The concept of axial spondyloarthritis. Lessons from the INFAST study

Henning Zeidler, Emeritus,
November 21, 2013

Dear Editor,

Sieper et al. evaluated whether combination therapy with Infliximab (IFX) and naproxen (NPX) was superior to treatment with NPX alone in patients who had active moderate-to-severe early (disease duration under 3 years) active axial spondyloarthritis (SpA) and who were naive to nonsteroidal anti-inflammatory drugs (NSAIDs) or had only been treated with a submaximal dose of NSAIDs (1). This study is the first investigation of the potential benefits of early TNF-antagonist treatment in active axial SpA patients who are not yet refractory to NSAID therapy. Additionally, this represents the first randomised controlled clinical trial to use the imaging portion of the Assessment of SpondyloArthritis International Society (ASAS) criteria for axial SpA with active inflammation of the SI joints on MRI at baseline. Most importantly, the evidence from this study supports early diagnosis and treatment of SpA with a full dose of NSAIDs first, escalating to combination NSAID+TNF antagonist treatment in patients who have insufficient response.
Moreover, this study provides important insights about the application of the new classification criteria for axial SpA in a clinical trial.
Approximately 60 % of patients had ankylosing spondylitis (AS) fulfilling the modified New York radiographic criteria. Thus 40% of patients had nonradiographic axial SpA classified by MRI; it would be of interest to know if in these patients the additional SpA features for classification were different from AS patients. Arthritis was quite often in both treatment arms (45.3% vs 26.9%, respectively). Importantly, the 66- joint swollen joint count and 68- joint tender joint count was ameliorated considerably in both treatment arms and significantly better for swollen joints with NSAID+TNF antagonist treatment. Also in other studies testing adalimumab against placebo and etanercept against sulfasalazine, respectively, arthritis was found in 29% up to 52% of patients with early axial SpA (2, 3, 4). Evidently, simultaneous peripheral symptoms are frequent in nonradiographic and early axial SpA.
This raises the question if future studies should include together patients fulfilling the axial and/or peripheral SpA criteria to establish treatment evidences for SpA in general; thus would be possible to promote approval of established and new treatments for most conditions unified under the umbrella of SpA instead of testing for each individual diagnosis and subgroup of clinical manifestations. However, this requires more attention to infections associated with reactive arthritis which have been included in the criteria for peripheral but not for axial SpA (5, 6, 7).
Preceding infection (balanitis, urethritis, cervicitis and/or acute diarrhea) is noted in 37% of patients with peripheral SpA (8). Furthermore 35% of the patients with peripheral SpA have radiographic sacroiliitis (8). This overlap between axial and peripheral symptoms demonstrates that the construct of separating SpA into predominant clinical manifestations is somewhat artificial and only partially reflect the clinical reality given the heterogeneous character and fluctuating course of the diseases belonging to the SpA concept. Especially in the early years of the disease, the main target of the new classification criteria, AS progresses by a series of flares involving localized area such as the knee, neck, ankle, or localized area of the back (9, 10, 11). Many patients with SpA at some time of the disease can have either prominent peripheral and axial symptoms concurrently or peripheral and axial symptoms successively. The classification may change from axial to peripheral and vice versa at different times in a given study, compromising the consistency of classification in long-term trials. Finally, the description of increased frequency of Chlamydia-positive synovial tissue samples in patients with chronic undifferentiated SpA, the growing insight into the etiology of persistent chlamydial infection, and the promising treatment of Chlamydia- induced arthritis with combination antibiotic therapy indicate the necessity of further splitting SpA into underlying disease entities such as reactive arthritis (c. f. 12).


1. Sieper J, Lenaerts J, Wollenhaupt J, et al. Efficacy and safety of infliximab plus naproxen versus naproxen alone in patients with early, active axial spondyloarthritis: results from the double-blind, placebo- controlled INFAST study, Part 1. Ann Rheum Dis Published Online First: [21 May 2013] doi:10.1136/annrheumdis-2012-203201

2. Sieper J, van der Heijde D, Dougados M et al. Efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis: results of a randomised placebo-controlled trial (ABILITY-1). Ann Rheum Dis 2013;72:815-22.

3. Haibel H, Rudwaleit M, Listing J, et al. Efficacy of adalimumab in the treatment of axial spondylarthritis without radiographically defined sacroiliitis: results of a twelve-week randomized, double-blind, placebo- controlled trial followed by an open-label extension up to week fifty-two. Arthritis Rheum 2008;58:1981-91.

4. Song IH, Hermann K, Haibel H et al. Effects of etanercept versus sulfasalazine in early axial spondyloarthritis on active inflammatory lesions as detected by whole-body MRI (ESTHER): a 48-week randomised controlled trial. Ann Rheum Dis 2011;70:590-6.

5. Rudwaleit M, van der Heijde D, Landew? R, et al. The Assessment of SpondyloArthritis international Society (ASAS) Classification Criteria for peripheral Spondyloarthritis and for Spondyloarthritis in general. Ann Rheum Dis 2011;70:15-21.

6. Zeidler H, Amor B. The Assessment in Spondyloarthritis International Society (ASAS) classification criteria for peripheral spondyloarthritis and for spondyloarthritis in general: the spondyloarthritis concept in progress. Ann Rheum Dis 2011;70:1-3.

7. Zeidler H. The historical concept of interrelated conditions lumped together as a family of distinct diseases is not outdated. Arthritis Rheum 2013;65:2214-5.

8. van den Berg R, van Gaalen F, van der Helm-van Mil A, Huizinga T, van der Heijde D. Performance of classification criteria for peripheral spondyloarthritis and psoriatic arthritis in the Leiden Early Arthritis cohort. Ann Rheum Dis 2012;71:1366-9.

9. Wilkinson M, Bywaters EG. Clinical features and course of ankylosing spondylitis; as seen in a follow-up of 222 hospital referred cases. Ann Rheum Dis 1958;17:209-28.

10. Brophy S, Calin A. Definition of disease flare in ankylosing spondylitis: the patients' perspective. J Rheumatol 2002;29:954-8.

11. Stone MA, Pomeroy E, Keat A et al. Assessment of the impact of flares in ankylosing spondylitis disease activity using the Flare Illustration. Rheumatology 2008;47:1213-8.

12. Zeidler H, Hudson AP. New insights into Chlamydia and arthritis. Promise of a cure? Ann Rheum Dis 2013 (in press).

Conflict of Interest:

None declared

Conflict of Interest

None declared