16
Ann Rheum Dis 000 (2025) 1−9
Contents lists available at ScienceDirect
Annals of the Rheumatic Diseases
journal homepage: https://www.sciencedirect.com/journal/annals-of-the-rheumatic-diseasesDepartment of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
17 Department of Rheumatology, Leiden University Medical Center, Leiden, The NetherlandsAxial spondyloarthritis
The Assessment of SpondyloArthritis International
Society (ASAS) Consensus-Based Expert Definition of
Difficult-to-Manage, including Treatment-Refractory,
Axial Spondyloarthritis
Denis Poddubnyy 1,2,*, Victoria Navarro-Comp
an 3, Murat Torgutalp 2,
Suzanne Arends 4, Sibel Zehra Aydin 5,6, Simone Battista 7,
Filip van den Bosch 8, Christine Bundy 9, Alberto Cauli 10, Jo Davies11,
Maxime Dougados 12, Tuncay Duru€oz 13, Bassel El-Zorkany 14,
Warren Fong 15,16, Floris van Gaalen 17, Rodrigo Garcia-Salinas 18,
Marco Garrido Cumbrera 19, P
al G
eher 20, Lianne Gensler 21,
Simeon Grazio 22, Feng Huang 23, Mitsumasa Kishimoto 24,
Robert Landew
e 25,26, Ying Ying Leung 27, Pedro M Machado 28,29,
Helena Marzo-Ortega 30, Bhowmik Meghnathi 31,32, Anna Molto 33,
Elena Nikiphorou 34, Sofia Ramiro 17, Martin Rudwaleit 35,
Carla G S Saad 36, Alexandre Sepriano 17,37, James Wei 38,39,40,
Xenofon Baraliakos 41, D
esir
ee van der Heijde 42, on behalf of ASAS
1 Division of Rheumatology, Department of Medicine, University of Toronto and University Health Network, Toronto, ON, Canada
2 Department of Gastroenterology, Infectiology and Rheumatology (including Nutrition Medicine), Charit
e − Universit€atsmedizin
Berlin, corporate member of Freie Universit€at Berlin and Humboldt-Universit€at zu Berlin, Berlin, Germany
3 Department of Rheumatology, La Paz University Hospital, IdiPaz, Madrid, Spain
4 Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, University of Groningen, Gronin-
gen, The Netherlands
5 Division of Rheumatology, Department of Medicine, University of Ottawa, Ottawa, ON, Canada
6Ottawa Hospital Research Institute, Ottawa, ON, Canada
7 Centre for Human Movement and Rehabilitation, School of Health and Society, University of Salford, Salford, Greater Manches-
ter, UK
8 Department of Rheumatology, Ghent University, Ghent University Hospital, Ghent, Belgium
9 School of Healthcare Sciences, Cardiff University, Wales, UK
10 Rheumatology Unit, Department of Medicine and Public Health, AOU and University of Cagliari, Cagliari, Italy
11 Axial Spondyloarthritis International Federation (ASIF), London, UK
12 Department of Rheumatology, Ho^pital Cochin, University Paris Cit
e, Paris, France
13 PMR Department, Rheumatology Division, Marmara University School of Medicine, Istanbul, Turkey
14 Department of Rheumatology, Cairo University, Cairo, Egypt
15 Department of Rheumatology and Immunology, Singapore General Hospital, Singapore*Correspondence to Dr Denis Poddubnyy, Division of Rheumatology, Department of Medicine, University of Toronto, Toronto, ON, Canada.
E-mail address: denis.poddubnyy@uhn.ca (D. Poddubnyy).
Handling editor Josef S. Smolen.
https://doi.org/10.1016/j.ard.2025.01.035
0003-4967/© 2025 The Author(s). Published by Elsevier B.V. on behalf of European Alliance of Associations for Rheumatology (EULAR). This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
al d
in
ran
Clin
25 Department of Rheumatology and Clinical Immunology, Amsterdam University Medical Center, Amsterdam, The Netherlands
26 Department of Rheumatology, Zuyderland M
27 Department of Rheumatology& Immunology
28 Department of Neuromuscular Diseases, UCL
29 Department of Rheumatology, Division of Me
30NIHR Leeds Biomedical Research Centre, Lee
Medicine, University of Leeds, Leeds, UK
31 Department of Rheumatology& Immunology
32 Department of Rheumatology, Marengo CIMS
33 Rheumatology Department Cochin Hospital, A
versit
e Paris Cit
e, Paris, France
34 Rheumatology Department, King’s College Ho
London, UK
35 Department of Internal Medicine and Rheuma
36 Rheumalogy Division, Hospital das Clinicas H
37NOVA Medical School, UNL, Lisbon, Portuga
38 Department of Allergy, Immunology& Rheum
39 Department of Nursing, Institute of Medicine,
40 ine, Ch
d Ruhr
Univers
Article history: Objectives: To develop a consensus-based expert definition of difficult-to-manage (D2M) axial
), incorporating treatment-refractory (TR) disease.
itions for D2M/TR
onducted in 2022
Delphi process, a
task force, includ-
oArthritis Interna-
failure (treatment
recommendations
matic drugs with
ontrol, and physi-
ts diagnosed with
t includes various
by the D2M defi-
s of inflammatory
roposed D2M def-
in January 2024,
s for identifying
ion and its clinical
rically known as
graphic, respec-
onsteroidal anti-
ith nonpharma-
cise and physio-
y is ineffective or
D. Poddubnyy et al. Ann Rheum Dis 00 (2025) 1−9Received in revised form 15 January 2025
Accepted 16 January 2025
Available online xxx
Methods: A literature review was conducted in 2022 to identify potential defin
axSpA from prior studies, followed by a 2-round Delphi consensus process c
and 2023 to identify components of D2M axSpA. Based on the results of the
draft of the D2M axSpA definition was developed and presented to the expert
ing patient representation, and, subsequently, to the Assessment of Spondyl
tional Society (ASAS) membership for endorsement in January 2024.
