention of structural damage, normalisation of function and social
participation; abrogation of inflammation is an important component to achieve these goals
E. When managing patients with PsA, extra-articular manifestations, metabolic syndrome, 9.51.0
cardiovascular disease and other comorbidities should be taken into account
Level of Grade of Level of agreement
Recommendations evidence recommendation (meanSD
1. Treatment should be aimed at reaching the target of remission or, alternatively, minimal/low disease 1b A 9.60.9
activity, by regular monitoring and appropriate adjustment of therapy
2. In patients with PsA, NSAIDs may be used to relieve musculoskeletal signs and symptoms 1b A 9.60.8
a
3. In patients with peripheral arthritis, particularly in those with many swollen joints, structural damage :3 B 9.40.8
b
in the presence of inflammation, high ESR/CRP and/or clinically relevant extra-articular : 1b
manifestationsa, csDMARDs should be consideredb at an early stagea, with methotrexate preferred in
those with relevant skin involvementb
4. Local injections of glucocorticoids should be considered as adjunctive therapy in PsAa; systemic a
: 3b C 9.11.2
glucocorticoids may be used with caution at the lowest effective doseb b
:4
5. In patients with peripheral arthritis and an inadequate response to at least one csDMARD, therapy 1b B 9.50.7
with a bDMARD, usually a TNF inhibitor, should be commenced
6. In patients with peripheral arthritis and an inadequate response to at least one csDMARD, in whom 1b B 9.11.1
TNF inhibitors are not appropriate, bDMARDs targeting IL12/23 or IL17 pathways may be considered
7. In patients with peripheral arthritis and an inadequate response to at least one csDMARD, in whom 1b B 8.51.4
bDMARDs are not appropriate, a targeted synthetic DMARD such as a PDE4-inhibitor may be
considered
8. In patients with active enthesitis and/or dactylitis and insufficient response to NSAIDs or local 1b B 9.11.2
glucocorticoid injections, therapy with a bDMARD should be considered, which according to current
practice is a TNF inhibitor
9. In patients with predominantly axial disease that is active and has insufficient response to NSAIDs, 1b B 9.60.6
therapy with a bDMARD should be considered, which according to current practice is a TNF inhibitor
10. In patients who fail to respond adequately to a bDMARD, switching to another bDMARD should be 1b B 9.60.7
considered, including switching between TNF inhibitors
The level of evidence was determined for different parts of the recommendation (referred to as a and b) where necessary.
The level of agreement was computed as a 010 scale.
bDMARD, biological DMARD; CRP, C reactive protein; csDMARDs, conventional synthetic disease-modifying antirheumatic drugs, such as methotrexate, sulfasalazine or leflunomide; ESR,
erythrocyte sedimentation rate; EULAR, European League Against Rheumatism; NSAIDs, non-steroidal anti-inflammatory drugs; PDE, phosphodiesterase; PsA, psoriatic arthritis; TNF,
tumour necrosis factor.
This recommendation is new and comprises previous over- It should be noted that this remission of inammation may not
arching principle E and Recommendation 2, but also elements equate to complete absence of all symptoms for many patients.
of previous overarching principle D.8 Targeting an optimal Indeed, recent work in PsA demonstrated that the impact of the
outcome by adjusting treatment in the context of regular disease disease on quality of life is related to pain, skin problems and
activity monitoring was deemed so important, that this recom- functional disability, and fatigue, as well as emotional and social
mendation was placed as number 1, especially given its general aspects of impact.31 Some of these aspects of impact may be less
strategic nature. accessible to pharmacological therapies of PsA, thus leading to a
In RA, attaining a state of remission or low disease activity residual impact in the absence of inammation.
