Treating to target in axial spondyloarthritis: defining the target and the arrow

Abstract

The treat-to-target concept is currently proposed in axial spondyloarthritis and aims for remission to be reached and maintained. Consensual definitions of remission and flare of the disease are currently lacking but are needed to validate this strategy and to confirm the window of opportunity hypothesis. The discovery of new therapeutic targets, such as IL-23 and IL-17, will enable and enlarge the possibility of targeted therapies in axial spondyloarthritis.

Keywords:

• ankylosing spondylitis
• IL 17
• IL 23
• remission
• spondyloarthritis
• treatment

Spondyloarthritis (SpA) is a chronic inflammatory disease involving mainly the spine and sacroiliac joints, entheses and less often peripheral joints. Some extra-articular manifestations are associated with SpA, including uveitis, psoriasis and inflammatory bowel disease. The overarching term of SpA encompasses ankylosing spondylitis, reactive arthritis, psoriatic arthritis, inflammatory bowel disease-related arthritis and undifferentiated SpA. Recent classification criteria led to the individualization of non-radiographic axial SpA and to the recognition of axial forms, peripheral arthritic forms and enthesitic forms of the disease [1]. SpA is a multifactorial disease, involving genetic factors (HLA-B27, but also ERAP-1, IL-23R) and environmental factors (infection, gut and smoking). Recently, immunopathologic hypotheses focused on IL-23/Th 17 pathway in this disease [2]. On the anatomic tissue level, involvement of the enthesis represents the hallmark of the disease, with a sequence of focal inflammation followed by secondary ossification with radiological expression, which may lead to ankylosis. The chronic evolution of the disease varies from one patient to another, with periods of low disease activity and flares. The burden of this disease, involving people in work activity, may be high [3], justifying efficacious and tailored therapy strategies.

Several recent recommendations are paving the way for the treatment strategies in SpA [4], according to the phenotype (axial/peripheral) of the disease. The concept of ‘treat to target’ (T2T) has been proposed for SpA [5,6] in its different forms. But may T2T be applied to axial SpA? T2T implies a clear target as remission or low disease activity and sustained over time, understanding treating flares and tight control. T2T makes sense only if this strategy demonstrates more efficacy than a traditional one, and if an early efficacious intervention is associated with a better outcome (reduced functional capacity impairment, reduced radiographic progression, for instance), highlighting the question of a window of opportunity in SpA.

Another consideration of T2T is to define suitable therapeutic weapons. TNF blockers represent the emblematic targeted therapy in SpA, and a major progress in the management of these patients, but not all develop a good response, and there is a need for alternative therapies in this condition.

Under these circumstances, some questions are arise when considering T2T in axial SpA

Target as outcome to be reached

If the target to be reached should be remission in axial SpA, we should emphasize that to date, there is no clear definition of remission [7]. In most of the cases, remission refers to disease activity, and a state of inactive disease may be considered as a proxy for remission. This is the case with the latest validated disease activity score (ASDAS) including clinical rheumatologic data, patient’s evaluation and a biologic marker (C reactive protein [CRP]), allowing to classify patients as inactive (score less than 1.3) and in moderate disease activity (score less than 2.1) [8]. But remission has several other dimensions in axial SpA, in particular extra-articular manifestations (e.g., uveitis), and imaging evaluation (MRI findings, radiographic damage progression), which should be included in the definition. The current treatment should also be taken into account, a drug-free remission being the gold standard. Finally, the duration of symptom-free (or equivalent) state may be another key point for defining remission, and a minimum of 3 or more months stable period may be required to classify remission.

Flare of the disease should as well be recognized and treated adequately to maintain a sustained state of remission/low disease activity according to the recommendation [5]. But here again, there is no consensual definition of flare. Based upon disease activity scores, flare may correspond to an absolute value about a threshold [9], or a relative variation (20 or 30% increase for example) from the remission or low disease activity state. Should extra-articular manifestations and underlying treatment be considered? This represents a subject of investigation in the ASAS group (Assessment in Spondyloarthritis International Society).

