The profiling of axial spondyloarthritis patient candidate to a biologic therapy: Consensus from a Delphi-panel of Italian experts

Accepted Manuscript The profiling of axial spondyloarthritis patient candidate to a biologic therapy: consensus from a Delphi-panel of Italian experts

Ennio Giulio Favalli, Andrea Becciolini, Roberto Caporali, Monica Todoerti, Florenzo Iannone, Liliana Dinoia, Marco Sebastiani, Amelia Spinella, Elisa Gremese, Francesco Cianci, Fabiola Atzeni, Francesca Bandinelli, Gianfranco Ferraccioli, Giovanni Lapadula, GISEA study group PII: DOI: Reference:

S1568-9972(18)30238-6 doi:10.1016/j.autrev.2018.07.002 AUTREV 2232

To appear in:

Autoimmunity Reviews

Received date: Accepted date:

9 July 2018 13 July 2018

Please cite this article as: Ennio Giulio Favalli, Andrea Becciolini, Roberto Caporali, Monica Todoerti, Florenzo Iannone, Liliana Dinoia, Marco Sebastiani, Amelia Spinella, Elisa Gremese, Francesco Cianci, Fabiola Atzeni, Francesca Bandinelli, Gianfranco Ferraccioli, Giovanni Lapadula, GISEA study group , The profiling of axial spondyloarthritis patient candidate to a biologic therapy: consensus from a Delphi-panel of Italian experts. Autrev (2018), doi:10.1016/j.autrev.2018.07.002

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ACCEPTED MANUSCRIPT The profiling of axial spondyloarthritis patient candidate to a biologic therapy: consensus from a Delphi-panel of Italian experts Ennio Giulio Favalli1, Andrea Becciolini1, Roberto Caporali2, Monica Todoerti2, Florenzo Iannone3, Liliana Dinoia3, Marco Sebastiani4, Amelia Spinella4, Elisa Gremese5, Francesco Cianci5, Fabiola Atzeni6, Francesca Bandinelli7, Gianfranco Ferraccioli 5, Giovanni Lapadula3, on behalf of GISEA study group. 1

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Department of Rheumatology, Gaetano Pini Institute, Milan, Italy Department of Rheumatology, University of Pavia, IRCCS Policlinico San Matteo Foundation, Pavia, Italy 3 Rheumatology Unit, Department of Emergence Medicine and Transplantation (DETO), University of Bari, Italy 4 Rheumatology Unit, University of Modena and Reggio Emilia, Modena, Italy 5 Rheumatology Unit, Fondazione Policlinico Universitario A. Gemelli-Catholic University of the Sacred Heart, Rome, Italy 6 Rheumatology, University of Messina, Italy 7 Rheumatology Unit, Hospital S. Giovanni di Dio, Florence, Italy


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Corresponding author: Ennio Giulio Favalli, MD Department of Rheumatology, Gaetano Pini Institute, Milan Via Gaetano Pini, 9 20122 Milan - Italy email address: [email protected] Phone: +39 0258296421 Mobile: +39 3289659778 FAX: +39 0258296315

ACCEPTED MANUSCRIPT ABSTRACT Objective: The project aimed to collect expert consensus statements for the profiling of patients with axial spondyloarthritis (axSpA) candidate to biologic agents (bDMARDs) treatment, in order to better define the drivers for the best treatment choice. Methods: The 6 more interesting topics about axSpA patient profiling were identified by the

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project steering committee and a panel of axSpA Italian experts. A systematic literature review (SLR) was performed for each of the selected topics according to the PICO format. Two rounds of a modified Delphi process were conducted. In the 1st round, the steering committee evaluated the results of the SLR in order to formulate statements for each topic. In the 2nd round, the experts

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panel discussed, rephrased when needed, and voted the level of agreement (on a 5-point Likert-

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type scale) for each statement. Consensus was defined as ≥66% agreement. Results: The topics selected for the analysis were the differential efficacy of available bDMARDs

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on enthesitis/dactylitis, uveitis, radiographic progression and cardiovascular involvement, and the

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clinical response in non radiographic-axSpA and in patients receiving a second-line bDMARD. The Delphi rounds formulated 19 statements, all reaching the defined level of consensus in a second

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round including 25 rheumatologists highly skilled in the management of axSpA.

