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ARD Online First, published on June 8, 2013 as 10.1136/annrheumdis-2013-203419
Clinical and epidemiological research Treating spondyloarthritis, including ankylosingspondylitis and psoriatic arthritis, to target:recommendations of an international task force Josef S Smolen,1,2 Jürgen Braun,3 Maxime Dougados,4 Paul Emery,5Oliver FitzGerald,6 Philip Helliwell,5 Arthur Kavanaugh,7 Tore K Kvien,8Robert Landewé,9,10 Thomas Luger,11 Philip Mease,12 Ignazio Olivieri,13John Reveille,14 Christopher Ritchlin,15 Martin Rudwaleit,16 Monika Schoels,2Joachim Sieper,17 Martinus de Wit,18 Xenofon Baraliakos,3 Neil Betteridge,18Ruben Burgos-Vargas,19 Eduardo Collantes-Estevez,20 Atul Deodhar,21Dirk Elewaut,22 Laure Gossec,23 Merryn Jongkees,18 Mara Maccarone,18Kurt Redlich,1 Filip van den Bosch,22 James Cheng-Chung Wei,24 Kevin Winthrop,25Désirée van der Heijde26 Handling editor Francis being aware that the evidence base is not strong and Background Therapeutic targets have been defined for needs to be expanded by future research. These For numbered affiliations see diseases like diabetes, hypertension or rheumatoid recommendations can inform the various stakeholders end of article.
arthritis and adhering to them has improved outcomes.
about expert opinion that aims for reaching optimal Such targets are just emerging for spondyloarthritis outcomes of SpA.
Correspondence toProfessor Josef S Smolen, Division of Rheumatology, Objective To define the treatment target for SpA Department of Medicine 3, including ankylosing spondylitis and psoriatic arthritis The approaches to the diagnosis, therapy and Medical University of Vienna, (PsA) and develop recommendations for achieving the follow-up of patients with ankylosing spondylitis Waehringer Guertel 18-20, target, including a treat-to-target management strategy.
Vienna A-1090, Austria; josef.
(AS) and psoriatic arthritis (PsA) have undergone a Methods Based on results of a systematic literature number of paradigmatical changes over the last review and expert opinion, a task force of expert decade. Especially considerations of the disease physicians and patients developed recommendations spectrum of spondyloarthritis (SpA) have recently Accepted 15 May 2013 which were broadly discussed and voted upon in a undergone remarkable changes. In addition to AS, Delphi-like process. Level of evidence, grade and strength of the recommendations were derived by changes in the sacroiliac joints, non-radiographic respective means. The commonalities between axial SpA, axial SpA (axSpA) has been defined based on the peripheral SpA and PsA were discussed in detail.
absence of such changes but presence of sacroiliitis Results Although the literature review did not reveal (as documented by MRI) and/or human leukocyte trials comparing a treat-to-target approach with another antigen B27. The term axSpA, therefore, includes or no strategy, it provided indirect evidence regarding an radiographic axSpA (AS) and non-radiographic optimised approach to therapy that facilitated the axSpA. On this basis, new classification criteria development of recommendations. The group agreed on 5 overarching principles and 11 recommendations; 9 of SpondyloArthritis international Society (ASAS),1 these recommendations related commonly to the whole novel therapies have proven efficacious,2–6 MRI has spectrum of SpA and PsA, and only 2 were designed been increasingly established as an imaging tool in separately for axial SpA, peripheral SpA and PsA. The SpA1 7 8 and new indices to assess disease activity main treatment target, which should be based on a have been developed.9–14 The novel approach to shared decision with the patient, was defined as classification has also differentiated the two pre- remission, with the alternative target of low disease dominant manifestations of SpA, axial and/or per- activity. Follow-up examinations at regular intervals that ipheral, and their potential parallel occurrence.15 depend on the patient's status should safeguard the The basis for the new classification lies in the evolution of disease activity towards the targeted goal.
sharing of characteristic features of SpA, such as Additional recommendations relate to extra-articular and sacroiliitis, spondylitis and enthesitis and common extramusculoskeletal aspects and other important factors, genetic markers and a positive family history.
such as comorbidity. While the level of evidence was Furthermore, extramusculoskeletal manifestations To cite: Smolen JS, Braun J, generally quite low, the mean strength of such as psoriasis in PsA, a preceding gastrointestinal Dougados M, et al. AnnRheum Dis Published Online recommendation was 9–10 (10: maximum agreement) for or urogenital infection as in the case of reactive First: [ please include Day all recommendations. A research agenda was formulated.
arthritis (ReA), and chronic inflammatory bowel Month Year] doi:10.1136/ Conclusions The task force defined the treatment diseases (IBD) like Crohn's disease and ulcerative target as remission or, alternatively, low disease activity, colitis, play a role in the definition of a clinical Smolen JS, et al. Ann Rheum Dis 2013;0:1–11. doi:10.1136/annrheumdis-2013-203419 Copyright Article author (or their employer) 2013. Produced by BMJ Publishing Group Ltd (& EULAR) under licence.
Clinical and epidemiological research syndrome as belonging to the concept of SpA. For the classifica- already at the steering committee meeting, was the question if tion of patients with PsA the Classification Criteria for Psoriatic diseases like AS, PsA, ReA and IBD arthritis should be seen as Arthritis (CASPAR) criteria are well established.16 Since the an entity or as different diseases. The respective decision would presence of psoriasis plays a role in both criteria sets, the ASAS have a bearing to the consensus finding process, since it would and the CASPAR criteria, there is some overlap between the mean to develop one, two or more documents. The initial delib- two. There is no international agreement whether and how they erations tended toward separating the individual diseases for can or should be differentiated. Finally, to account for thera- several reasons: (1) despite many commonalities, some import- peutic developments, management recommendations have ant clinical manifestations are distinct between these conditions recently been presented.17–20 and certain health professionals (such as dermatologists and gas- Despite all these advances, a variety of challenges exist when troenterologists) may not be sufficiently aware of the more uni- considering the management of patients with SpA,21–24 not least fying concept of SpA or its relevance when dealing with these because the definition of a clear therapeutic target and strategies conditions; (2) further, the existing distinction between PsA and to reach such target are not yet optimally defined.