Results: Consensus was reached on a D2M definition encapsulating treatment
according to the ASAS-European Alliance of Associations for Rheumatology
and failure of ≥2 biological or targeted synthetic disease-modifying antirheu
different mechanisms of action unless contraindicated), suboptimal disease c
cian or patient acknowledgement of problematic signs/symptoms in patien
axSpA by the rheumatologist. This definition represents a broad concept tha
reasons that lead to an unsatisfactory treatment outcome. TR axSpA is covered
nition but requires a history of treatment failure, the presence of objective sign
activity, and the exclusion of noninflammatory reasons for nonresponse. The p
inition incorporating TR disease was endorsed by ASAS at the annual meeting
with 89% votes (109/123) in favour of it.
Conclusions: The ASAS D2M axSpA definition, including TR disease, allow
patients with unmet needs, paving the way for further research in this condit
care improvement.
INTRODUCTION
Axial spondyloarthritis (axSpA) is an immune-mediated
inflammatory condition primarily affecting the axial skeleton
(spine and sacroiliac joints) [1,2]. Based on the presence or
absence of definitive radiographic sacroiliitis according to the
radiographic criterion of the modified New York criteria [3],
axSpA can be classified as radiographic, histo
ankylosing spondylitis (AS) [4], or nonradio
tively.
The first-line therapy for axSpA consists of n
inflammatory drugs (NSAIDs) in conjunction w
cological interventions, including regular exer
therapy [5]. In patients where first-line therapReceived 18 September 2024 spondyloarthritis (axSpAGraduate Institute of Integrated Medic
41 Rheumazentrum Ruhrgebiet, Herne an
42 Department of Rheumatology, Leiden
A R T I C L E I N F Oedical Center, Heerlen, The Netherlands
, Singapore General Hospital, Duke-NUS Medical School, Singapore
Queen Square Institute of Neurology, University College London, London, UK
dicine, University College London, London, UK
ds Teaching Hospitals Trust and Leeds Institute of Rheumatic and Musculoskeletal
, SVP Hospital & Smt. NHL Municipal Medical College, Ahmedabad, India
Hospital & RheumaCARE, Ahmedabad, India
PHP, INSERM U-1153, Centre de Recherche en Epid
emiologie et Statistiques, Uni-
spital, Centre for Rheumatic Diseases, Centre for Education, King’s College London,
tology, Klinikum Bielefeld, University of Bielefeld, Bielefeld, Germany
CFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil
l
atology, Chung Shan Medical University Hospital, Taichung, Taiwan
Chung Shan Medical University, Taichung, Taiwan
ina Medical University, Taichung, Taiwan
-University, Bochum, Germany
ity, Leiden, The Netherlands
A B S T R A C TDepartment of Rheumatology and Immunology, Chinese PLA General Hospital, Beijing, China
24 Department of Nephrology and Rheumatology, Kyorin University School of Medicine, Tokyo, Japan18 Rheumatology Unit, Hospital Italiano de La Plata − Universidad Nacion
19Health& Territory Research (HTR), Universidad de Sevilla, Seville, Spa
20 Semmelweis University, Budapest, Hungary
21 Division of Rheumatology, University of California San Francisco, San F
22 Department of Rheumatology, Physical and Rehabilitation Medicine,
Croatia
232e La Plata, La Plata, Argentina
cisco, CA, USA
ical University Centre, Sestre Milosrdnice, Zagreb,
D. Poddubnyy et al. Ann Rheum Dis 00 (2025) 1−9WHAT IS ALREADY KNOWN ON THIS TOPIC
 Despite the availability of several efficacious treatment options,
a significant proportion of patients with axial spondyloarthritis
(axSpA) do not achieve satisfactory treatment outcomes.
 There has been no consistent or universally accepted definition
of ‘difficult-to-manage’ (D2M) or ‘treatment-refractory’ (TR)
axSpA, hindering the identification and management of
patients with unmet needs.
WHAT THIS STUDY ADDS
 This study presents a consensus-based definition of D2M axSpA
incorporating key elements such as treatment failure (defined
by failure of at least 2 biological or targeted synthetic disease-
modifying antirheumatic drugs), suboptimal disease control,
and the perception of problematic signs and symptoms by both
rheumatologists and patients.
 The definition includes a specific subset of patients with TR
axSpA, characterised by objective signs of inflammatory activ-
ity despite optimal treatment, distinguishing them from
patients who may have noninflammatory reasons for nonre-
sponse.
 The definition was endorsed by the Assessment of SpondyloAr-
thritis International Society, reflecting a broad consensus
among experts in the field.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR
POLICY
 The proposed definition provides a standardised framework for
identifying patients with D2M and TR axSpA, facilitating tar-
geted research into the underlying mechanisms, epidemiology,not tolerated, second-line therapy should be considered. This
includes biological or targeted synthetic disease-modifying anti-
rheumatic drugs (b/tsDMARDs). The first group of these drugs
includes tumour necrosis factor (TNF) inhibitors and interleu-
kin-17 (IL-17) inhibitors. The second group consists of Janus
kinase (JAK) inhibitors [5].
The primary treatment target in axSpA is sustained remis-
sion, defined as the absence of clinical (signs and symptoms)
and laboratory (primarily C-reactive protein [CRP]) indicators
of disease activity [5,6]. The Axial Spondyloarthritis Disease
Activity Score (ASDAS) is the preferred composite measure of
disease activity in axSpA [5,6]; ASDAS < 1.3 is considered an
inactive disease state and corresponds to remission, while
ASDAS between 1.3 and 2.1 is classified as a low disease activity
state and should be used as the alternative treatment target if
remission is unachievable [7]. A clinically important improve-
ment in ASDAS (Δ ASDAS ≥ 1.1) is used as a criterion for decid-
ing on the continuation of b/tsDMARDs as outlined in the
Assessment of SpondyloArthritis International Society (ASAS)-
European Alliance of Associations for Rheumatology (EULAR)
management recommendations for axSpA [5]. The ASAS 40 and
20 response criteria are frequently used in clinical trials as key
outcome parameters [8].