leads to better structural and functional outcomes than allowing Furthermore, remission may be difcult to achieve in
moderate, let alone high, disease activity.20 21 In PsA, there exist PsA.24 3234 Factors associated with higher remission rates
few data regarding natural history, treatment objectives and appear to be younger age, lower functional impairment and
remission.11 2225 However since in PsA inammation is related higher C reactive protein levels in some cases.35 While in RA
to long-term outcomes of joint involvement,2630 this recom- stringent remission criteria have been agreed upon and validated
mendation states that the objective in patients with PsA is remis- as being associated with optimal outcomes,36 remission is still
sion or if remission cannot be achieved, a low or minimal insufciently dened in PsA.11 37 We suggest that the use of out-
disease activity state. Remission is dened here as the absence of comes where remission/low disease activity have been dened,
clinical and laboratory evidence of signicant inammatory should be considered. This is now the case for several scores
disease activity.11 In addition to absence of inammation in the used in PsA, some of which focus only on arthritis whereas
joints, absence of enthesitis and dactylitis are also important. others encompass various aspects of psoriatic disease.38
Gossec L, et al. Ann Rheum Dis 2015;0:112. doi:10.1136/annrheumdis-2015-208337 3
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As regards joint involvement, a stringent remission denition 3. In patients with peripheral arthritis, particularly in those
and criteria for low disease activity by the Disease Activity with many swollen joints, structural damage in the presence
index for PSoriatic Arthritis (DAPSA) have been recently of inammation, high erythrocyte sedimentation rate/C
dened and validated.25 However, minimal/low disease may also reactive protein and/or clinically relevant extra-articular
be a relevant target especially for long-standing disease, as strin- manifestations, csDMARDs should be considered at an early
gent remission may not be achievable in these patients or in stage, with MTX preferred in those with relevant skin
some patients with comorbidities that preclude escalation of involvement.
therapy. Minimal disease activity in PsA has been dened as ve This recommendation combines items 2 and 3 of the 2012
of the seven criteria comprising musculoskeletal and skin mani- recommendations. However, in 2012 the term active disease
festations and patient-reported outcomes.3943 This outcome was used, whereas here it was replaced by peripheral arthritis
has been shown in one study to be predictive of less structural since this is more precise (active disease also meaning poten-
degradation, and in the recent Tight control in PsA (TICOPA) tially active skin disease). As in 2012, the experts considered
trial to be a valid treatment target.44 that patients with peripheral arthritis and poor prognosis should
Denitions of remission and acceptable residual disease activ- be promptly started on csDMARDs, and also with milder
ity levels in PsA, its predictors and its relationship with long- disease if arthritis persisted despite NSAID therapy and despite
term outcomes are still a part of the research agenda and more glucocorticoid injections if indicated. Peripheral arthritis in this
thorough assessment of prognostic markers of severity (related context is dened globally as one or more tender and swollen
to risk of progressive disease, structural damage, physical disabil- joints.
ity and quality of life) must still be addressed. The natural history of PsA is variable and not well known
This recommendation also addresses monitoring and the prin- given the lack of large, long-term cohorts;54 thus prognostic
ciple of treating to target and tight control which have recently factors are still part of the research agenda in PsA. Poor prog-
been expanded to PsA and updated for RA.11 12 20 Because of nostic factors, as agreed upon by the Task Force, are a high
the lack of data regarding the best interval for patient monitor- number of actively involved joints, either tender or swollen
ing, the recommendation states regular monitoring, but we (dened as ve or more); radiographic damage ( joint destruc-
suggest in usual care patients with active disease should be seen tion), in particular if there is also inammation; elevated acute
between monthly to every 3 months. Similarly, treatment should phase reactants (ie, any value above the upper limit of normal as
be adjusted appropriately: more data regarding monitoring and serological indication of inammation); and extra-articular man-
treatment adaptation are needed in PsA. The only randomised ifestations, in particular dactylitis.26 28 5558 The presence of
trial addressing specically a tight control approach in PsA is the any one factor is sufcient to recommend early csDMARD
recently published TICOPA trial.10 44 In this trial, patients with therapy, but usually more than one will be present in patients
active PsA randomised to the tight control arm had a treatment with bad prognosis.