AS is well known for and accepted by patients and changes in In many areas of medicine, such as diabetes care or cardi- terminology may cause confusion regarding the understanding ology, clear therapeutic targets are available.25–30 More recently, of their ‘new' diagnosis; (3) to date, clinical trials have been per- a treatment target has also been advocated for rheumatoid arth- formed almost entirely in individual subentities (AS, PsA) rather ritis (RA), namely remission or low disease activity,31 32 a rec- than SpA, and even most recently trials in a highly specific novel ommendation based on insights from various clinical trials as subset, non-radiographic axSpA, have been performed38; (4) the revealed by systematic literature reviews (SLRs).33 34 Much less current drug approval process by regulatory agencies is also information on the value of defining therapeutic targets is cur- related to the individual diseases rather than SpA; and (5) there rently available for AS or PsA. Therefore, a task force was is some overlap between the different subgroups, but there are formed to discuss and develop a consensus on recommendations also major distinctions, for example, PsA with symmetric polyar- aimed at defining a treatment target for, and thus at improving thritis as the predominant feature would not fit well into either the management of axial and peripheral SpA in clinical practice.
the axial or peripheral SpA group. Therefore, the provisionalchoice was to develop at least two documents, one for axSpA and one for PsA. The discussions took place in separate break- The consensus finding consisted of a three-step process. In a first out sessions devoted to these topics and in a plenary session. At step, the first and last author invited leading experts, defined on the plenary session, certain items were reformulated and reor- the basis of their citation frequency in the field and previous con- dered and two provisional sets of recommendations developed, tributions to similar activities to form a steering committee. This with decisions made using a modified Delphi technique.32 The steering committee, which included rheumatologists experienced group then realised how similar the individual statements in in the care of patients with, and/or clinical research in axial and/ each of the two documents were, but left further decisions to or peripheral SpA (several of them Department chairs and thus the next stage of the process.
in managerial functions), a dermatologist experienced in psoria- With these two documents prepared and having in mind that sis, and patients being diagnosed with one of these diseases and/ peripheral SpA (such as ReA) had not yet been dealt with in or experienced in consensus finding processes, met in March 2011 in Vienna to discuss unmet needs in the therapeutic man- (Amsterdam); its membership comprised the initial task force agement of and the potential of using treatment targets in AS and expanded by consideration of a more international scope to also PsA. To this end, the debate focused on axial and peripheral SpA include experts from Latin America and Asia, aside from previ- separately in two breakout groups with a subsequent common ous participants from Europe and North America. Again, the assessment. In the course of these discussions there was unani- scope and background of this activity was discussed and the pro- mous agreement that defining therapeutic targets and an appro- visional recommendations presented. The issue of disease defin- priate strategic treatment approach would be valuable, but that ition and the need of developing one, two or three documents evidence for its validity may be lacking. Therefore it was decided were addressed. The committee separated into three breakout to perform a SLR and respective PICO (Patient, Intervention, groups discussing axSpA, peripheral SpA and PsA. In the course Control, Outcome) and search terms were formulated, in line of the breakout discussions and the plenary session, the initial with European League Against Rheumatism (EULAR) and Appraisal of Guidelines for Research and Evaluation recommen- Importantly, when looking at the individual items, the partici- dations.35 36 In the course of defining the scope of this activity, pants felt that most of them were very similar and a broad deci- the target populations were also specified, namely health profes- sion was then taken to develop a single document comprising sionals involved in care of and patients affected by axial and/or overarching principles and items common to SpA in general, peripheral SpA. In addition, social security officials, hospital but within that common document to develop a few individua- managers and policy makers at national and international levels lised items for axSpA, PsA and peripheral SpA.
were considered potential stakeholders in this activity.
Each statement, which had been formulated as a draft for At a subsequent meeting in November 2011 (Dusseldorf ) voting in the course of the breakout sessions and by the whole comprising an expanded task force with increased international task force, was subjected to voting as ‘yes' (agreement with the participation, the SLR was presented. These invitations were a wording) or ‘no' (disagreement). Statements supported by consequence of the individuals' contributions to the field and ≥75% of votes were immediately accepted while those with deliberations among members of the steering committee. The ≤25% were rejected outright. Others were subjected to further literature search had revealed that currently no strategic trials discussion and subsequent voting, where ≥67% support or, in addressing a target-oriented, steered therapy were published, an eventual third round, a majority of ≥50% was needed.
although some indirect evidence on optimal therapeutic After the face-to-face meeting, the statements were distributed approaches was available to inform the next stages of the to the committee members by email for final comments. Only process.37 A major focus of discussion at this meeting, but also suggestions for improvements of clarity of wording or Smolen JS, et al. Ann Rheum Dis 2013;0:1–11. doi:10.1136/annrheumdis-2013-203419 Clinical and epidemiological research addressing redundancies were considered, while any changes to B. SpA and PsA are often complex systemic diseases; as the meaning were not accepted.
needed, the management of musculoskeletal and extra-articular Finally, the group voted anonymously by email on the level of manifestations should be coordinated between the rheumatolo- agreement, that is, strength of recommendation, with each of gist and other specialists (such as dermatologist, gastroenterolo- the derived bullet points (in the form it was ultimately agreed upon by the qualified majority of participants) using a 10-point This item is supposed to inform patients, healthcare profes- numerical rating scale (1=do not agree at all, 10=agree sionals with less experience in the care of SpA and non-medical stakeholders that patients with SpA are frequently sufferingfrom extramusculoskeletal manifestations and are often in need of multidisciplinary care for optimal therapy. When multiorgan The evidence base involvement is present, a harmonised approach among specia- The SLR, which is published separately,37 revealed that in con- lists is required which should ideally be coordinated by the trast to findings in RA33 no randomised controlled clinical trial rheumatologist, especially if the musculoskeletal involvement has evaluated a targeted therapeutic approach in comparison causes major complaints.
with routine therapy. However, several publications had C. The primary goal of treating the patient with SpA and/or PsA employed therapeutic targets and respective time requirements is to maximise long-term health related quality of life and social as endpoints or before escalating therapy, although this is often participation through control of signs and symptoms, prevention the placebo arm of a study that was allowed to escape or then of structural damage, normalisation or preservation of function, escalated to active treatment. These comprised 14 studies in AS avoidance of toxicities and minimisation of comorbidities.
and 7 studies of PsA which were found suitable to inform the The significant burden of axSpA and PsA in terms of disabil- task force. Nevertheless, given the lack of studies evaluating ity, loss of quality of life and work productivity has only target-steered versus non-steered treatment, the level of evidence recently been appreciated.47–52 This generally formulated item for the developed recommendations is low and mainly based on addresses the importance to control signs and symptoms like expert consensus.
pain, structural changes such as ankylosis,53 54 comborbid-ities55–57 and the importance of focusing on the totality ofdisease manifestations and complications when determining the proposal for a treatment target.