Despite several efficacious anti-inflammatory treatment
options, only about 40% to 50% of patients with axSpA achieve
a relevant treatment response, and an even smaller proportion
(approximately 10%-20%) reach remission or an inactive disease
activity state within 16 to 24 weeks of treatment initiation,
according to data from randomised controlled trials with b/
and potential interventions for these patient populations.
 This definition may inform policy-making, supporting the
development of clinical guidelines and resource allocation for
the management of patients with D2M axSpA.
3tsDMARDs [9]. After the failure of 1 b/tsDMARD and in the
presence of active disease, a switch to another b/tsDMARD is
recommended [5]. However, a group of patients with non- or
incomplete responses remains despite exposure to multiple
advanced therapies. There are several potential reasons for non-
response or partial response in axSpA, which may be related to
the disease itself or factors other than inflammatory activity (eg,
nonnociceptive pain mechanisms [10−12]). A misdiagnosis
could also contribute to the observed nonresponse. The mecha-
nisms underpinning nonresponse remain incompletely under-
stood, and there are no evidence-based approaches to address
this issue in clinical practice.
In recent years, the concept of ‘difficult-to-treat’ rheumatoid
arthritis (RA) has evolved [13], leading to the development
of specific recommendations for its management in clinical prac-
tice [14].
As part of the ASAS Difficult-to-Manage (D2M) axSpA initia-
tive, which aims to define D2M axSpA and provide manage-
ment guidance, we sought to develop a consensus-based expert
definition of D2M axSpA, incorporating treatment-refractory
(TR) disease, which will help facilitate further initiatives to
improve the clinical care of these patients and research in this
area.
METHODS
The process of developing the D2M definition involved form-
ing a task force and conducting a literature review to inform the
task force and a 2-round Delphi survey. Importantly, ASAS
intended to develop a consensus-based definition and not classi-
fication criteria, which determined the methodology of the pro-
cess. The first Delphi round was conducted among ASAS
members to determine the main elements of the future defini-
tion. Following the discussion of the results within the task force
and at the ASAS annual meeting, the second Delphi round
focused on specific definition elements. Based on the results of
this round, a draft of the D2M axSpA definition was developed
and presented to the task force and, subsequently, to the ASAS
membership for endorsement.
Task force
After the ASAS executive committee approved the project, a
task force consisting of 29 rheumatologists and full ASAS mem-
bers, 2 young ASAS representatives (a rheumatologist and an
epidemiologist, full ASAS members), 2 patient representatives,
1 psychologist and behavioural medicine specialist, 1 physio-
therapist, and 1 physical medicine specialist (full ASAS member)
was convened.
Literature review
A literature review aimed at identifying potential definitions
for D2M axSpA from prior studies was conducted in 2022,
including a Medline (via PubMed) search using established
review methods and the search terms outlined in Supplementary
File S1. Following the RA model, the term ‘difficult-to-treat’ was
utilised in the first search strategy. Recognising that the termi-
nology in the literature might vary, a second, broader search
strategy using terms reflecting treatment nonresponse in axSpA
was implemented (Supplementary File S1). The search was per-
formed for all types of articles published in English and based
on studies in humans, with a publication date between 2012
and 2022. After excluding duplicates, titles and abstracts were
D. Poddubnyy et al. Ann Rheum Dis 00 (2025) 1−9screened, followed by a full-text review by MT and DP. From the
included publications, information was retrieved on the defini-
tion of treatment failure, the definition of active disease, and the
terminology used to characterise the concept of ‘difficult-to-
manage’ disease.
The first Delphi round
The first Delphi round focused on defining the following
main elements of the definition: uncontrolled disease (clinical
manifestations, composite outcome measures, objective signs of
inflammation, and radiographic progression), treatment failure
(types and number of treatment options applied), and other
potential factors that might contribute to the D2M situation. At
this stage, we used the term ‘difficult-to-treat,’ which was later
replaced with ‘difficult-to-manage’ (see Results). The first Del-
phi round included 9 questions related to the D2M topic, includ-
ing 1 open question (Supplementary File S2). It was conducted
from November to December 2022, with all ASAS members and
co-opted members of the D2M initiative—including 2 patient
representatives, a psychologist and behavioural medicine spe-
cialist, and a physiotherapist, all of whom were non-ASAS mem-
bers—invited to participate. The survey results were discussed
with the members of the task force at a dedicated virtual meet-
ing and subsequently with ASAS members at the annual meeting
in January 2023.
The second Delphi round, draft definition, and endorsement
Taking the results of the discussions with task force members
and at the ASAS meeting in January 2023 into account, we
drafted the second Delphi round, which focused on refining the
criteria for the D2M axSpA definition, including precise defini-
tions for insufficient control of signs and symptoms, required
treatment history, the number of prior b/tsDMARDs, discontinu-
ations due to intolerability or side effects, and differentiation
between primary and secondary treatment failure. This round
included 11 questions related to the D2M definition, including
an open question (Supplementary File S3). Before completing
the survey, participants (the same group as in the first round)
were informed about the outcomes of the previous stage. This
round was conducted from September to October 2023 and was
followed by discussions with the members of the task force and
all ASAS members at the annual meeting in January 2024. As an
outcome, the ASAS D2M definition was drafted, followed by a
vote on endorsement by the full ASAS membership. A majority
of votes in favour of the definition was sought for endorsement.
RESULTS
Literature review
A total of 198 publications were identified using both search
strategies. After the exclusion of 12 duplicates, 186 publications
were screened based on their titles and abstracts. A total of 134
publications were excluded: 128 were not related to the subject
of interest, 4 were related to paediatrics, and 2 were not related
to axSpA. Of the 52 publications whose full texts were evalu-
ated, 41 were excluded as unrelated to the subject of interest.
However, 4 new publications not captured by the original search
strategies were included after a cross-reference check. Ulti-
mately, 15 publications were included in the review: 2 case
reports, 5 observational studies, 3 open-label clinical trials, 3
randomised controlled trials, and 2 review articles (see the4Supplementary Fig and Supplementary Table). In summary, the
literature review revealed only a few relevant works with no
consistent definition of D2M axSpA due to the heterogeneity of
the criteria used for defining active disease and history of treat-
ment failure. Furthermore, there was no established terminology
to characterise the group of interest.