escalation starting with csDMARDs up to bDMARDs, if the pre- The time that can elapse without structural or functional con-
dened target of minimal disease activity was not reached: the sequence before a csDMARD is started in the presence of active
group with tight control had more favourable outcomes. peripheral PsA is unclear. The phrasing at an early stage
The best ways to monitor disease activity in PsA are uncer- implies starting treatment within a maximum of 3 months if the
tain.37 4548 The recommended Core Set for PsA comprises per- PsA is active (in particular with active synovitis), particularly in
ipheral joints, pain, patient global assessment, physical function, the presence of the bad prognostic markers mentioned above.
quality of life, fatigue and acute phase reactants.45 In any case, There are several recently published studies showing that a pro-
it is important to use validated and quantied measurements.49 longed delay before diagnosis and/or before starting a
The validity of the individual measures has been compared in a csDMARD is associated with less favourable outcomes.5963
recent study.37 These studies encourage earlier treatment commencementthe
In clinical practice, although such measures are imperfect, it question of a window of opportunity in PsA still constitutes an
can be suggested to use composite measures focusing on joint important part of the research agenda.
involvement and thus including joint counts, such as the Disease Based on the available literature (Ramiro S et al, Submitted to
Activity Score or the Simplied Disease Activity Index or the ARD 2015) and similarly to the 2012 recommendations, the
Clinical Disease Activity Index (all originally developed for experts recommended MTX as the rst-choice csDMARD. This
RA);50 the Composite Psoriatic Disease Activity Index;51 the decision took into account the relative lack of data from rando-
DAPSA;52 or the Psoriatic ArthritiS Disease Activity Score.38 53 mised controlled trials, as noted in the 2012 SLR4 and the ran-
These scores have been shown to exhibit partly different dis- domised controlled trial of MTX published in 2012 which did
criminative abilities.37 However, further work is needed, espe- not reach the primary end point.64 The group was also aware of
cially since it is not clear if using a composite measures across the lack of demonstration of structural efcacy of MTX. The
disease tissues which may (indeed appear to) have differential Task Force however also considered data on the wide use and
therapeutic responses is appropriate. good treatment maintenance of MTX in PsA. Indeed, MTX
2. In patients with PsA, non-steroidal anti-inammatory drugs maintenance was around 65% at 2 years in the Norwegian
(NSAIDs) may be used to relieve musculoskeletal signs and DMARD registry, which appeared similar to its maintenance in
symptoms. RA.65 66 Moreover, the TICOPA trial revealed that 22% of
This recommendation remains unchanged. NSAIDs have been treated patients achieved minimal disease activity on MTX
shown to be efcacious on joint symptoms and especially alone.44 When treating with MTX, careful consideration must
patients with mild joint disease may benet from NSAIDs, be given to the prescription of an efcacious dose which is
though there is no demonstrated efcacy on skin lesions and usually in the 1525 mg/week range, to the route (subcutaneous
risks and contraindications need to be considered. However, a or oral) and to folate substitution.67
benet from NSAIDs should be seen within a few weeks and In patients with clinically relevant psoriasis, MTX is specic-
NSAIDs should not be the only therapy above 3 months if ally mentioned as the preferred option, given its demonstrated
patients have active disease as dened in Recommendation 3. efcacy on skin involvement.68 Although this recommendation
Gossec L, et al. Ann Rheum Dis 2015;0:112. doi:10.1136/annrheumdis-2015-208337 5
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does not refer to composite skin indices such as the PASI (which a high retention rate over time in cohort studies.74 75 There