The individual statements receiving a positive vote by the major- D. Abrogation of inflammation is presumably important to ity of the expert committee members comprise 5 overarching achieve these goals.
principles and 11 recommendations. The overarching principles PsA and SpA are inflammatory diseases and inflammation and 9 of the statements are recommended for SpA in general, leads to their signs and symptoms, functional impairment as whereas the last 2 statements have been individualised for well as structural changes.7 11 58–61 Therefore, stopping inflam- axSpA, peripheral SpA and PsA. The recommendations are mation appears to be of key importance to optimise outcome.
shown in table 1. They are discussed in detail below and this Indeed, in many patients non-steroidal anti-inflammatory drugs detailed description should be regarded as part and parcel of (NSAIDs) can lead to cessation of signs and symptoms, normal- isation of physical function and potentially inhibition of struc-tural damage in the spine.62 63 Interference with the Overarching principles proinflammatory cytokine tumour necrosis factor (TNF) sup- In the Committee's view, a number of elements related to treat- presses inflammation effectively and can lead to disappearance ing SpA are so representative of good clinical practice that they of signs and symptoms and maximal improvement of physical form a general framework for more specific recommendations.
function. Thus, the task force was convinced that disappearance These were therefore termed overarching principles, and five of inflammation conveys the best outcome. However, current such principles were developed and voted on.
evidence indicates that TNF inhibition does not prevent pro- A. The treatment target must be based on a shared decision gression of structural changes in AS.64 65 Moreover, it has not between patient and rheumatologist.
been determined if a state of remission leads to better long-term Patient involvement in therapeutic decision-making has outcome of SpA and/or PsA than low disease activity. Thus, this become a mandate in patient care, especially when dealing with item is somewhat more controversial than most other ones.
chronic diseases. This is a general patient right, and has been Therefore the word ‘presumably' was added. This point consti- shown to improve mutual understanding and outcome39–42 and tutes a backbone for some of the subsequent individual is also increasingly recognised to be important in SpA.43–45 The committee was convinced that patients must be informed about E. Treatment to target by measuring disease activity and the proposed treatment target, therapeutic options to reach the adjusting therapy accordingly contributes to the optimisation of target and reasons for recommending the target also in light of short and/or long-term outcomes.
the risk related to treatment and risk related to the disease; on The SLR has revealed that patients with AS who do not reach the other hand, patients should actively participate in this dis- predefined, measurable treatment targets can achieve further cussion. This aspect is subsequently reinforced in recommenda- improvement upon adaptation of their therapy. While for PsA tion number 8 and these two items received the highest level of this has not yet been established, the task force regarded the need agreement among all bullet points. The principle also specific- to measure disease activity and amend therapy with persistently ally mentions the rheumatologist, since it is the rheumatologist active disease as a general necessity and, therefore, as a principle.
who should coordinate treatment of patients with SpA.
The level of agreement with these five principles was very Evidence regarding RA suggests that patient outcome is better high, ranging between 9.1 (item D) and 9.7 (item A) on a scale when care is provided by a rheumatologist,46 and this might of 10 (table), indicating that this large and quite heterogeneous also be so for the musculoskeletal manifestations of PsA and task force had arrived at a quite unanimous view on the princi- pal importance of certain approaches to treatment of SpA.
Smolen JS, et al. Ann Rheum Dis 2013;0:1–11. doi:10.1136/annrheumdis-2013-203419 Clinical and epidemiological research Recommendations to treat all forms of Spondyloarthritis to target Overarching principles The treatment target must be based on a shared decision between patient and rheumatologist SpA and PsA are often complex systemic diseases; as needed, the management of musculoskeletal and extra-articular manifestations should be coordinated between the rheumatologist and other specialists (such as dermatologist, gastroenterologist, ophthalmologist) The primary goal of treating the patient with SpA and/or PsA is to maximise long-term health related quality of life and social participation through control of signs and symptoms, prevention of structural damage, normalisation or preservation of function,avoidance of toxicities and minimisation of comorbidities Abrogation of inflammation is presumably important to achieve these goals Treatment to target by measuring disease activity and adjusting therapy accordingly contributes to the optimisation of short term and/ or long term outcomes Common items for all forms of SpA A major treatment target should be clinical remission/inactive disease of musculoskeletal involvement (arthritis, dactylitis, enthesitis, axial disease), taking extra-articular manifestations into consideration The treatment target should be individualised according to the current clinical manifestations of the disease Clinical remission/inactive disease is defined as the absence of clinical and laboratory evidence of significant inflammatory disease Low/minimal disease activity may be an alternative treatment target Disease activity should be measured on the basis of clinical signs and symptoms, and acute phase reactants The choice of the measure of disease activity and the level of the target value may be influenced by considerations of comorbidities, patient factors and drug-related risks Once the target is achieved, it should ideally be maintained throughout the course of the disease The patient should be appropriately informed and involved in the discussions about the treatment target, and the risks and benefits of the strategy planned to reach this target Structural changes, functional impairment, extra-articular manifestations, comorbidities and treatment risks should be considered when making clinical decisions, in addition to assessing measures of disease activity Specific items for individual types of Spondyloarthritis Axial Spondyloarthritis (including ankylosing spondylitis) Validated composite measures of disease activity such as the BASDAI plus acute phase reactants or the Ankylosing Spondylitis Disease Activity Score, with or without measures of function such as BASFI, should be performed and documented regularly in routine clinicalpractice to guide treatment decisions; the frequency of the measurements depends on the level of disease activity Other factors, such as axial inflammation on MRI, radiographic progression, peripheral musculoskeletal and extra-articular manifestations, as well as comorbidities may also be considered when setting clinical targets Quantified measures of disease activity, which reflect the individual peripheral musculoskeletal manifestations (arthritis, dactylitis, enthesitis) should be performed and documented regularly in routine clinical practice to guide treatment decisions; the frequency of themeasurements depends on the level of disease activity Other factors. such as spinal and extra-articular manifestations, imaging results, changes in function/quality of life, as well as comorbidities may also be considered for decision Psoriatic arthritis Validated measures of musculoskeletal disease activity (arthritis, dactylitis, enthesitis, axial disease) should be performed and documented regularly in routine clinical practice to guide treatment decisions; the frequency of the measurements depends on the levelof disease activity; cutaneous manifestations should also be considered Other factors, such as spinal and extra-articular manifestations, imaging results, changes in function/quality of life, as well as comorbidities may also be considered for decision An asterisk in the LoE column denotes that for this item indirect evidence is available from the literature search which was nevertheless not sufficient for a higher grading of theevidence level.
BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; BASFI, Bath Ankylosing Spondylitis Functional Index; GoR, grade of recommendation; LoE, level of evidence; PsA, psoriaticarthritis; SoR, strength of recommendation (level of agreement); SpA, spondyloarthritis.