The first Delphi round
A total of 212 ASAS members (both full and associate), along
with 4 co-opted members of the D2M initiative, were invited;
123/212 (58%) responded and completed the survey in full. The
majority of the respondents (53%) supported using an ASDAS ≥
2.1 as an indicator of active disease in the context of D2M axSpA
(referred to as difficult-to-treat in this round). Additionally, 73%
indicated that objective signs of inflammatory activity (elevated
CRP and/or active inflammation on magnetic resonance imag-
ing [MRI]) should be incorporated into the definition of active
disease. Moreover, 77% of the respondents believed that all
manifestations of spondyloarthritis (axial, peripheral, and extra-
musculoskeletal) should be considered in the definition. Con-
cerning the definition of treatment failure, the predominant
response (46%) was ‘≥2 NSAIDs in full anti-inflammatory doses
and ≥2 b/tsDMARDs with different modes of action,’ without
differentiating between primary and secondary nonresponse
(79%). Regarding the question of whether intolerability or con-
traindications to NSAIDs or b/tsDMARDs should be considered
as an alternative to insufficient efficacy in the definition, 48% of
experts responded positively for both NSAIDs and b/tsDMARDs,
while 16% supported this consideration for b/tsDMARDs only.
According to 53% of the respondents, radiographic progression
should be part of the definition, and 51% indicated that symp-
toms unrelated to the inflammatory activity of axSpA should not
be considered.
In subsequent discussions with the task force and the ASAS
membership during the ASAS 2024 annual meeting, it was
decided to change the nomenclature from ‘difficult-to-treat’ to
‘difficult-to-manage.’ The main reason for this change is that
the management of axSpA better incorporates all management
aspects, not only drug treatment, and this is also in line with the
ASAS-EULAR management recommendations. Furthermore, it
was agreed that the D2M axSpA definition should be broad and
inclusive, similar to the difficult-to-treat RA framework, as
opposed to the TR scenario, which, being part of the D2M (and
therefore covered by the D2M definition), relates to cases where
inflammatory activity cannot be controlled with currently avail-
able treatments.
The second Delphi round
A total of 205 ASAS members (active at the time of invitation,
both full and associate), along with 4 co-opted members, were
invited, and 186/205 (91%) responded to the survey. In the first
part of this round, we sought components for the definition of
insufficient control of signs/symptoms of axSpA. The majority
of respondents (59%) favoured using ASDAS ≥ 2.1 as the com-
posite outcome measure threshold indicative of insufficient con-
trol of signs/symptoms in the context of the D2M axSpA
definition. Other selected components included objective signs
of inflammation (elevated CRP and active inflammation on MRI
of sacroiliac joints or spine), which should be mandatory but
only in TR patients (supported by 62% of the respondents), rapid
radiographic spinal progression (defined as the development of
>2 new syndesmophytes or bony bridges in 2 years [15], 63%),
and the presence of axSpA symptoms that cause a reduction in
quality of life, even if axSpA is controlled according to the crite-
ria mentioned above (80%).
The second part of the survey dealt with the treatment
aspects of the D2M axSpA definition. The definition refers to the
current version of the ASAS-EULAR management recommenda-
tions; therefore, no specific definition of minimal treatment
duration was deemed necessary by 58% of the respondents. The
leading response regarding the minimal sufficient treatment his-
tory (with 50% of the respondents in favour) was ‘At least
2 b/tsDMARDs with different modes of action,’ while 18% fav-
oured ‘At least 2 b/tsDMARDs with the same or different modes
of action,’ and 17% preferred ‘At least 3 b/tsDMARDs with the
same or different modes of action.’ Treatment discontinuation
due to intolerability/side effects was favoured by 75% of the
respondents, and 70% favoured the incorporation of contraindi-
cations for treatment with b/tsDMARDs into the D2M definition,
meaning that a patient could fulfil the definition without a trial
of a b/tsDMARD. Furthermore, 51% of the respondents indi-
cated no need for differentiation between primary and second-
ary nonresponse in the D2M context. Concurrently, 82% of the
respondents believed that a lack of access to treatment should
not be a part of the definition.
The draft definition followed minor modifications to the pro-
posed wording; consensus was reached. The final version of the
ASAS D2M axSpA definition, as shown in Figure 1, was endorsed
by ASAS at the annual meeting in January 2024 with 89% of the
votes (109 out of 123 full members).
The D2M axSpA should only be applied to patients with a def-
inite diagnosis of axSpA made by a rheumatologist. It consists of
3 main components: (1) treatment according to the ASAS-
EULAR recommendations and failure of ≥2 b/tsDMARDs with
different mechanisms of action (unless contraindicated); (2)
insufficient control of signs/symptoms of axSpA; and (3) the
present signs/symptoms being perceived as problematic by the
rheumatologist and/or the patient (see Fig 1 for details).
TR axSpA, according to the endorsed definition, is considered
a subgroup of D2M axSpA. Patients with D2M axSpA (assuming
correct diagnosis, which should be the first step in the evalua-
tion and treatment compliance) can be considered TR if
≥2 b/tsDMARDs failed, have high or very high disease activity
according to ASDAS (ASDAS ≥ 2.1) plus objective signs of
inflammatory activity (elevated CRP or active inflammation on
MRI of sacroiliac joints or spine), and if other causes, likely
responsible for signs and symptoms (concurrent conditions, non-
compliance, etc) are excluded before making a decision on the
presence of TR axSpA (Fig 2).