are widely used in trials, but not by rheumatologists in clinical were no evident differences regarding the efcacy of the differ-
practice), the present criteria for clinically relevant skin psoria- ent TNFis on the joints, although no head-to-head comparisons
sis would correspond, in dermatological terms, to moderate to exist (Ramiro S et al, Submitted to ARD 2015).4 However, for
severe psoriasis, dened as a body surface area involvement psoriatic skin involvement, it seems that the TNF receptor con-
>10%, or more limited psoriasis leading to signicant impact struct etanercept is less efcacious, or at least has a slower onset,
on quality of life (eg, face/hand/genital involvement). than for the other TNF targeting drugs (although there are,
There were no new data prompting us to modify our previous again, no head-to-head comparisons available). Likewise,
recommendation on other csDMARDs including sulfasalazine, bsDMARDs of TNFis approved by the European Medical
leunomide, ciclosporine (although its use is limited by toxicity Agency are regarded by the Task Force to be indeed similar to
issues), and in some cases gold salts and azathioprine, though and thus equally applicable as the biological originator TNFis in
for these last drugs the level of evidence is low.4 Their effect on PsA and psoriasis. Also biosimilar TNFis which are approved by
skin involvement is usually smaller than that of MTX. Although FDA and/or EMA are regarded to be similar to the respective
there is little evidence on efcacy of csDMARD combinations, biological originator TNFis. Indeed, a biosimilar iniximab
these may be considered.10 69 agent has been recently approved by The European Medicine
4. Local injections of glucocorticoids should be considered as Agency based on studies in RA and ankylosing spondylitis and
adjunctive therapy in PsA; systemic glucocorticoids may be extrapolated to all other indications for which iniximab has
used with caution at the lowest effective dose. been approved.76
This recommendation remained unchanged. While no new Recent data suggest that continuation of a concomitant
evidence has accumulated since the last recommendations, we csDMARD therapy in combination with TNFis is benecial in
reiterate that intra-articular glucocorticoids may have a place in PsA in terms of treatment maintenance and levels of response,
the treatment of patients with PsA, in particular in patients with especially in patients using monoclonal antibodies, but more
monoarthritis/oligoarthritis.70 Glucocorticoid injections may data are warranted including the effect of concomitant
also be helpful in dactylitis (tendon sheath injections) and in csDMARD on immunogenicity.75 77 78
enthesitis, for example, at the elbow or the retrocalcaneal Regarding safety, the new data available since the 2012
bursae in Achilles enthesitis. Ultrasound can help guide these recommendations were published suggest that bDMARDs have
injections if needed. The fear of reactivation of psoriasis by glu- a similar and acceptable risk prole in PsA as in psoriasis or
cocorticoids use in the rheumatology setting is not substantiated RA.79
by evidence, but long-term use of systemic glucocorticoids In the 2012 recommendations, the exceptional use of TNFis
should be avoided based on the signicant risks of adverse in a very active patient nave of disease-modifying treatment
events and in particular the adverse event prole of longer- had been addressed in Recommendation 8. This has been
term glucocorticoid therapy needs to be taken into consider- deleted in the current recommendations given the lack of data
ation when initiating and especially continuing oral and the lack of consensus and, thus, no longer constitutes a
glucocorticoids.71 72 recommendation.
5. In patients with peripheral arthritis and an inadequate 6. In patients with peripheral arthritis and an inadequate
response to at least one csDMARD, therapy with a response to at least one csDMARD, in whom TNFis are not
bDMARD, usually a TNFi, should be commenced. appropriate, bDMARDs targeting interleukin (IL) 12/23 or
The meaning of this recommendation remained essentially IL-17 pathways may be considered.