Common recommendations As mentioned previously, after intensive deliberations the com- 1. A major treatment target should be clinical remission/inactive mittee had decided to create just one document covering axial disease of musculoskeletal involvement (arthritis, dactylitis, and peripheral SpA, including PsA. To this end, nine unified enthesitis, axial disease), taking extra-articular manifestations recommendations and two additional items dealing separately into consideration (level of evidence (LoE): 5, grade of recom- with PsA, axial SpA and peripheral SpA were developed in the mendation (GoR): D).
course of the discussions. These recommendations applied the Hitherto, no clinical trial has compared outcomes of PsA or results of the SLR, but given the low available evidence in the axSpA for progression of structural changes or improvement of literature, they were mostly based on expert opinion, albeit con- physical function or quality of life when remission rather than sensual opinions of a large group of experts. The sequence of another state was targeted. Definitions for remission (which is the recommendations follows a logical order, but also reflects called inactive disease in AS) or at least minimal disease activity the level of importance considered by the committee for each (MDA) exist for PsA and AS,12 66 67 but in contrast to RA the individual bullet point.
long-term benefits of remission have not yet been sufficiently Smolen JS, et al. Ann Rheum Dis 2013;0:1–11. doi:10.1136/annrheumdis-2013-203419 Clinical and epidemiological research established. Also, no clear definition of remission for extra- established,66 especially given that in PsA most composite mea- articular musculoskeletal features, such as enthesitis or dactylitis, sures have been borrowed from RA while a composite measure is currently available. Moreover, it is not sufficiently known at specific for PsA has only recently been validated,10 but criteria present how remission of musculoskeletal symptoms relates to for disease activity states have not yet been defined. Importantly, remission of skin disease in PsA or bowel disease in IBD.
the term ‘significant' was added deliberately, indicating that Therefore, the formulation of this first bullet point reflects the the presence of a minute extent of residual activity, such as the general lack of data, by saying ‘a major' rather than ‘the major' presence of a tender joint or residual swollen but painless joint, treatment goal, or by expanding the term ‘clinical remission' to or residual axial pain that does not appear to relate to inflamma- the somewhat less stringent term ‘inactive disease'. However, tion, would still be compatible with remission. On the other the lack of thorough evidence and the unwillingness of the hand, the committee wished to have a stringent definition of group to arrive at a more determined and clear verbalisation of remission which would not allow significant residual disease this bullet point must not be mistaken as an uncertainty of the activity, such as several swollen joints or significant back pain, task force regarding the necessity of treating patients to become even if dramatically improved by therapy, to be called remission.
free of signs and symptoms of their peripheral joint or axial Also, this bullet point speaks of ‘clinical remission' indicating disease. On the contrary, the task force deemed this approach to that clinical rather than imaging measures should be used to be of utmost importance for short-term benefit and long-term define remission, at least currently. In this respect it should be outcome. Therefore it was placed as the first recommendation.
noted that MRI shows evidence of inflammation in AS and that Importantly, the group focussed the terms ‘remission'/‘inactive a negative MRI can be regarded as imaging remission; however, disease' to the musculoskeletal manifestations of SpA and not the relationship between clinical and imaging remission still the extramusculoskeletal abnormalities, although it clearly stated needs to be elaborated. Statement 3, which like the previous in the last part of this item that this must not be neglected in ones is based on expert opinion, received approval by 83% of the therapeutic decision making. After several rounds of discus- the committee members and a SoR of 9.0±1.4.
sion, 83% of the participants agreed with the formulation of 4. Low disease activity/MDA may be an alternative treatment this bullet point and the strength of recommendation amounted target (LoE: 5; GoR: D) to 9.5±0.9.
While remission (inactive disease) constitutes an ideal goal, 2. The treatment target should be individualised according to the clinical practice, stringently as it was defined in bullet point current clinical manifestations of the disease (LoE: 5, GoR: D) number 3 it may be difficult to achieve in many patients, espe- This item emphasises that every patient should be treated cially those with established/long-standing disease. Indeed, according to her or his current clinical manifestations and that patients with axSpA with longer disease duration are less likely in light of their heterogeneity each of these manifestations has to attain partial remission than those with early disease.72 38 to be accounted for when setting the therapeutic target.
Thus, while remission is the ultimate and an ideal goal, low However, it also implies that at certain points in time the mus- disease activity constitutes a useful alternative in the opinion of culoskeletal symptoms may not be in the foreground, such as the task force, since it is assumed that physical function and when extra-articular manifestations prevail and need appropri- quality of life may not be much worse than in remission and ate attention. Again, no data exist in the literature to support or progression of structural damage, while possibly not halted, refute this recommendation which was voted for by 87% of the would be minimal. Indeed, as included in the bullet point, low participants and attained a strength of recommendation (SoR) disease activity can also be regarded as ‘MDA'. Thus, minor of 9.3±1.0.
residual signs and symptoms may still exist differentiating this 3. Clinical remission/inactive disease is defined as the absence state from inactive disease. Importantly, by stating that low of clinical and laboratory evidence of significant inflammatory disease activity is an alternative goal to remission, the committee disease activity.
also clearly implies that any other, higher state, even moderate This bullet point provides a definition for item 1 in order to disease activity, would not be acceptable and its presence should clarify the definition of remission. Remission of an inflammatory elicit therapeutic adaptations. More research will be needed to rheumatic disease ideally comprises the absence of its signs and provide information on the optimal time point for achieving the symptoms, the maximal improvement in physical function and treatment target. However, given that in clinical trials of AS halt of structural changes. While there is compelling evidence maximal improvement was achieved between week 12 and week that these three characteristics go along with each other in RA, 24 regarding all outcome measures including ASAS partial this is not yet sufficiently known in AS and PsA. However, in remission4 73 74 and that similar observations have been made in PsA, progression of joint damage is correlated with swollen joint PsA,2 75 76 a maximum of 6 months for reaching the treatment counts and dactylitis59 68 and, therefore, it may be assumed that target of low disease activity or remission seems appropriate, clinical remission will also lead to halt of structural progression.
but it is advisable to adapt therapy earlier if no significant reduc- This is not quite clear in AS, since progression of syndesmo- tion in disease activity is observed within 3 months. Recently, phyte formation has been observed even when patients were in thresholds for disease activity states including inactive disease clinical remission on TNF inhibitors and formation of syndes- (equivalent to remission) have been defined for axSpA using the mophytes occurred without presence of MRI inflamma- ASDAS,12 and ASAS definition of partial remission is also avail- tion.8 64 65 69 On the other hand, elevated levels of acute phase able67; a measure of MDA has been developed for PsA which is reactants (APRs) are associated with progression of structural beginning to be used in clinical trials.77 78 Additional research changes in AS.70 Further, physical function and quality of life in this respect will be required, especially for PsA and peripheral are related to symptoms of these diseases.71 For all these reasons SpA. This item was accepted as defined by 79% of the partici- the task force defined remission as stated above. Definitions of pants and received a SoR of 9.4±0.9.
remission or partial remission are available for AS, when using 5. Disease activity should be measured on the basis of clinical mere patient reported outcomes67 or the more recently signs and symptoms, and APRs (LoE: 5, GoR: D).