tion; we did not aim to develop classification criteria, which
SAS
e-m
ing
D. Poddubnyy et al. Ann Rheum Dis 00 (2025) 1−9Figure 1. The Assessment of SpondyloArthritis International Society (A
Axial Spondyloarthritis Disease Activity Score; bDMARD, biologic diseas
Alliance of Associations for Rheumatology; MRI, magnetic resonance imagDraft definition and endorsement
The results of the second Delphi round were discussed by the
task force. It was agreed to incorporate components of treatment
history and insufficient symptom control into the draft defini-
tion based on the outcomes of the Delphi process. Specific atten-
tion was given to the items that received less than 70% of votes
in the Delphi exercise. Additionally, the third component of the
definition, which relates to the perception of the current situa-
tion as problematic by the rheumatologist and/or the patient,
was also included following a discussion involving patient repre-
sentatives. The decision to use ‘and/or’ instead of ‘and’ was
made to ensure an appropriate representation of both patients’
and physicians’ views on the situation and to keep the definition
inclusive.5) difficult-to-manage axial spondyloarthritis (axSpA) definition. ASDAS,
odifying antirheumatic drug; CRP, C-reactive protein; EULAR, European
; tsDMARD, targeted synthetic disease-modifying antirheumatic drug.DISCUSSION
The developed expert consensus-based definition of D2M
axSpA, including TR disease, is an important first step of the
D2M initiative with the ultimate goal of improving treatment
outcomes in axSpA. This initiative, led by ASAS, not only aims
to define D2M and TR axSpA but also includes the development
of management recommendations for D2M axSpA, encompass-
ing TR cases. Here, we report the finalised definitions while the
recommendation development process is ongoing. Importantly,
patients are involved in the entire development process. Another
important aspect is that the development process involved
reaching a consensus among the members of an expert organisa-
ruct
eum
d sig
ts m
rugs
nd
nan
D. Poddubnyy et al. Ann Rheum Dis 00 (2025) 1−9Figure 2. The difficult-to-manage axial spondyloarthritis (axSpA) const
manage and treatment-refractory axSpA, is the diagnosis of axSpA by a rh
ment failure (or intolerance/contraindications), indicators of uncontrolle
lematic situation. A treatment-refractory situation (**) is present in patien
treatment failure (assuming appropriate compliance, tolerance of the d
according to the Axial Spondyloarthritis Disease Activity Score (ASDAS), a
vated C-reactive protein [CRP]: CRP+ or inflammation on magnetic resowould have required a different methodological approach. We
believe that a consensus-based expert approach is appropriate in
this case, as there was no unified definition or terminology for
the clinical situation described by the definition at the start of
the initiative. Furthermore, we are defining not a disease or a
permanent condition but rather a disease state that may change
over time. Moreover, we followed a similar methodology that
was used to develop the EULAR difficult-to-treat definition for
RA [13].
The developed definition consists of 3 criteria, which must be
present in a patient with axSpA diagnosed by a rheumatologist:
1. Treatment according to the ASAS-EULAR recommenda-
tions and failure of ≥2 b/tsDMARDs with different mechanisms
of action (unless contraindicated).
This criterion defines the minimal requirement for treatment
history and implies a lack of response to the standard treatment
approach, including at least 2 b/tsDMARDs with different mech-
anisms of action. It implies the failure of b/tsDMARDs with
proven efficacy in axSpA, which are incorporated in the ASAS-
EULAR recommendations, currently TNF, IL-17, and JAK inhibi-
tors. It is assumed that other treatment options, including
NSAIDs and nonpharmacological measures, have been
exhausted as well, either before or in parallel with b/tsDMARDs.
In axSpA, only 3 classes of b/tsDMARDs are effective and
approved for treatment; therefore, experts decided that at least
2 out of 3 classes should be tried before making a conclusion
about the presence of D2M axSpA. Treatment failure includes
both primary and secondary nonresponses since both may be
associated with treatment challenges and a D2M situation. This
other causes, likely responsible for signs and symptoms (including incorre
before deciding on the presence of treatment-refractory axSpA. bDMARD, bio
manifestations; MM, musculoskeletal manifestations; QoL, quality of life; tsDM
6. The starting point in this construct, which applies to both difficult-to-
atologist. A difficult-to-manage situation (*) is present in cases of treat-
ns/symptoms related to spondyloarthritis, and the perception of a prob-
eeting the definition of difficult-to-manage axSpA if there is evidence of
, and sufficient treatment duration), high or very high disease activity
objective signs of uncontrolled inflammatory activity (as reflected by ele-
ce imaging [MRI] of sacroiliac joints or spine: MRI+). It is assumed thatcriterion does not imply any specific time aspect: neither the
duration of treatment, which must be in accordance with current
recommendations, nor the timing of the treatment failure. How-
ever, this criterion should be considered in the context of other
criteria; for instance, the definition of D2M axSpA will not be
fulfilled in a patient with a history of b/tsDMARD secondary
failure in the past if there are treatment options available or if
the current treatment line is associated with a good clinical
response. The same applies to the discontinuation of b/
tsDMARDs due to intolerability or side effects (which are
defined broadly in the D2M context as any event that results in
the discontinuation of a drug). Patients with contraindications
to 1 or several classes of b/tsDMARDs represent a particular
group, which might be considered D2M despite the lack of for-
mal evidence of b/tsDMARD failure. This means that this crite-
rion may be fulfilled in a patient who failed 1 bDMARD and has
contraindications to the use of others. When defining TR axSpA,
which is a subgroup of D2M axSpA, evidence of treatment fail-
ure (at least 2 b/tsDMARDs belonging to different classes with
proven efficacy in axSpA) and no discontinuation due to intoler-
ability, side effects, or contraindications is required. This dis-
tinction is deemed necessary to differentiate between axSpA
patients not responding to currently available treatment options
and those who could have responded to the therapy but cannot
receive it due to tolerability or safety issues.
2. Insufficient control of signs and symptoms of axSpA.
At least 1 of the following 4 indicators of insufficient control
should be present: (i) high or very high disease activity accord-
ing to the validated outcome measure ASDAS; (ii) presence of
ct diagnosis, concurrent conditions, noncompliance, etc), are excluded
logic disease-modifying antirheumatic drug; EMM, extramusculoskeletal
ARD, targeted synthetic disease-modifying antirheumatic drug.