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Conclusion: Identified consensus statements can help clinicians to apply to routine-care settings the results from clinical studies and international recommendations, providing a guide for individualization of treatment strategy in axSpA patients. KEYWORDS: Axial spondyloarthritis, biologic drugs, personalised therapy, expert consensus

ACCEPTED MANUSCRIPT 1. INTRODUCTION Spondyloarthropathies (SpA) encompass a group of chronic inflammatory diseases sharing common genetic and clinical features, such as the involvement of the axial (sacroiliac joints and spine) or peripheral skeleton (usually asymmetric monoarthritis or oligoarthritis predominantly affecting the joints of the lower extremities); the presence of dactylitis, enthesitis, and typical

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extra-articular manifestations such as psoriasis, acute anterior uveitis, and inflammatory bowel disease (IBD); the association with HLA-B27 antigen (1). According to the current classification provided by the Assessment of Spondyloarthritis International Society (ASAS) in 2011, SpA may be separated into axial (axSpA) or peripheral depending on the body sites in which the disease

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predominantly manifests (2). Moreover, the ASAS definition of axSpA distinguishes SpA depending

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on the presence or absence of structural bone damage detectable on X‐ray scans of the sacroiliac

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joints: ankylosing spondylitis (AS) or nonradiographic axSpA (nr‐axSpA). The management of axSpA has dramatically improved over the last decades due to the

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development of new classification criteria allowing an earlier identification of patients with recent

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onset disease, and by the implementation even in SpA of those treat-to-target strategies previously successfully applied in rheumatoid arthritis patients (3). Current treatment

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recommendations include physical exercise, physiotherapy, and nonsteroidal anti-inflammatory drugs (NSAIDs) as first line treatments in axSpA (4,5). Biologic drugs (bDMARDs), particularly tumor necrosis factor alpha inhibitors (TNFis), have led to a dramatic change in the therapeutic approach and are currently widely used for the management of axSpA after NSAIDs failure (6). To date, five TNFis (infliximab, adalimumab, etanercept, and more recently golimumab and certolizumab pegol) have been licensed for SpA by the European Medicines Agency and the US Food and Drug Administration according to the favourable results from randomized controlled trials (RCTs) conducted in both AS (7-11) and nr-axSpA (8,12-15). Although the existence of several

ACCEPTED MANUSCRIPT biologic drugs with the same mechanism of action seems to be redundant, the clinical experience has clearly demonstrated dissimilar efficacy and safety profiles across TNFi class due to individual differences in biochemical structures and properties, immunogenicity, bioavailability, and mechanism of action (16). Recent advances in understanding axSpA pathogenesis have drawn the attention on interleukin 17 (IL-17) as a new potential treatment target, expanding the number of

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available treatment options by the approval of IL-17 blockers such as secukinumab (17).

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The described increasing number of therapeutic options for the treatment of axSpA has progressively increased the need for strategies to better define the profile of patients candidate to each individual bDMARD according to a tailored approach and to date the identification of specific

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drivers of treatment choice represents an important clinical challenge.

In order to fill this gap, the Gruppo Italiano per lo Studio delle Early Arthritis (GISEA) constituted a

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task-force of expert rheumatologists with the aim to systematically review the literature analysing selected topics related to axSpA patient profiling and to formulate consensus statements

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providing guidance on treatment strategy in routine clinical practice.

2. MATERIALS AND METHODS

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2.1. Overall methodology and task force definition

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A modified Delphi process (18) was used to generate and achieve consensus on the profiling of axSpA candidates to a bDMARD treatment. Delphi is an anonymous, indirect, iterative process aimed to achieve consensus among experts, in consecutive stages based on the systematic feedback from the results of the previous rounds (19). The GISEA task force involved in the process included a steering committee composed of 8 senior rheumatologists (EGF, FI, RC, FA, MS, EG, GF, and GL) responsible for defining the project aim, identifying the treatment areas to be addressed by the consensus, elaborating the statements to be voted, and drafting the final manuscript; a methodologist, who advised on the entire consensus

ACCEPTED MANUSCRIPT process; 6 fellows (AB, FB, FC, LD, MT, AS), who conducted the systematic literature review (SLR), graded the strength of evidence, and developed an evidence report for the final discussion with the entire task force; a voting panel of 25 rheumatologists who were highly trained and had extensive experience in axSpA management, selected by the steering committee from the GISEA rheumatology centres and involved in the final discussion and agreement of the statements. Selection of topics to be addressed

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2.2.

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A preliminary consensus was performed by the steering committee and the panel of experts in order to assess the 6 topics to be addressed. Each senior member of the committee indicated the most relevant and uncovered areas of interest about axSpA profiling for bDMARD therapy,

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producing a list of 12 potential topics to be voted. Each member of the expert panel was then asked to vote the 3 of 12 preferred topics by using a dedicated online platform and finally the 6

2.3.