Traditionally, given that the spine is not as accessible to phys- ical examination of signs of inflammation like a peripheral joint, Smolen JS, et al. Ann Rheum Dis 2013;0:1–11. doi:10.1136/annrheumdis-2013-203419 Clinical and epidemiological research disease activity in axSpA has been evaluated by employing the therapy will lead to reactivation of AS83 and PsA.84 While the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) present consensus statement is not designed to provide recom- which comprises only patient reported variables related to mendations on therapies with particular agents but rather on symptoms of the disease. However, axSpA is an inflammatory treatment strategies, the task force nevertheless points to the disease with involvement of various inflammatory cells and importance of maintaining the targeted therapeutic state once cytokines.79 80 Indeed, inhibition of TNF is one of the main- achieved and advises against stopping a successful therapy based stays of treatment today, leading to relief of symptoms, and on the available evidence. However, it has not yet been studied inhibition of prostaglandin synthesis can reduce clinical symp- sufficiently if dose reduction or expansion of treatment intervals toms, and retard progression of structural changes62 63; this allows maintaining a good clinical state. Approval was given appears to be particularly prominent in patients with elevated by 90% of the task force's members and the SoR amounted APRs, and the latter seem to be associated with progression of to 9.4±0.8.
syndesmophyte formation.70 81 82 Consequently, disease activity 8. The patient should be appropriately informed and involved assessment during follow-up and in the course of targeting a in the discussions about the treatment target, and the risks and good outcome should comprise the assessment of clinical benefits of the strategy planned to reach this target (LoE: 5, aspects of the disease as well as laboratory abnormalities, that is, APR measurement. This can be done separately by looking at While this statement has already been partly covered in the for example, BASDAI and c-reactive protein (CRP), or by using overarching principles, it was felt important to also raise this a measure that comprises both aspects, such as ASDAS.11 Along point in the context of the actual recommendations to bolster the same line, PsA as an inflammatory and potentially destruc- the importance of interaction between health professionals and tive joint disease should be followed using measures that relate their patients in all regards: setting and agreeing on the treat- to the joints and the serological inflammatory response; these ment target, discussing the strategies available to reach that are contained in RA-related composite measures of disease activ- target and the time it may take to attain it, and laying out the ity, such as Disease Activity Score (DAS), DAS28 and Simplified benefits and risks of the recommended treatment and consider Disease Activity Index (SDAI), but also in the Disease Activity in the totality of clinical disease manifestations (including the PsA and the psoriatic arthritis disease activity score.13 The extramusculoskeletal ones) and of comorbidities. This point also current recommendation does not relate to systemic features of comprises the need to discuss steps to be taken if the treatment SpA, but solely to the musculoskeletal manifestations. For sys- target is not achieved, such as adjustment of or switch to a new temic features, other measures are needed and, according to the therapy. In this respect patient education programmes or book- EULAR recommendations for treatment of PsA,18 this should be lets may provide additional helpful means. This item was approved by 81% of the participants and the SoR was 9.8±0.5.
Recommendation 5 received approval by 97% of participants 9. Structural changes, functional impairment, extra-articular and the SoR amounted to 9.4±1.1.
manifestations, comorbidities and treatment risks should be con- 6. The choice of the measure of disease activity and the level of sidered when making clinical decisions, in addition to assessing the target value may be influenced by considerations of comorbid- measures of disease activity.
ities, patient factors and drug related risks (LoE: 5; GoR: D) This point is focused on considerations involved in thera- Patients with chronic musculoskeletal diseases are frequently peutic decision making. Although the last part of this recom- also suffering from comorbidities that (1) may be related to the mendation emphasises the importance of regular assessment of overall spectrum of the disorder (such as IBD, uveitis or psoria- disease activity with appropriate measures (see items 5 and 6), sis), (2) may occur as a consequence of chronic inflammation the first part suggests taking into account results of other investi- (such as cardiovascular disease), (3) may be related to therapy gations for treatment decisions, such as by imaging (especially (such as gastric ulcer or infection), or (4) just may occur con- structural changes in PsA), physical function and extra-articular comitantly by chance. The presence of such comorbidities may manifestations. The latter comprise enthesitis or dactylitis as alter the level of the treatment target, since the risk of aggravat- well as extramusculoskeletal disease. This is of importance, ing the comorbid condition may outweigh the benefit conveyed since treatment approaches to PsA will differ in the presence of by more intensive therapy to achieve the treatment target of the enthesitis compared with patients who do not suffer from musculoskeletal manifestations. Further, the choice of follow-up entheseal affection.18 Moreover, organ disease, such as lung measure may have to be changed under certain circumstances.
involvement, aortitis, intestinal or skin manifestations as well as For example, a concomitant disease which raises pain levels or uveitis, may require involvement of other specialists (see over- APRs may influence the result of measuring disease activity.
arching principle B). In particular uveitis can present across the Likewise, when following patients on therapies that affect the spectrum of SpA and may reflect disease activity, and inflamma- APRs independently of clinical benefit one may have to recon- tory bowel disease and psoriatic skin involvement must be con- sider the choice of a measure that contains an APR. Therefore, sidered in the respective disorders and do not strongly correlate this point focuses on the application (and sometimes restricted with the degree or extent of musculoskeletal involvement. Risks applicability) of particular disease activity measures. This recom- and comorbidities are also reiterated here in the context of mendation was approved by 97% of the task force members treatment decisions; before they were indicated with respect to and received a SoR of 9.4±1.0.
the choice of measures of disease activity (see recommendation 6) 7. Once the target is achieved, it should ideally be maintained and in relation to patient information (item 8). This recommen- throughout the course of the disease (LoE: 5; GoR: D) dation achieved 100% agreement and a SoR of 9.5±0.8.