The question of a potential window of opportunity in axial SpA is a matter of debate [10]. The objective of preventing or slowing the development of structural damage assessed by radiographic ossification is difficult to attain. Recent studies suggest that early effective treatment may influence radiographic outcome [11,12], even if data about benefit of a tight control strategy in axial SpA are lacking. Identification of patients with poor prognosis is another need, and the ongoing prospective cohorts of patients with early axial SpA [13] will hopefully bring some answers in this field.

Molecular target for therapies

Even if TNF blockade demonstrated clear efficacy in axial SpA, there is currently no other pharmacological possibilities besides NSAIDs and anti-TNF agents in this condition. One-third of these patients do not respond adequately to anti-TNF agents, illustrating the need of new therapeutic targets. Immunological knowledge drawn from human and animal studies allows testing of new targeted therapies. As previously mentioned, the involvement of IL-23/Th17 axis in SpA represents a link between genetic, environmental factors, gut, entheses and inflammation [2]. IL-23 and IL-17 may be inhibited using monoclonal antibodies. Some results from clinical studies are available, stimulating further evaluation.

Ustekinumab is an anti-IL-12/23 monoclonal antibody directed against the p40 subunit, common between IL-12 and IL-23. Already licensed in the treatment of psoriasis and psoriatic arthritis, this biodrug has been evaluated in a prospective open label study (TOPAS study) [14] in 20 patients (without history of non response to anti TNF agents) with active ankylosing spondylitis, with subcutaneous injection of 90 mg at weeks 0, 4 and 16, and response evaluation at week 24. At week 24, 75% of the patients were ASAS 20 responders (moderate response), 65% ASAS 40 response (good response), 35% in ASDAS inactive disease, with statistically significant improvement in function, metrology (mobility), quality of life, NSAID intake score and MRI osteitis score (sacroiliac and spine) compared to baseline. Ustekinumab was well tolerated.

Secukinumab is a monoclonal antibody directed against IL-17A. It was used in a randomized double-blind, proof-of-concept study [15], including 30 patients with active ankylosing spondylitis (24 secukinumab iv. 2 × 10 mg/kg, 6 placebo). At week 6, ASAS 20 response estimates were 59% on secukinumab, and 24% on placebo, with decrease in biologic markers and MRI scores. These results were recently confirmed by a large international controlled Phase III study (MEASURE 1) [16], including 371 patients with active ankylosing spondylitis with inadequate response to NSAIDs, disease modifying anti rheumatic drugs and/or anti TNF, randomized in three groups: secukinumab iv. 10 mg/kg (weeks 0, 2, 4) followed by secukinumab sc. 75 mg every 4 weeks; secukinumab iv. 10 mg/kg (weeks 0, 2, 4) followed by secukinumab sc. 150 mg every 4 weeks and placebo, with evaluation at weeks 16 and 52. Primary objective was percentage of patients with ASAS 20 response at week 16. Mean age was 42 years, with disease duration of 7.5 years; 27% were anti-TNF inadequate responders. Primary endpoint was reached, with an ASAS 20 response in 59% in the secukinumab groups versus 28% in the placebo group (p < 0.01), with a sustained response until week 52, even in previous anti-TNF inadequate responders. Significant reduction in CRP and MRI inflammation scores were observed at week 16, without particular side effects (no systemic candidiasis). This is the first biologic agent demonstrating clear efficacy in a Phase III trial in SpA patients after failure of anti-TNF therapy.

The therapeutic concepts derived from rheumatoid arthritis may not be fully extrapolated to axial SpA, and to date has not been clearly validated in this condition. There is a need for a universal definition of the target, and the best way to reach it.

Financial & competing interests disclosure

D Wendling receives speaking fees and/or consultancy fees from Abbott, MSD, Pfizer, Roche Chugai, BMS, Amgen, Nordic Pharma, Swedish Orphan Biovitrum and UCB. He receives grants from Abbott, MSD, Pfizer, Roche Chugai and BMS. He is a national co-ordinator and investigator of the study CAIN 457F2305 (secukinumab in Ankylosing Spondylitis, Novartis) and national co-ordinator and investigator of the study ALIGN (sarilumab in Ankylosing Spondylitis, Sanofi-Aventis). The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.