unchanged though the terminology has been updated and the Drugs with two novel mechanisms of action, namely the
sole reference to TNFis in 2012 has been expanded to IL-12/23 and IL-17 pathways, have recently demonstrated clinic-
bDMARDs in general, but with a primary focus on TNFi. In ally relevant efcacy in PsA (Ramiro S et al, Submitted to ARD
contrast to 2012, more biologicals have shown efcacy in PsA, 2015). Regarding the IL-12/23 pathway, ustekinumab is cur-
and some have either been approved or are under consideration rently the bDMARD with most available data;8084 the IL-23
for approval; this will be dealt with in subsequent blockers guselkumab and tildrakizumab have to date only been
recommendations. assessed with good efcacy in skin psoriasis.85 86 Regarding the
In patients with peripheral arthritis in whom a csDMARD IL-17 pathway, secukinumab is the drug with most available
(usually MTX because of its effects on joints and skin, but also data.8789 Ixekizumab is currently being tested in PsA whereas
leunomide, sulfasalazine or others, see above) is not efcacious brodalumab has shown efcacy, but its development is currently
(ie, the treatment target of at least low disease activity has not on hold.90
been reached) even though the treatment has been taken for an The Task Force felt that the place of these new drugs and in
appropriate length of time (usually 36 months), a bDMARD particular of the licensed drugs ustekinumab (for psoriasis and
can be considered. Treatment escalation is relevant if the disease PsA) and secukinumab (at the time of the Task Force meeting
is active, that is, if there is evidence of active arthritis in terms licensed for psoriasis, not PsA, but with efcacy demonstrated
of swollen joints and/or at least moderate disease activity by a in PsA phase 3 trials) in the treatment algorithm in 2015 should
composite disease activity measure. be after an inadequate response to at least one csDMARD (this
The focus on TNFi among the bDMARDs is based here on means: as second-line DMARD). However, it should be kept in
the opinion of the experts, who felt that given the long-term mind that both agents have shown less efcacy numerically in
experience, the well established efcacy/safety balance in PsA, patients who had previously received TNFi compared with
and usual practice, currently TNFi treatment would usually be those who had only failed csDMARDs (see Recommendation
the rst choice. All the available originator TNFis (adalimumab, 10); this reduced responsiveness is also observed with sequential
certolizumab pegol, etanercept, golimumab and iniximab) have TNFi use. While the safety proles of these new agents are not
demonstrated efcacy in PsA, for skin and joint involvement, as unfavourable, long-term safety data are needed to fully appreci-
well as in preventing radiographic damage (Ramiro S et al, ate their benet:risk prole. Therefore, in light of the efcacy/
Submitted to ARD 2015).4 73 Furthermore, TNFis have shown safety prole of these drugs, the Task Force felt that these new
6 Gossec L, et al. Ann Rheum Dis 2015;0:112. doi:10.1136/annrheumdis-2015-208337
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drugs should usually be recommended for patients in whom Comparisons across trials were difcult because different
TNFis may not be appropriate. No particular sequence was outcome measures are used. However, as stated above, the
recommended between these two new bDMARDs. Further, it is longest experience exists for TNFis. Thus the recommendation
currently not possible to recommend the continuation of a was worded accordingly. This recommendation was in fact
csDMARD with the new bDMARDs, given the lack of evidence reworded during the process of developing the recommenda-
for an added benet from co-medication in the randomised con- tions to be in line with the fact that the evidence base is not
trolled trials (in post hoc analyses), although it is not needed to different for enthesitis or dactylitis than for arthritis and
discontinue csDMARDs and not at all an error to continue axial disease. It should be noted that while apremilast has
them (Ramiro S et al, Submitted to ARD 2015). Elucidation of shown some efcacy on enthesitis, the Task Force felt that
this question constitutes part of the research agenda. more data were needed than available at the time of the devel-
Patients in whom TNFis may not be appropriate include, for opment of these recommendations. In general, physicians must
example, patients with comorbidities or those with a history of apply good clinical judgement when faced with dactylitis/enthe-
infections or patients who prefer not to be treated with a TNFi. sitis towards appropriate use of bDMARDs without overusing
7. In patients with peripheral arthritis and an inadequate them.
response to at least one csDMARD, in whom bDMARDs are 9. In patients with predominantly axial disease that is active
not appropriate, a tsDMARD, such as a PDE4-inhibitor, may and has insufcient response to NSAIDs, therapy with a
be considered. bDMARD should be considered, which according to current
Apremilast is a tsDMARD acting as a PDE4-inhibitor and has practice is a TNFi.