D. Poddubnyy et al. Ann Rheum Dis 00 (2025) 1−9active spondyloarthritis manifestations (musculoskeletal or
extramusculoskeletal), including objective signs of inflamma-
tory activity; (iii) rapid radiographic spinal progression, as
defined by published data-driven criteria [15]; and (iv) other
axSpA symptoms that are attributable to axSpA and cause a
reduction in quality of life, even if points i to iv are not met. The
criteria are broad and inclusive, aiming to capture the majority
of clinical situations where axSpA might be considered insuffi-
ciently controlled. It is assumed that the mentioned signs and
symptoms are present at, or are closely related temporally to,
the time of the D2M status evaluation. The criterion of radio-
graphic spinal progression specifically refers to the past 2 years.
However, this must be contextualised with other parameters
and the timing of treatment initiation since the effects of anti-
inflammatory treatment, such as those shown for TNF inhibitors,
typically become evident between years 2 and 4 of treatment
[16]. There was significant discussion regarding the necessity of
point iv. This point was retained in the final definition to ensure
the inclusivity of the D2M definition, aiming to cover a broad
range of clinical situations (eg, a patient with prominent fatigue
or substantial functional limitations related to structural damage
without significant pain or inflammatory activity). Although the
mechanisms contributing may vary, inclusivity is vital for cap-
turing these diverse scenarios. For defining TR disease, we pro-
pose that objective signs of inflammatory activity (elevated CRP
that is attributable to axSpA and not to other causes, or active
inflammation on MRI of sacroiliac joints or spine) be mandatory,
in addition to the presence of high/very high disease activity
according to ASDAS. Of note, patients experiencing rapid radio-
graphic spinal progression would not be classified as TR if active
inflammation is otherwise controlled. Radiographic progression
in the spine can still be observed in the initial years following
the introduction of effective anti-inflammatory treatment, often
slowing over time [17]. Therefore, we do not classify patients
with structural damage progression as TR if disease activity has
been controlled by effective anti-inflammatory treatment, as
there is a reasonable likelihood that progression will decelerate
over time due to a time-shifted effect [16].
3. The present signs/symptoms are perceived as problematic
by the rheumatologist and/or the patient.
This aspect is crucial as it brings together the physician’s and
patient’s perspectives into the definition. It ensures that the eval-
uation of the D2M status is not merely based on formalised crite-
ria relating to the number of previous treatment lines and
composite outcome measures but also considers the global eval-
uation of the current situation in the context of the D2M con-
cept. As mentioned above, in the broad and inclusive D2M
definition, the opinion of the patient is as important as the opin-
ion of the physician. No specific instruments are proposed to
capture the perception of the disease as problematic from either
the physician’s or the patient’s perspective.
What are the potential implications of the developed defini-
tion? We expect that it will stimulate research focusing on iden-
tifying reasons for D2M and would draw attention to D2M
patients in daily clinical practice. We encourage investigators to
prospectively collect information related to the elements of this
definition in both interventional and observational studies on
axSpA. The reasons for D2M may vary from setting to setting
but most likely will belong to 1 of 2 main groups, which are
important in both daily clinical practice and research contexts:
1. The true nonresponse to anti-inflammatory treatment
resulted in a TR case. The exact frequency of this phenome-
non, as well as the underlying mechanisms, warrant7investigation, including the generation of epidemiological
data, exploration of pathophysiology, and conduction of
interventional studies.
2. Signs and symptoms not caused by inflammation but rather
by nonnociceptive pain mechanisms (ie, nociplastic or neuro-
pathic pain), concurrent conditions (which might be present
even if the diagnosis of axSpA is correct), and other factors—
including but not limited to socio-psychological aspects,
work, beliefs about the condition, and coping mechanisms—
should be further investigated. The list is not exhaustive and
should be defined in subsequent steps, as the relevance of
these factors may vary across settings. This group of patients
also requires further investigations, including identifying the
underlying reasons and developing strategies incorporating a
multidisciplinary approach to address various aspects of the
D2M situation in clinical practice.
Importantly, the criteria presented above assume the correct-
ness of the diagnosis and patient compliance with the prescribed
treatment. These are relevant aspects to consider as the first steps
when dealing with D2M axSpA patients and defining TR patients.
In the next step of the D2M initiative, we plan to develop recom-
mendations on how to approach D2M and TR patients.
Our work has several limitations, which should be acknowl-
edged. First, the approach we used was based on expert and
patient opinions rather than being data-driven. While this
approach is certainly less rigorous than a data-driven approach
(such as that used for classification criteria), we believe that, in
the absence of unified definitions and terminology at the outset
of the project, this was the only feasible way to progress. A uni-
fied definition was necessary as a starting point to stimulate
research and develop management recommendations for this
patient group. Second, the literature review was conducted as a
scoping review rather than a systematic review. However, we
believe this did not compromise the work, as the goal of the
review was to provide a foundation for expert consensus rather
than an exhaustive synthesis of evidence. As previously men-
tioned, evidence synthesis would not have been possible with-
out a unified definition and nomenclature. Third, even within
the expert organisation, there was some heterogeneity of views
on certain aspects of the definition, as reflected in the results of
the Delphi exercises. Nonetheless, through discussion and
refinement, a broad consensus was achieved, with 89% of the
members endorsing the final definition.
The D2M axSpA initiative aligns well with similar efforts in
other inflammatory rheumatic conditions, such as RA (termed
‘difficult-to-treat’) [13] and psoriatic arthritis [18,19]. In these
conditions, both rheumatologists and patients often encounter
challenges in achieving complete control of disease signs and
symptoms, even with state-of-the-art treatments. It is anticipated
that common mechanisms, such as central sensitisation, along
with disease-specific factors, contribute to the development of
D2M/difficult-to-treat situations. This understanding likely
extends to TR disease as well, thereby stimulating research into
these mechanisms across different rheumatic diseases.
In conclusion, the ASAS D2M axSpA definition allows for
clear identification of patients with unmet medical needs, indi-
cating the way forward for improved clinical management and
further research.