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most voted were chosen for the final analysis. Systematic review of the literature

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SLR was performed by the fellows to identify relevant evidence about the 6 selected topics. The

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questions in each area were rephrased according to the PICO format (Patients, Interventions, Comparisons and Outcomes)(20) as reported in the table 2. Additionally, the references of

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relevant articles were hand-searched for identification of other potentially suitable papers. The

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literature search was performed in Medline and Embase limiting the analysis to adults ≥18 years, to English language publications, and to the period not covered by the SLR informing the 2010 update of ASAS/EULAR recommendations for the management of ankylosing spondylitis (from 2010 January, 1st to 2016 June, 30th). Duplicate references were removed. The eligible study types were defined as systematic reviews, meta-analyses, randomized controlled trials (RCTs), and observational studies (including case series). The hierarchy of study types was reported by levels of evidence (LoE) as suggested by the Oxford University (https://www.cebm.net/2009/06/oxfordcentre-evidence-based-medicine-levels-evidence-march-2009/).

ACCEPTED MANUSCRIPT 2.4.

Delphi rounds

From October 2016 to January 2017, two Delphi rounds were conducted.
In the first one, the steering committee, the fellows, and the methodologist met for a full day face-to-face meeting with the aim of discussing the results of the SLR and to formulate 3-4 summarising statements for each topic. In the second round, the whole task force including the panel of 25 experts met for

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discussing and eventually rephrasing each statement according to the results of the SLR. Finally,

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the 25 experts were invited to express individually the level of agreement by rating each statement on a 5-point Likert-type scale: (1) Strongly disagree; (2) Disagree; (3) Neither agree nor disagree; (4) Agree; (5) Strongly agree. The definition of the consensus was determined before the

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were blinded to the results during analysis.

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analysis and was set at ≥66% of participants indicating a score between 3 and 5. Investigators

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3. RESULTS

The results of the topic selection process for identifying the areas to be addressed by the SLR are

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reported in table 1. In general, all the proposed statements achieved the defined level of

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consensus, as detailed in table 3.

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3.1. Efficacy in axSpA patients with enthesitis and/or dactylitis Overall, we found only 4 papers focused on axSpA, thus in the first Delphi round we decided to include for the final analysis also 19 studies conducted in PsA populations, where dactylitis and enthesitis have been more extensively evaluated.

3.1.1. Adalimumab and etanercept are effective and safe in the treatment of enthesitis in axial SpA (LoE: 2b).

ACCEPTED MANUSCRIPT 3.1.2 Adalimumab does not show a significant efficacy in dactylitis (LoE: 2b); no data are available on dactylitis for etanercept. Adalimumab was effective and safe in the treatment of enthesitis in axSpA, but not in PsA patients (21,23-26). Furthermore, it did not show a significant efficacy on dactylitis (21,23-26). Etanercept has proven to be effective and safe in the treatment of enthesitis in SpA patients (14,27), whereas

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no data on dactylitis are available.

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3.1.3 Data on golimumab, infliximab, certolizumab pegol, ustekinumab, and secukinumab are available only in psoriatic arthritis (PsA) patients. They are effective and safe in the treatment of enthesitis and dactylitis (LoE: 2b).

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Data on golimumab, infliximab, certolizumab pegol are available only in PsA patients, where these drugs have shown efficacy and safety in the treatment of both enthesitis and dactylitis (26,28-33).

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In RCTs on PsA patients (with or without axial involvement), ustekinumab significantly improved active PsA signs/symptoms, including dactylitis score and MASES for enthesitis, with an acceptable

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safety profile. TNFi-experienced patients proved significant results too, and the response was

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more pronounced in patients with only one previous TNFi versus 2 or more (34-37). According to RCTs FUTURE 1 and 2, significant improvements were observed with secukinumab with higher rate

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of enthesitis and dactylitis resolution versus placebo. Clinical benefits were noted in both TNFi-

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naive and TNFi-non responder patients (38,39).