It is clear that no patient's successfully targeted disease activ- ity state should deteriorate during follow-up, since reactivation Disease specific recommendations of disease may again lead to reduced quality of life and disabil- As indicated above, items 10 and 11 have been formulated spe- ity. There is evidence that on demand NSAID therapy, in con- cifically for axSpA, PsA and peripheral SpA to account for the trast to regular NSAID treatment, is associated with progression differences between certain characteristics of the different of radiographic changes in AS63 and that stopping TNF-blocker Smolen JS, et al. Ann Rheum Dis 2013;0:1–11. doi:10.1136/annrheumdis-2013-203419 Clinical and epidemiological research Axial SpA (including AS) treatment decisions; the frequency of the measurements depends 10. Validated composite measures of disease activity such as on the level of disease activity; cutaneous manifestations should BASDAI plus APRs or ASDAS, with or without measures of func- also be considered.
tion such as Bath Ankylosing Spondylitis Functional Index Specific mention of skin disease tailors this recommendation (BASFI), should be performed and documented regularly in to PsA, although skin may also be involved in axial and periph- routine clinical practice to guide treatment decisions; the fre- eral SpA. Further, in addition to arthritis, dactylitis and enthesi- quency of the measurements depends on the level of disease tis, axial disease assessment is specifically brought forward here.
Finally, a reminder is provided that the results of the various This item is an expansion of recommendation numbers 5 and 9.
measures (and also the treatment target) should be documented.
It mentions those disease activity measures which have been Clearly, with highly active disease patients should be seen fre- repeatedly validated and are already in use in contemporary quently, such as monthly to every 3 months, while with low clinical trials. In line with recommendation 5, when BASDAI is disease activity or remission, follow-up examinations may be employed, an APR, such as CRP or erythrocyte sedimentation done only every 6–12 months. However, skin involvement also rate, should also be determined. The ASDAS already comprises has to be taken into account. The voting achieved 92% approval such a measure among its components.12 In addition, this rec- and the SoR amounted to 9.4±0.8.
ommendation also suggests the use of a particular functional 11. Other factors such as spinal and extra-articular manifesta- measure, but other validated measures can also be applied tions, imaging results changes in function/quality of life, as well (therefore the tem ‘such as'). With highly active disease, as comorbidities may also be considered for decision.
follow-up examinations will have to be more frequent than with As for the other disease entities, this last recommendation inactive disease/remission. Moreover, the recommendation expands item 9 and also the preceding one by reiterating the requests documentation of the measured results. Among task importance of comorbidities, and axial and soft tissue manifes- force members, 88% approved this item and SoR amounted to tations of PsA in the course of making treatment decisions.
Approval was granted by 100% of the participants and the SoR 11. Other factors such as axial inflammation on MRI, radio- amounted to 9.3±1.0.
graphic progression, peripheral musculoskeletal and extra- A final anonymous vote on whether the task force members articular manifestations, may also be considered when setting felt influenced by the fact that support for this activity was pro- clinical targets.
vided by a company, the result was 0.4±1.3 (0 meaning no and Again, this recommendation expands item 9, but specifically 10 meaning heavy influence), indicating that the participants felt mentions MRI as a highly valuable imaging method for the potential follow-up of axSpA. Likewise, non-axial disease mani-festations will influence not only the therapeutic approach but have to be considered when setting treatment targets. Approval Since none of the recommendations is based on evidence, the was voted for by 88% of the members and the SoR was 9.3±0.8.
research agenda has to comprise the search for evidence for allof them. However, beyond mere therapeutic aspects, insightsinto the relationships between individual musculoskeletal mani- festations, damage and disability are still incomplete especially 10. Quantified measures of disease activity, which reflect the for the peripheral SpA, including PsA. Table 2 lists a research individual peripheral musculoskeletal manifestations (arthritis, agenda as mentioned during the task force's meetings.
dactylitis, enthesitis) should be performed and documented regu-larly in routine clinical practice to guide treatment decisions; the frequency of the measurements depends on the level of disease Recommendations to treat axSpA and PsA have been developed over the recent years.17–19 However, none of these addressed a This recommendation, while expanding items 5, is here spe- clear therapeutic target and a strategy to reach this target. This cifically tailored to peripheral SpA, such as ReA, IBD arthritis or has now been done in the present set of recommendations, and former ‘undifferentiated' peripheral SpA. Measures of disease additional strategic aspects of treatment approaches are pre- activity are available and have been validated for the arthritis sented. Thus, the present consensus on treatment targets and component of ReA9 and there exist measures for dactylitis and general treatment approaches complements the published man- enthesitis which have not been primarily developed for periph- agement recommendations,17–20 but a notable difference is the eral SpA, but rather for PsA or AS.85–87 While they will have to absence of suggestions or recommendations regarding a particu- be validated in peripheral SpA, they can be assumed useful for lar drug in any of the overarching principles or individual clinical practice until proven otherwise. Also this recommenda- tion calls for documentation of the measured results. Of the par- Treatment recommendations should usually be based on evi- ticipants, 100% approved this item and the SoR score achieved dence. However, where evidence is missing, expert opinion has was 9.3±0.9.
to come into play. The recommendations presented here are not 11. Other factors such as spinal and extra-articular manifesta- based on hard evidence, because strategic therapeutic trials, in tions, imaging results, changes in function/quality of life, as well which therapy was consistently adapted to reach a prespecified as comorbidities may also be considered for decision.
treatment target and compared with a non-steered approach, as This item reiterates and expands recommendation 9 and performed in RA,88 89 are currently not available for axSpA, achieved 100% approval; the SoR was 9.4+0.8.
peripheral SpA or PsA, and other pertinent literature is scarce.
While a SLR has provided indirect evidence from clinical trials Psoriatic arthritis which targeted specific endpoints37 and thus supplied some 10. Validated measures of musculoskeletal disease activity (arth- information towards the work of the task force, the individual ritis, dactylitis, enthesitis, axial disease) should be performed recommendations can only be regarded as expert opinion (con- and documented regularly in routine clinical practice to guide sensus) and therefore call for more research in the field.
Smolen JS, et al. Ann Rheum Dis 2013;0:1–11. doi:10.1136/annrheumdis-2013-203419

Clinical and epidemiological research behind other disease areas which have already defined their targets years to decades ago, when at least indirect evidence for Specific questions the benefit of attaining certain treatment targets is available; and(2) the tremendous therapeutic advances of the past decade Composite activity measures Validation where needed, definition of have greatly improved the chances of achieving good outcomes (mainly PsA and peripheral SpA) disease activity states and responsecategories and, therefore, setting stringent treatment milestones has Remission definition Is it important that all clinical domains of become a reality which should not be concealed. Moreover, in axial SpA, peripheral SpA or PsA are in the course of its initial discussions on this issue, the task force remission or is it sufficient to define some of felt that with these advances and the concomitant formulation of a research agenda, investigations towards providing respective Is there a difference in long-term outcome evidence could be fostered and accelerated. Importantly, this when comparing remission with low disease view was shared among all task force members, which com- prised patients and an international group of physicians with Activity and damage What is the progression of joint damage indifferent disease activity states in PsA? expertise in SpA.