been demonstrated to be efcacious in PsA (Ramiro S et al, This recommendation applies to the subgroup of patients
Submitted to ARD 2015). The SLR performed for the current with PsA who have predominant and active axial disease.
task found a moderate efcacy of apremilast on joints, skin and Active disease here is usually dened in reference to a Bath
entheses in PsA.9193 Thus, apremilast is a new drug, which will Ankylosing Spondylitis Disease Activity Index above 4 points.
expand the pharmacopoeia in PsA. Given the moderate effect In these patients, bDMARDs can be considered even if no
size of apremilast on most outcomes in PsA, the Task Force dis- csDMARDs have been tried, since csDMARDs have no proven
cussed at length the position of this drug. Like all agents, the rela- efcacy in axial disease.96 Given the limited data on the ef-
tionship between benet, risk and costs has to be considered. cacy of ustekinumab and the lack of data for secukinumab in
Taking into account apremilasts relatively low efcacy, not insig- patients with PsA with axial involvement, the experts held that
nicant costs, the lack of structural data and studies comparing it TNFis would currently be the rst choice of bDMARD in
with MTX, other csDMARDs or bDMARDs, and the good these patients (Ramiro S et al, Submitted to ARD 2015).
overall safety prole, we suggest the place for this drug should at Indeed, we do not currently have sufcient published data on
this time in most cases be limited to patients who failed to reach efcacy of ustekinumab or secukinumab in patients with anky-
the treatment target on csDMARDs and for whom bDMARDs losing spondylitis, and even less data on those patients with
may not be appropriate. This would include, for example, axial disease associated to psoriasis or PsA.97 This is also
patients with comorbidities or a history of infections contraindi- reected in the current indication for these drugs (ustekinumab
cating any bDMARD. Such a recommendation cannot be consid- approved for PsA but not for axial spondyloarthritis). Thus,
ered as based mainly on evidence, as this use was not studied these agents may be useful but are recommended here only as
specically in the large apremilast phase 3 programme, which alternatives, especially if TNFis fail or cannot be applied. No
included mostly patients who were naive to bDMARDs. Thus in data were available to the Task Force on the effects of apremi-
some cases apremilast can also be considered earlier in the algo- last on axial disease.
rithm, perhaps for patients without markers of severe prognosis 10. In patients who fail to respond adequately to a bDMARD,
or those who explicitly do not wish to receive a parenteral medi- switching to another bDMARD should be considered,
cation; this would however be at the discretion of the physician, including switching between TNFis.
as the group did not reach consensus on such a situation. This This recommendation is derived from studies indicating a
recommendation received the lowest level of agreement among good efcacy of a second TNFi in PsA (Ramiro S et al, Submitted
all bullet points, reecting the diversity of opinions. to ARD 2015). There is a lack of direct data of non-TNF inhibit-
8. In patients with active enthesitis and/or dactylitis and insuf- ing bDMARDs in such situations, but in randomised controlled
cient response to NSAIDs or local glucocorticoid injections, trials of ustekinumab and secukinumab many patients (3360%)
therapy with a bDMARD should be considered, which had previously been treated with TNFis, although their response
according to current practice is a TNFi. rates were somewhat lower than seen in patients who had not
This recommendation deals with the subgroup of patients previously experienced a bDMARD.84 87 88 Thus, current ther-
with predominant enthesitis/dactylitis. In this patient popula- apies with a different molecular target do not appear to be more
tion, no data-driven denition of active disease (relative to efcacious than another TNFi in this patient population by indir-
enthesitis/dactylitis) exists and the Task Force considered at least ect judgement of the experts.
one active localisation as active disease, taking into account Switches are possible including for more than one switch and
quality of life consequences as most relevant in these patients. including intraclass or interclass switches (including switches
In these patients, after failure of local or non-specic anti- from a bDMARD to a tsDMARD); it appears efcacy of third
inammatory therapy, bDMARDs may be applied even if no or fourth bDMARDs might be lower at the population level.