3.2. Efficacy in axSpA patients with uveitis

3.2.1. TNFis reduce the incidence of both new-onset and recurrent uveitis in axSpA patients (LoE: 2b) This item has not been directly addressed in any head-to-head RCT. Several pooled analyses of RCTs compared rates of uveitis in patients treated with TNFis or placebo, reporting an overall

ACCEPTED MANUSCRIPT reduced incidence in the biologic treated group (40-42). Moreover, these findings were confirmed by some open label studies addressing the effectiveness of adalimumab in reducing the recurrence rate of anterior uveitis in patients with AS (43,44). Similarly, in observational studies reporting real-life experiences, the rate of both new onset and recurrent anterior uveitis in

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patients with axSpA was found to be reduced after the introduction of TNFi treatment. (45-48)

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3.2.2. New-onset and recurrent uveitis are less frequent in axSpA patients treated with anti-TNF monoclonal antibodies when compared to etanercept (LoE: 3b)

Although no head-to-head RCTs among available TNFis have been performed yet, several

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retrospective studies clearly demonstrated a lower incidence of new-onset and recurrent uveitis in axSpA patients treated with anti-TNF monoclonal antibodies compared with etanercept (45,46,49-

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52). Accordingly, multiple case reports showed that treatment with infliximab, adalimumab, certolizumab, and golimumab (47,48,53-55) is associated with beneficial effect on axSpA

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associated uveitis, whereas etanercept is not effective and may carry a potential role of trigger

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factor (56,57).

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3.3. Efficacy on radiographic progression in axSpA

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3.3.1. AS patients with a delay of more than 10 years from diagnosis to anti-TNFα therapy start are more likely to exhibit radiographic progression (LoE: 2b). In a prospective analysis by Haroon et al. including 334 AS patients (58), treatment duration, considered either as a whole and as the proportion of overall disease duration, showed to substantially impact on subsequent radiographic; patients who were on biologic therapy for more than 50% of their global disease duration had lower odds of progression. Moreover, patients with a delay longer than 10 years in starting TNFi therapy were more likely to progress compared to

ACCEPTED MANUSCRIPT those who started earlier. Thus, both the duration of therapy and the timing of treatment initiation are important in the ultimate effect on the rate of spine damage in AS patients.

3.3.2. The presence of radiographic damage at baseline, together with male gender, smoking history and high CRP at baseline, is an independent strong predictor of radiographic

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progression in AS patients (LoE: 2b).

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In several studies baseline radiographic damage (defined as the baseline modified Stoke Ankylosing Spondylitis Spinal Score, mSASSS) and the number of syndesmophytes at baseline were associated with progression (58,59). In the German Spondyloarthritis Inception Cohort, smoking

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was significantly associated with radiographic progression at 2 years in patients with axSpA with disease duration ≤ 10 years (60). In the cohort described by Haroon et al. the higher the pack-

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years of smoking, the greater the rate of mSASSS progression, with the highest rate seen in smokers with more than a 10 pack-year history (58). Baseline values of ESR and CRP were

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independently associated with radiographic progression after adjusting for baseline radiographic

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damage (58).

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3.3.3. In AS patients, anti-TNFα therapy, independently from the specific agent, does not impact

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on radiographic progression in the short-term (2-4 years), when compared with standard of care. (LoE: 2b)

Radiographic progression, measured according to mSASSS, was evaluated in several open label extensions of clinical trials, did not seem to be different at 2 years from baseline between patients receiving TNFis (infliximab, adalimumab, etanercept) compared with patients under conventional therapy (NSAIDs and/or cDMARDs) (61-64). A slight reduction of progression rate in infliximabtreated patients after 4 years (when comparing radiographs obtained at baseline with those at 2 and 4 years) was observed in a study from Baraliakos et al.; however this study had several

ACCEPTED MANUSCRIPT limitations, as it included only 33 patients and radiographs were evaluated in chronological order, which might be more prone to identify a difference in radiographic changes (65).

3.3.4. In AS patients, anti-TNFα therapy, independently from the specific agent, can slow radiographic progression on the long-term (after at least 4 years of continuous treatment)

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suggesting a non linear time-dependent effect. (LoE: 2b).

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In a prospective study, the mean progression rate over 6 years was reported to be lower in TNFis treated patients (adalimumab, infliximab, etanercept) when compared with conventional treatment (data from OASIS cohort): 1.3 vs 2.0 mSASSS units per 2 years, respectively (66).

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Radiographic progression showed similar course in TNFis and non TNFis-treated patients during the first 4 years of treatment, but a significant reduction of progression rate in TNFis-treated

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patients was observed between year 4 and 8; this non-linear relationship between radiographic-

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inflammation by TNFis (59,67).