Competing interests
DP has received research support from AbbVie, Eli Lilly,
MSD, Novartis, Pfizer, consulting fees from AbbVie, Biocad,
Lilly, Galapagos/Alfasigma, Janssen, MSD, Novartis, Pfizer,
Alphasigma, BMS, Eli Lilly, Janssen, Medscape, Novartis,
D. Poddubnyy et al. Ann Rheum Dis 00 (2025) 1−9Bristol-Myers Squibb, Eli Lilly, Janssen, Moonlake, Novartis,
Pfizer, and UCB, and speaker fees from AbbVie, Canon, DKSH,
Eli Lilly, Janssen, MSD, Medscape, Novartis, Peervoice, Pfizer,
and UCB. DP is a member of the executive committee of ASAS.
VN-C has received consultancy/speaker/research grants from
AbbVie, Alphasigma, BMS, Fresenius Kabi, Galapagos, Janssen,
Eli Lilly, Moonlake, MSD, Novartis, Pfizer, Roche, and UCB. VN-
C is a member of the executive committee, executive secretary,
and elected president of ASAS. MT: none declared. SA has
received consulting fees from Argenx, Bristol-Myers Squibb, Gal-
apagos, and Novartis. SZA has received grants from AbbVie, Eli
Lilly, Jannsen, Novartis, Pfizer, and UCB, consulting fees from
AbbVie, Eli Lilly, Jannsen, Novartis, Pfizer, and UCB, and hono-
raria from AbbVie, Eli Lilly, Jannsen, Novartis, Pfizer, and UCB.
SB: none declared. FvdB: none declared. CB has received finan-
cial support from Novartis, AbbVie, Galapagos, Novartis, Pfizer,
and UCB. AC has received grant support from BMS, Lilly, and
Novartis, honoraria from Alfa Sigma, AbbVie, Amgen, BMS, Eli
Lilly, Galapagos, Novartis, Pfizer, and UCB, and travel/meeting
attendance support from AbbVie and UCB. JD: none declared.
MD has received grant support from Pfizer, UCB, and AbbVie,
consulting fees from Novartis and Pfizer, travel/meeting atten-
dance support from Novartis, and participation on a Data Safety
Monitoring Board or Advisory Board for Galapagos. TD has
received honoraria from AbbVie, Amgen, Novartis, Koc¸ak, and
Lilly and travel/meeting attendance support from Celltrion,
Lilly, AbbVie, Amgen, Novartis, and Nobel. BE-Z has received
consultancy, research grants, and speaker’s honoraria from Abb-
Vie, Amgen, BMS, Eva, Hekma, Janssen, Lilly, MSD, New Bridge,
Novartis, Pfizer, Roche, Sanofi-Aventis, Servier, and Sobi. WF
has received speaker/consulting fees/grants from Novartis,
Janssen and Janssen, GlaxoSmithKline, and Diethelm Keller
Siber Hegner (DKSH). FvG has received consulting and speaker
fees from AbbVie, ASAS, BMS, Galapagos, Janssen, Lilly, Novar-
tis, Pfizer, and UCB. RG-S has received consultancy/speaker/
research grants from AbbVie, BMS, Janssen, Eli Lilly, Novar-
tis, Pfizer, Roche, UCB, GSK, Biogen, Amgen, Raffo, and
Adium. MGC has received grant support and travel/meeting
attendance support from Novartis. PG: none declared. LG:
none declared. SG has received honoraria from AbbVie, Alta-
medics, Amgen, Eli Lilly, Johnson & Johnson, Krka, Medis,
MSD, Novartis, Pfizer, Sandoz, Sobi, Stada, Viatris, Teva, and
Zentiva and support for attending meetings/travel from Abb-
Vie, Novartis, and Pfizer. FH: none declared. MK has
received honoraria from AbbVie, Amgen, Asahi-Kasei
Pharma, Ayumi Pharma, BMS, Chugai, Daiichi-Sankyo, Eisai,
Eli Lilly, Gilead, Janssen, Novartis, Ono Pharma, Tanabe-Mit-
subishi, and UCB Pharm. RL has received consulting fees
from AbbVie, Pfizer, UCB, Eli Lilly, Novartis, Jansen Pharma,
and Galapagos, honoraria from UCB and AbbVie, partici-
pated in a DSMB for a UCB trial, is ASAS and METEOR
board member and director of Joint Imaging BV, and of
Rheumatology Consultancy BV. YYL has received speaking
fees from AbbVie, DKSH, Janssen, Novartis, and Pfizer. PMM
has received honoraria from AbbVie, BMS, Celgene, Eli Lilly,
Galapagos, Janssen, MSD, Novartis, Orphazyme Pfizer,
Roche, and UCB. HM-O has received research grants from
Janssen, Novartis, Pfizer, and UCB and speaker fees/hono-
raria from AbbVie, Amgen, Biogen, Eli Lilly, Janssen, Moon-
lake, Novartis, Pfizer, and UCB. BM has received honoraria/
participated in advisory boards and/or received speaker fees
from IPCA, Cipla, Torrent, RPG Lifesciences, and Novartis.
AM has received speaker honoraria/participated in advisory
boards, and/or received research grants from Biogen, BMS,8The authors thank all members of the Assessment of Spondy-
loArthritis International Society who contributed their valuable
expertise and knowledge to the Delphi exercises, significantly
influencing the refinement of the definition through engaging
live discussions. HM-O is supported by the National Institute for
Health Research (NIHR) Leeds Biomedical Research Centre. The
views expressed are those of the authors and not necessarily
those of the (UK) National Health Service, the NIHR, or the (UK)
Department of Health.
Contributors
Members of the steering committee (DP, DvdH, VN-C, and
XB) initiated and conducted the project, supervised the litera-
ture review, developed the surveys, and analysed their results.
They also drafted the definition and the manuscript. MT con-
ducted the literature review and supported the project’s conduc-
tion and manuscript development. All authors contributed to
the project’s development, interpretation of survey results, draft-
ing of the definition, and revising the manuscript for important
intellectual content. All authors have approved the final version
of the manuscript. DP acts as the guarantor author of this
manuscript.
Funding
The project has been conducted under the auspices and with
the support of the Assessment of SpondyloArthritis International
Society (ASAS). The work of MT was supported by an ASAS
research grant.Peervoice, Pfizer, and UCB. President of ASAS and EULAR.