Are there differences in responsiveness and At all three steps of this activity, which included initial discus- thus differences in attaining certain targets sions by the steering committee, formulation of recommenda- with different disease duration in PsA? tions by an expanded working group and development of Treatment to target There is a need to design therapeutic trials treatment recommendations for all three entities, axSpA, periph- that compare steered therapy aiming at eral SpA and PsA, unanimous agreement was attained.
remission or low disease activity withnon-steered treatment (like TICORA)88 Moreover, all items achieved strong consensus in an anonymous Axial involvement in PsA Do spinal and peripheral involvements voting process, with the lowest result being a mean of 9.0 on a respond similarly or differently? scale of 0–10, indicating that the task force stood quite united Enthesitis, dactylitis More data need to be attained on the behind the recommendations.
response of dactylitis or enthesitis to different The complexity of the current endeavour resulted from the heterogeneity of the diseases covered. After long discussions and Care by rheumatologist Is care of axial SpA, peripheral SpA or PsA by the intermediate development of more than one document, it a rheumatologist advantageous for outcomes was decided to produce a single set of recommendations for when compared with care bynon-rheumatologists? axSpA, peripheral SpA and PsA, in line with recent criteria for Maintenance of response How can response be maintained? Can the classification of SpA.15 Five overarching principles and nine dose of the therapy employed be reduced or recommendations were developed in common for all forms of the interval of applications be expanded and SpA, including PsA. Only two recommendations were separately outcome maintained? produced for axSpA, peripheral SpA and PsA, although their Is outcome different when patients are general scope was still very similar and differences only very informed in a structured way when comparedwith more general means of information? subtle. The overall activity was partly influenced by the treat-to-target recommendations for RA.32 PsA, psoriatic arthritis; SpA, Spondyloarthritis.
Several of the recommendations stand out in their import- ance, while others can be seen as supportive or operational.
So why then were the recommendations developed now A call for remission or inactive disease became item 1, because rather than waiting for more evidence? Because the definition of this was regarded the foremost treatment target. Indeed, we can a treatment target and strategy is timely at present in light of anticipate that reducing inflammation and disease activity to the two major aspects: (1) a field like that of SpA should not stay minimum is optimal for the patients, at least for their quality of Algorithm to treat spondyloarthritis (SpA) to target. Thealgorithm depicts the main (remission)and the alternative target (low diseaseactivity), the need to adapt therapy ifthe target is not reached, therequirement to use measures thatreflect clinical activity and acute phasereactants and the sustainment ofremission (developed in considerationof the figure for the rheumatoidarthritis algorithm).32 Smolen JS, et al. Ann Rheum Dis 2013;0:1–11. doi:10.1136/annrheumdis-2013-203419 Clinical and epidemiological research life. However, the members were aware that remission may not 22Laboratory for Molecular Immunology and Inflammation, Department of be achievable in all patients and, therefore, formulated an alter- Rheumatology, Ghent University Hospital, Ghent, Belgium native treatment target, especially for patients with long-standing Department of Rheumatology, Pitié Salpêtrière Hospital, Pierre et Marie Curie University, Paris, France disease, namely low disease activity (recommendation 4).
24Division of Allergy, Immunology and Rheumatology, Institute of Medicine, Chung Importantly, this acknowledgement indicates that disease activity Shan Medical University Hospital, Taichung, Taiwan states other than remission or low disease activity constitute 25Department of Public Health and Preventive Medicine, Oregon Health & Science unacceptable clinical states, unless justified because of other University, Portland, Oregon, USA 26Department of Rheumatology, Leiden University Medical Center, Leiden, reasons, such as comorbidity (items 6, 9 and 11). Importantly, while validated measures of disease activity are available for PsA Contributors All authors participated in the development of the consensus and ReA, disease activity states have not yet been sufficiently statement and the voting process and provided inputs into the statements presented.
defined, contrasting the situation in AS. Another complexity Funding This study was supported by an unrestricted grant from Abbott/AbbVie to relates to the necessity to use measures that reflect the individual the Medical University of Vienna.
manifestations of a patient which in some instances may involve Competing interests JSS received grant support from and/or provided expert assessment of peripheral joint disease, axial involvement, dacty- advice or speaking engagements for Abbott, Celgene, Janssen, MSD, Pfizer and litis and enthesitis. To identify an individual treatment goal can UCB. JB received grant support from and/or provided expert advice to AbbVie, in itself be seen as an important part of a treatment strategy Celltrion, Janssen, MSD, Novartis, Pfizer, UCB. MD has participated in advisory when an intervention is initiated and should be accompanied by boards and symposia organised by Pfizer, AbbVie, UCB and Roche; his departmenthas received research grants from Pfizer, AbbVie, UCB, Roche, Lilly, MSD and Sanofi.
a monitoring programme. It is also important that the agreed PE has undertaken clinical trials and provided expert advice to MSD, Pfizer, Abbott goal is documented in the records of the patient.
and Novartis. OF received grants from AbbVie, Pfizer, BMS, Roche and MSD and Patient involvement in defining the treatment target and selec- served as speaker at meetings for AbbVie, Pfizer, MSD, UCB and Celgene.
tion of therapies based on their risks and benefits was deemed PH received honoraria from Abbott, Celgene, BMS, Pfizer, Merck, J&J and UCB.
so important, that it is stated in the first overarching principle AK conducted clinical research sponsored by AbbVie, Amgen, UCB and Jannsen,and provided expert advice for AbbVie. TKK received honoraria for speaking and/or and additionally in one of the recommendations.
consulting engagements from AbbVie, AstraZeneka, BMS, Hospira, MSD/ As indicated above, given the small evidence base, the research Schering-Plough, Nicox, Pfizer, Roche and UCB and Diakonhjemmet Hospital agenda is of utmost importance. Research activities should focus received research funds from AbbVie, BMS, MSD, Pfizer, Roche and UCB. RL has on strategic therapeutic trials, and on addressing missing infor- received research grants from Abbott, Amgen, Centocor, Novartis, Pfizer, Roche,UCB; speaker fees from Abbott, Amgen, BMS, Janssen, MSD, Pfizer, Roche, UCB mation, such as the definition of disease activity states in PsA.