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damage progression and time may suggest a delayed effect of long-term inhibition of

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3.4. Efficacy on the management of cardiovascular risk in axSpA

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3.4.1. Cardiovascular risk factors remain unchanged in AS patients during anti-TNF treatment (LoE: 2b).

The prevalence of metabolic syndrome and cardiovascular risk factors in men with AS treated with TNFis is significantly increased and correlates with disease activity (68), but TNF blockers seem to had no negative impact on macrovascular (clinical and ultrasonographic) or dysmetabolic parameters, with no apparent difference between TNFis (infliximab, adalimumab, etanercept) and cDMARDs or NSAIDs (69-72). A study by Mathieu showed a significant increase in HDL cholesterol after 14 weeks of infliximab or adalimumab treatment (73).

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3.4.2. The clinical efficacy of infliximab is reduced in obese and overweight SpA patients (LoE: 2b).

A significantly lower effectiveness of infliximab (but not adalimumab or etanercept) according to increased BMI was described in an Italian observational study reporting a BASDAI50 response of

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16.7, 56.7, and 79% in obese, overweight, and normal weight patients, respectively (74). Similar

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results have been reported by Ottaviani et al. in a real-life cohort of 155 AS patients (75). Interestingly, a similar trend was previously observed even in rheumatoid arthritis subjects treated with infliximab in the Italian registry GISEA (76)

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3.4.3. Adalimumab, infliximab, and etanercept are protective on endothelial dysfunction in AS

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patients (LoE: 2b).

Several studies showed that adalimumab, infliximab, and etanercept have a preventive role on

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endothelium damage, according to evaluation of fibrinolysis and coagulation markers (77), nitroxide metabolism (78), circulating endothelial and platelet microparticles (79), or oxidation

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status (80). All the above endothelial dysfunction markers were significantly down-regulated in

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TNFis treated patients compared with cDMARDs and/or NSAIDs.

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3.4.4. The higher platelet aggregation due to inflammation in AS similarly decreases during antiTNF and conventional DMARD treatment (LoE: 4). Increased platelet aggregation linked to inflammation and disease activity has been observed in AS patients (81,82). Both synthetic (methotrexate and sulfasalazine) and biologic DMARD (infliximab) treatment were associated with significant decrease in platelet abnormalities probably due to their anti-inflammatory efficacy rather than their ability to inhibit aggregation (81,82).

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3.5. Clinical response of bDMARDs in nr-axSpA 3.5.1. In TNFi naive nr-axial SpA patients, the first course of TNFi could provide significant (LoE: 1a) and persistent amelioration (LoE: 2a) of disease activity. A meta-analysis by Callhoff included 5 double-blinded placebo-controlled trials (2 on adalimumab,

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1 on etanercept, 1 on infliximab and 1 on certolizumab pegol) which were published between

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2008 up to 2014 and which enrolled nr-axSpA patients (83). RAPID-axial SpA trial enrolled mixed axSpA population with very comparable results when stratifying by underlying indication (8). OR for ASAS40 response was 3.6 [95% CI 2.5 to 5.3] for TNFis over placebo. Performance of

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golimumab was later assessed in GO-AHEAD trial: ASAS20 and ASAS40 responses were achieved by significantly more patients in the golimumab group compared with placebo (71.1% versus

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40.0%; P <0.0001, and 56.7% versus 23.0%; P <0.0001, respectively) at week 16 (13). In the open label extension of RAPID-axial SpA, certolizumab pegol maintained clinical benefits over 96 weeks

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in the overall axSpA population regardless of dosage regimen (200 mg versus 400 mg) and

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baseline structural damage (84). Two adjunctive trials assessed TNFi efficacy with respect to an active comparator (etanercept vs sulfasalazine and golimumab vs pamidronate), but only the

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ESTHER trial involved a relevant number of early axSpA patients with baseline active inflammatory

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lesions on whole-body MRI: etanercept treated patients experienced significantly more clinical and imaging benefits compared to sulfasalazine group (85,86).

3.5.2. In nr-axSpA differences in clinical responses among available TNFis might be dependent on heterogeneity in characteristics of target populations (number of patients, concomitant extra-articular manifestations, disease duration, age, MRI+, elevated CRP), concomitant allowed medication with csDMARDs/CS, timing of collecting endpoints (LoE: 1B).