csDMARDs have been tried, since the latter have not been Although the Task Force discussed the issues of treatment
proven efcacious in treating these aspects of PsA, especially tapering when the treatment target has been reached, it was felt
enthesitis.94 95 The experts felt the data did not allow a deni- that the available data were insufcient to develop a separate
tive primary choice between a TNFi or bDMARDs targeting recommendation.98102
IL-12/23 or IL-17 pathways, since there are no head-to-head As shown in table 1, the levels of evidence were quite high
comparisons and based on the available data all these agents for most of the items, although some are still mainly driven by
appear to have similar efcacy on enthesitis and dactylitis. expert opinion (particularly Recommendations 3 and 4).
Gossec L, et al. Ann Rheum Dis 2015;0:112. doi:10.1136/annrheumdis-2015-208337 7
Downloaded from http://ard.bmj.com/ on May 3, 2017 - Published by group.bmj.com
Interestingly with one exception, all items received a mean level DISCUSSION
of agreement that exceeded 9 of 10. The updated recommendations for the pharmacological man-
agement of PsA presented here contain 5 overarching principles
Research agenda and 10 recommendations. As would be expected, many of the
As in 2012, a research agenda was developed/updated (table 2). recommendations have remained largely unchanged compared
with those provided in 2012. However, in 2012, patients with drugs in the therapeutic algorithm or in terms of denitions of
PsA had only TNFi available, once csDMARDs had failed, the target treatment population. However, the Task Force has
while meanwhile new bDMARDs, a bsDMARD and a very thoroughly considered overall efcacy (none of the new
tsDMARD have been, or are in the process of being approved agents is numerically more efcacious than the TNFis), safety
for PsA, thus expanding the treatment armament importantly. (some of the new agents indeed appear safer than TNFis) and
Moreover, strategic trials had not been previously performed costs, as far as comparatively available or known. Importantly,
for PsA and this has changed meanwhile. Thus, the updated currently long-term experience on efcacy and safety exists for
recommendations propose a new algorithm which integrates all the TNFis, but not the new agents, and it is only such data that
these recent developments that include drugs with novel modes can elicit an amendment of these recommendations in the near
of action as well as novel strategic evidence and new data on future. Our aim is certainly to encourage further research and
already previously addressed agents or principles. These recom- innovation in the eld of rheumatic diseases, including accrual
mendations should provide physicians who treat patients with of efcacy and particularly safety data of new agents in registries
PsA with a practical approach to prescribing the most appropri- and long-term extension trials. Thus, we feel that the proposed
ate treatments for patients with PsA based on the most recent algorithm addresses all relevant issues related to an indirect
insights. comparison of drugs, namely efcacy, safety, ease of use, costs
Beyond physicians, the EULAR recommendations are also and long-term experience.
aimed at patients with PsA so that they are informed about It must also be borne in mind that the Task Force presents
current treatment goals, strategies and opportunities. recommendations, not opposable guidelines, and thus the indi-
Importantly, patient representatives have also participated in the vidual items reect a majority view of many experts, including
Task Force. It may, however, be useful to reformulate these patient representatives, but at the same time provides sufcient
recommendations into patient-friendly wording to enhance leeway to the individual physician and national societies to con-
their implementation. Moreover, other stakeholders, such a sider a different approach than advocated herethis by no
policy makers as well as representatives of hospital management means would be wrong. However, the very high level of agree-
and social security agencies are targeted to gain information on ment among the Task Force members across almost all recom-
the latest therapeutic developments and approaches in the eld. mendations supports their appropriateness and validity.