and is director of Rheumatology Consultancy BV, a registered company under Dutch The recommendations are summarised in a simplified form in law. TL has no conflict to declare. PM has received research grants, consultation an algorithm presented in figure 1. Like most types of recom- fees and/or speaker honoraria from AbbVie, Amgen, BiogenIdec, BMS, Celgene, mendations, it will be necessary to revise the current document Genentech, Glaxo SmithKline, Lilly, MSD, Novartis, Pfizer, UCB, Vertex. IO has in due course, presumably in about 4 years or 5 years or earlier, received consulting fees, research or institutional support and educational grantsfrom AbbVie, MSD and Pfizer. JR has consulted for AbbVie and UCB and has when significant evidence accumulates regarding the individual participated in clinical trials of AbbVie and UCB on axial SpA. CR received research points of the recommendations. The task force hopes for an support from Amgen, Janssen, UCB and has consulted for AbbVie, Amgen, Janssen, expansion of high quality research activities that either allow UCB, Boehringer Ingleheim, Regeneron and Lilly. MR has received honoraria from or confirmation or modifications of its conclusions.
has served as consultant for AbbVie, BMS, MSD, Pfizer, Roche/Chugai, UCB. MShas received honoraria from AbbVie. JS has received grant support from AbbVie,MSD, Pfizer, Janssen and Honoraria for consultancies and/or lecturing from AbbVie, Author affiliations Merck, Pfizer, Janssen, UCB, Novartis, Lilly, Sanofi, Roche. MdW received honoraria 1Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, from Abbott. XB has received research grants and consultant's, advisory boards' and/or speaker's honoraria from AbbVie, Celgene, Janssen, Chugai, MSD, Novartis, 22nd Department of Medicine, Hietzing Hospital Vienna, Vienna, Austria Pfizer, UCB. NB has received consultancy fees from Roche, BMS and Pfizer.
3Rheumazentrum Ruhrgebiet, Herne, Germany RB-V has received honoraria for speaking and/or advisory board engagements from 4Department of Rheumatology B, Cochin Hospital, René Descartes University, Paris, AbbVie, BMS, Pfizer, Roche and UCB. EC-E declares no conflicts. AD has participated in advisory board activities for UCB, Pfizer, AbbVie and has received 5Division of Rheumatic and Musculoskeletal Disease, Leeds Institute of Molecular research grants from AbbVie, Amgen, Janssen, Novartis, Pfizer and UCB. DE received Medicine, University of Leeds, Chapel Allerton Hospital, Leeds, UK grant support from Merck and Abbott. LG has received honoraria from AbbVie, 6Department of Rheumatology, St. Vincents University Hospital, Dublin, UK Chugai, Pfizer, Roche and UCB. MJ declares no conflicts. MM declares no conflicts.
7Division of Rheumatology, Allergy, Immunology, University of California, San Diego, KR has received grant support and/or provided expert advice and/or presentations for AbbVie, BMS, Glaxo, MSD, Novartis-Sandoz, Pfizer, Roche and UCB. FvdB 8Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway provided advice for Abbott. JC-CW declares no conflicts. K-W has received research 9Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands grants from Pfizer and consulting fees from Pfizer, UCB, Genentech and AbbVie.
10Atrium Medical Center, Heerlen, The Netherlands DvdH has received consulting fees and/or research grants from AbbVie, Amgen, 11Clinic and Polyclinic of Dermatology, University of Münster, Münster, Germany AstraZeneca, Augurex, BMS, Centocor, Chugai, Daiichi, Lilly, Glaxo-Smith-Kline, 12Swedish Medical Center and University of Washington, Seattle, Washington, USA Janssen Biologics, MSD, Novartis, Novo-Nordisk, Otsuka, Pfizer, Roche, 13Rheumatology Department of Lucania, San Carlo Hospital of Potenza and Sanofi-Aventis, UCB and Vertex, and is Director of Imaging Rheumatology bv.
Madonna delle Grazie Hospital of Matera, Potenza, Italy 14Division of Rheumatology, University of Texas Health Science Center at Houston, Provenance and peer review Not commissioned; externally peer reviewed.
Houston, Texas, USA Open Access This is an Open Access article distributed in accordance with the 15Allergy, Immunology and Rheumatology Division, The Center for Musculoskeletal Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits Medicine, University of Rochester Medical Center, Rochester, New York, USA others to distribute, remix, adapt, build upon this work non-commercially, and license 16Endokrinologikum Berlin, Berlin, Germany their derivative works on different terms, provided the original work is properly cited and 17Medical Department I, Rheumatology, Charité Campus Benjamin Franklin, Berlin, the use is non-commercial. See: 18EULAR standing committee of People with Arthritis/Rheumatism in Europe (PARE),Zurich, Switzerland 19Rheumatology Department, Faculty of Medicine, Hospital General de MéxicoUniversidad Nacional Autónoma de México, Mexico City, Mexico 20Department of Rheumatology, Reina Sofia University Hospital of Córdoba/IMBIC, Rudwaleit M, van der Heijde D, Landewe R, et al. The development of Assessment of SpondyloArthritis international Society classification criteria for axial 21Division of Arthritis and Rheumatic Diseases, Oregon Health & Sciences University, spondyloarthritis ( part II): validation and final selection. Ann Rheum Dis Smolen JS, et al. Ann Rheum Dis 2013;0:1–11. doi:10.1136/annrheumdis-2013-203419 Clinical and epidemiological research Kaltwasser JP, Nash P, Gladman D, et al. Efficacy and safety of leflunomide in the Conroy RM, Pyorala K, Fitzgerald AP, et al. Estimation of ten-year risk of fatal treatment of psoriatic arthritis and psoriasis: a multinational, double-blind, cardiovascular disease in Europe: the SCORE project. Eur Heart J randomized, placebo-controlled clinical trial. Arthritis Rheum 2004;50:1939–50.
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Giant species layout 10-04-02.pdf

Mekong River Commission Mekong giant fish species: on their management and biology MRC Technical Paper April 2002 Report prepared by the MRC Fisheries Programme at the request of the Technical Advisory Body on Fisheries Management in the Lower Mekong Basin Published in Phnom Penh in April 2002 by


Brain Research 1010 (2004) 151 – 155 Stimulation of the superior cerebellar peduncle during the development of amygdaloid kindling in rats Carmen Rubioa, Vero´nica Custodioa, Francisco Jua´rezb, Carlos Paza,* a Departamento de Neurofisiologı´a, Instituto Nacional de Neurologı´a y Neurocirugı´a M.V.S., Insurgentes Sur 3877, Mexico 14269 D.F., Mexico b Instituto Nacional de Psiquiatrı´a R.F., Mexico