ACCEPTED MANUSCRIPT 3.5.3. Younger patients, with shorter disease duration and signs of inflammation at baseline (MRI+, elevated CRP) could better benefit from TNFi therapy, regardless of the TNFi agent (LoE: 1B). RCTs subanalyses suggest that in nr-axSpA patients, larger clinical improvement of clinical efficacy measures were almost univocally associated with younger age, shorter disease duration, elevated

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CRP and/or positive baseline MRI at baseline (83). Thus, differences across available studies could

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partly account for apparent divergent performance of TNFis . Specifically, in the GO-AHEAD study most patients had very short disease duration (< 1year), whilst in the RAPID-axSpA inclusion criteria requested CRP elevation and/or positive MRI; such factors might explain higher ASAS

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response rates for golimumab and certolizumab pegol respectively, when indirectly compared with other TNFis (8,13). Open label studies in real life settings variably confirmed the validity of

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such predictive factors in nr-axial SpA (87,88).

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3.6. Clinical response in patients receiving a second-line bDMARD

TNFi (LoE: 2b).

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3.6.1. Switching between TNFi is effective in ax-SpA patients who failed to respond to the first

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Data on switching TNFi come from observational studies and data analysis from national registers

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and are mostly focused on infliximab, adalimumab and etanercept (24,89-96). Switching to a second TNFi is effective in axSpA patients, although response rate and drug survival seem to be lower than in non-switchers. The sequence and type of TNFi switch do not seem to impact the effectiveness of subsequent TNFi (24,91), but the reason for stopping the first TNFi may affect the rate of response to a second one. Patients discontinuing prior TNFi because of primary inefficacy have significantly less chance to improve with a second TNFi than those patients switching due to secondary inefficacy or adverse events (24,92,95). Furthermore, failure to a first TNFi due to the

ACCEPTED MANUSCRIPT production of anti-drug antibodies seems to predict a better clinical response to a second TNFi (96).

3.6.2. Switch to a third TNFi is possible although the literature shows a lower persistence rate (LoE: 2b)

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There is evidence that switching between anti-TNFα agents is useful for axSpA patients who failed

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to respond to the first and also to a second TNFi, although often the number of patients treated with a third TNFi is rather small (89,91,93,94). These studies do not show differences in efficacy among the different TNFi, therefore switches are possible including for more than one switch and

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including intra-class switches, but switchers have poorer treatment response and shorter drug

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survival than non-switchers.

3.6.3. Secukinumab is effective in AS patients who failed to respond or are intolerant to the first

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TNFi (LoE: 1b)

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In randomized, double-blind, placebo-controlled phase 3 study of secukinumab (MEASURE 2) 38% of patients with active AS were previously treated with only one TNFi. Secukinumab provided

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sustained improvements in signs and symptoms of AS, although the response was generally

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greater in anti-TNF-naive than in anti-TNF-inadequate/intolerance response (-IR) subjects (17). Regarding ustekinumab, data on efficacy in anti-TNF-IR patients with axSpA are not available. Indeed, in the randomized trial PSUMMIT-2, BASDAI or ASAS response rate were not taken in account in TNF-experienced patients (36), and in a subsequent post-hoc analyses, although significantly more patients treated with ustekinumab achieved BASDAI20/50/70 responses and higher proportion of subjects achieved ASDAS-CRP improvements than in the placebo group, the efficacy was assessed in a mixed cohort (TNF-naive plus TNF-IR) (37). Furthermore, there are no

ACCEPTED MANUSCRIPT controlled trials comparing switching between TNFis and drugs with a different mechanism of action.

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CONCLUSION

Given the progressively increasing number of treatment options, tailoring bDMARD therapy to

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maximise outcomes and deliver safe and cost-effective care is a key target in the management of

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axSpA. Despite the advances in the identification of potential predictive tools, nowadays individualisation of axSpA treatment is not yet a reality and international recommendations do not provide clear indications about the choice of bDMARD according to patient characteristics.

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We performed a SLR mainly focused on uncovered areas of axSpA management with the aim to output a consensus document by a task force of axSpA experts providing an update on potential

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drivers of bDMARD selection. Despite the lack of definite indications, our analysis confirmed that some patient’s features, such as the presence of SpA extra-articular manifestations, may be

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considered as clear drivers for treatment approach. In conclusion, identified consensus statements

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may help clinicians to apply to routine-care settings results from clinical studies, providing a guide for the personalisation of treatment for axSpA patients (Figure 1). The challenge for future

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research is to design studies to identify more specific (bio)markers and to validate all available

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explored and promising findings relevant to clinical practice.

ACCEPTED MANUSCRIPT FIGURE LEGEND

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Figure 1: summary of the evidences about the main topics reported in the final statements

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Figure 1