The Task Force was convinced that modern therapy of PsA The Task Force was aware that some agents covered here were
should be target-oriented and governed by a strategic treatment not yet approved for PsA by the European Medicine Agency at
approach. Remission or at least low disease activity, if remission the times of the meeting and manuscript development.
cannot be attained, was reafrmed as the therapeutic goal. However, we based our assessments and decisions on the avail-
However, similarly to 2012, the literature review yielded sparse able and thoroughly evaluated and discussed literature and felt
data regarding the natural history, prognosis, treatment targets that the recommendations should include them in our aspiration
and treatment strategies in PsA, in contrast to the situation in to support physicians when taking treatment decisions now and
RA.55 57 Moreover, the denition of remission remains to be in the near future.
validated in PsA.11 25 39 Finally, as has been the case over the last decade, it is to be
The updated EULAR recommendations are an international anticipated that new data on existing or new drugs or thera-
document, designed and intended to serve a large array of stake- peutic strategies will emerge over the next few years and that
holders throughout Europe and beyond, although we are aware some of the open questions as formulated here may be answered
of the fact that not all agents mentioned here are universally by then. Therefore, we will carefully observe the developments
available or accessible. in the eld and assume that an amendment of these recommen-
While we are aware that, in parallel, the Group for Research dations may be needed in 23 years time.
and Assessment of Psoriasis and Psoriatic Arthritis is also updat-
ing management recommendations, these recommendations may Author afliations
1
have a relatively prominent dermatology focus,103 104 while we Sorbonne Universits, UPMC Univ Paris 06, Institut Pierre Louis dEpidmiologie et
de Sant Publique, GRC-UPMC 08 (EEMOIS), Paris, France
very deliberately aimed and aim at developing recommendations 2
Department of rheumatology, AP-HP, Piti Salptrire Hospital, Paris, France
that have a major focus on the musculoskeletal manifestations of 3
Division of Rheumatology, Department of Medicine 3, Medical University of Vienna,
PsA, since societies representing rheumatologists, other health Vienna, Austria
4
professionals working in the eld of rheumatology and patients 5
Second Department of Medicine, Hietzing Hospital, Vienna, Austria
Department of Rheumatology, Leiden University Medical Centre, Leiden, The
with musculoskeletal disorders form EULARs constituency.
Netherlands
These recommendations reect the current state of evidence 6
EULAR, representing People with Arthritis/Rheumatism in Europe (PARE), London,
and opinions in the area of PsA pharmacological management. UK
7
The 5 overarching principles and 10 practical recommendations Research Laboratory and Clinical Division of Rheumatology, Department of Internal
have a high level of face validity and feasibility, and the develop- Medicine, University of Genova, Viale Benedetto, Italy
8
Medicine Faculty, Paris Descartes University, Paris, France
ment of a scientic agenda will guide future research. However, 9
Rheumatology B Department, APHP, Cochin Hospital, Paris, France
while many recommendations are based on high levels of evi- 10
Leeds NIHR Musculoskeletal Biomedical Research Unit, LTHT, Leeds, UK
11
dence, some of them are solely based on expert opinion, imply- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds,
ing that the research agenda is extensive and important. Leeds, UK
12
Department of Clinical Immunology & Rheumatology, Amsterdam Rheumatology
In this respect it is important to bear in mind that, despite the
Center, Amsterdam, The Netherlands
evidence of their efcacy from randomised controlled trials, 13
Atrium Medical Center, Heerlen, The Netherlands
only expert opinion can currently dene the place of the new 14
North Devon, UK
15
drugs in the treatment algorithm. We are aware that this place- Rheumazentrum Ruhrgebiet, Herne and Ruhr-Universitt Bochum, Herne, Germany
16
ment in the algorithm will be a topic of intense discussions in Department of Rheumatology and Clinical Immunology, CharitUniversity
Medicine Berlin, Germany
the rheumatology community. Indeed, some will contend that 17
Arthritis Unit, Department of Rheumatology, Hospital Clnic and IDIBAPS,
the Task Force has been too proactive and others will argue that Barcelona, Spain
18
it has been too limitative in terms of placement of the new Belgrade University School of Medicine, Belgrade, Serbia
These include:
References This article cites 98 articles, 59 of which you can access for free at:
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Notes