DvdH has received consulting fees from AbbVie, Alfasigma,
Argenx, BMS, Eli Lilly, Grey-Wolf Therapeutics, Janssen,
Novartis, Pfizer, Takeda, and UCB Pharma and is director of
Imaging Rheumatology bv. DvdH is the associate editor of
Annals Rheumatic Diseases, an editorial board member of
the Journal of Rheumatology and RMD Open, and an advisor
to Assessment of Axial Spondyloarthritis International
Society.
AcknowledgementsSanofi, and UCB. MR has received consulting and/or speaker
fees from AbbVie, Chugai, Boehringer-Ingelheim, Eli Lilly,
Janssen, Novartis, and UCB. CGSS has received consulting
and speaker fees from AbbVie, Janssen, Novartis, and Pfizer.
AS has received speaking and/or consulting fees from Abb-
Vie, Novartis, UCB, and Lilly. Support for attending conferen-
ces: Janssen. JW has received research grants, speaker fees,
or advisor board from Pfizer, Abbott, AbbVie, Bristol-Myers
Squibb, Eli Lilly, JNJ, UCB, MSD, GSK, Chugai, Roche, Cel-
gene, Sanofi-Aventis, and Novartis. XB has received research
support from AbbVie, Eli Lilly, and Novartis, consulting fees
from AbbVie, Alphasigma, BMS, Eli Lilly, Janssen, Moonlake,
Novartis, Pfizer, and UCB, and speaker fees from AbbVie,UCB, Pfizer, Johnson & Johnson, Novartis, Amgen, Gilead,
Galapagos, AbbVie, Lilly, and Pfizer. EN has received speaker
honoraria/participated in advisory boards, and/or received
research grants from UCB, Pfizer, Gilead, Galapagos, AbbVie,
Eli Lilly, Alfasigma, Fresenius, and Pfizer. SR has received
research grants and/or consultancy fees from AbbVie, Eli
axial spondyloarthritis. Ann Rheum Dis 2022;81(9):1252–9.
[17] Poddubnyy D, Sieper J. Mechanism of new bone formation in axial spondy-
D. Poddubnyy et al. Ann Rheum Dis 00 (2025) 1−9Patient consent for publication
This project actively involved patients with axial spondyloar-
thritis (axSpA) throughout the study design, consensus-building
process, and the development of the final definition of difficult-
to-manage axSpA. Two patient representatives were included
as coauthors and contributed significantly to all stages of the
project.
Ethics approval
No ethics committee approval was required for this study.
Provenance and peer review
Not commissioned; externally peer reviewed.
Data availability statement
Not applicable.
Supplementary materials
Supplementary material associated with this article can be
found in the online version at doi:10.1016/j.ard.2025.01.035.
Orcid
Denis Poddubnyy: http://orcid.org/0000-0002-4537-6015
Victoria Navarro-Comp
an: http://orcid.org/0000-0002-
4527-852X
Murat Torgutalp: http://orcid.org/0000-0003-4600-9484
Suzanne Arends: http://orcid.org/0000-0002-4422-7640
Sibel Zehra Aydin: http://orcid.org/0000-0001-8792-4449
Simone Battista: http://orcid.org/0000-0002-7471-1951
Filip van den Bosch: http://orcid.org/0000-0002-3561-5932
Christine Bundy: http://orcid.org/0000-0002-5981-3984
Alberto Cauli: http://orcid.org/0000-0002-7955-6786
Maxime Dougados: http://orcid.org/0000-0003-3009-6229
Tuncay Duru€oz: http://orcid.org/0000-0003-3584-2788
Bassel El-Zorkany: http://orcid.org/0000-0003-2704-9712
Warren Fong: http://orcid.org/0000-0003-1891-1892
Floris van Gaalen: http://orcid.org/0000-0001-8448-7407
Rodrigo Garcia-Salinas: http://orcid.org/0000-0002-5928-
1092
Marco Garrido Cumbrera: http://orcid.org/0000-0001-9727-
1189
P
al G
eher: http://orcid.org/0000-0002-4543-9629
Lianne Gensler: http://orcid.org/0000-0001-6314-5336
Simeon Grazio: http://orcid.org/0000-0003-3407-0317
Feng Huang: http://orcid.org/0000-0002-2319-873X
Mitsumasa Kishimoto: http://orcid.org/0000-0002-4007-
1589
Robert Landew
e: http://orcid.org/0000-0002-0577-6620
Ying Ying Leung: http://orcid.org/0000-0001-8492-6342
Pedro M Machado: http://orcid.org/0000-0002-8411-7972
Helena Marzo-Ortega: http://orcid.org/0000-0002-9683-
3407
Bhowmik Meghnathi: http://orcid.org/0000-0001-7337-
5194
Anna Molto: http://orcid.org/0000-0003-2246-1986
Elena Nikiphorou: http://orcid.org/0000-0001-6847-3726
Sofia Ramiro: http://orcid.org/0000-0002-8899-9087
Martin Rudwaleit: http://orcid.org/0000-0001-5445-548X9loarthritis. Curr Rheumatol Rep 2017;19(9):55.
[18] Marzo-Ortega H, Harrison SR, Nagy G, Machado PM, McGonagle DG, Aydin
SZ, et al. Time to address the challenge of difficult to treat psoriatic arthritis:
results from an international survey. Ann Rheum Dis 2024;83(3):403–4.
[19] Ribeiro AL, Singla S, Chandran V, Chronis N, Liao W, Lindsay C, et al. Deci-
phering difficult-to-treat psoriatic arthritis (D2T-PsA): a GRAPPA perspective
from an international survey of healthcare professionals. Rheumatol Adv
Pract 2024;8(3):rkae074.Carla G S Saad: http://orcid.org/0000-0001-9720-0719
Alexandre Sepriano: http://orcid.org/0000-0003-1954-0229
James Wei: http://orcid.org/0000-0002-1235-0679
Xenofon Baraliakos: http://orcid.org/0000-0002-9475-9362
D
esir
ee van der Heijde: http://orcid.org/0000-0002-5781-
158X
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