Clinical Pearls: What We Know About Nonradiographic Axial Spondyloarthritis

ACR BEYOND LIVE—Much, if not all, of rheumatology relies on clinical interpretation of historical, laboratory and imaging information to formulate a coherent diagnosis and treatment plan—even when such information is incomplete or has multiple possible interpretations. One of the best examples of this situation pertains to nonradiographic axial spondyloarthritis (nr-axSpA), a condition that is just now being recognized and described in a uniform manner.

At the 2020 ACR State-of-the-Art Clinical Symposium, John Reveille, MD, professor and vice chair of medicine, University of Texas Health Science Center at Houston, discussed nr-axSpA in detail.

Progression of Criteria
In 2009, the Assessment of SpondyloArthritis International Society (ASAS) published classification criteria for nr-axSpA in which a patient who was younger than age 45 and had at least three months of chronic back pain could qualify for the diagnosis.

In one arm, patients who have HLA-B27 meet classification criteria if they also demonstrate two or more features of spondyloarthritis (i.e., inflammatory back pain, arthritis, heel enthesitis, uveitis, dactylitis, psoriasis, inflammatory bowel disease, good response to non-steroidal anti-inflammatory drugs [NSAIDs], family history of spondyloarthritis or elevated C-reactive protein [CRP]). In the other arm, patients with at least one clinical feature of spondyloarthritis plus inflammatory findings on magnetic resonance imaging (MRI) that are strongly suggestive of sacroiliitis—but lacking sacroiliac joint changes on radiographs that are not bilateral grade 2 or unilateral grade 3 or higher—would also meet criteria for nr-axSpA.^1,2

It’s important to note these criteria have been met with criticism. For example, the term nonradiographic axial spondyloarthritis can be unclear in that it includes patients with early radiographic sacroiliitis (e.g., grade 1 sacroiliitis bilaterally or grade 2 sacroiliitis unilaterally, as seen on radiography), and the ASAS criteria are unclear regarding whether radiographic changes can include the spine or only the sacroiliac joints.³

Nevertheless, Dr. Reveille made clear in his talk that the prevalence and burden of disease with respect to nr-axSpA should not be underestimated. In evaluating the 2009–10 National Health and Nutrition Examination Survey (NHANES), Weisman et al. noted the age-adjusted U.S. prevalence of inflammatory back pain by Calin criteria was 5.0%.⁴ 

Deodhar et al. explained that in most cohorts and also in the NHANES study, the ratio of patients with nr-axSpA to those with ankylosing spondylitis (i.e., patients meeting radiographic imaging criteria) is 1:1.³ Yet in a study published last year describing diagnostic delay in identifying axial spondyloarthritis, the mean delay was 5.7 years, and factors associated with delayed diagnosis included female sex, those who are young at symptom onset, HLA-B27-negative status and the presence of psoriasis.⁵

In addition, Dr. Reveille discussed the 2019 Update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis. Dr. Reveille noted that the recommendations for treatment of ankylosing spondylitis and nr-axSpA are quite similar in this update.

Tumor necrosis factor inhibitor (TNFi) therapy is recommended over secukinumab or ixekizumab as the first biologic to be used, but either of the latter two medications is recommended over the use of a second TNFi in patients with primary nonresponse to the first TNFi. Co-administration of low-dose methotrexate with TNFi is not recommended, and sulfasalazine is recommended only for persistent peripheral arthritis when TNFi therapy is contraindicated.

With regard to patients with unclear disease activity, MRI of the spine or pelvis can be used to aid in assessment, but routine monitoring of radiographic changes with serial spine radiographs is not recommended in the 2019 guideline.⁸

Disease Progression
On this note, discussion of the best way to monitor disease activity in axial spondyloarthritis has been ongoing. In an editorial reflecting on the 2019 guideline, Michelena and Marzo-Ortega explain there are limitations in using MRI for disease monitoring in light of the limited knowledge on correlation between MRI lesions and treatment response and the uncertainty regarding the clinical significance of subclinical inflammatory changes on MRI. The authors also write that no therapies have yet been proved to be disease modifiers in axial spondyloarthritis and that data are limited regarding the potential effects from NSAIDs, TNFi’s and interleukin-17 inhibitors on slowing structural damage.⁹

Clinicians and patients alike also wonder what percentage of patients with nr-axSpA are likely to progress to radiographic axial spondyloarthritis over time. In a recent review on this subject, the authors note that most studies report 10–40% of patients with nr-axSpA progress to radiographic axial spondyloarthritis over a period of 2–10 years.⁶

Dr. Reveille noted in his lecture that male sex and elevated CRP are among the best predictors of radiographic progression. For this reason, Dr. Reveille advocates for repeat imaging of the sacroiliac joints when following patients over time, and this may include MRI studies when they can be covered by the patient’s insurance.

Studies in Radiology journals have noted that MRI can show new bone formation in the sacroiliac joints and peri-discal new bone formation in the spine.⁷ The proper use of such imaging for screening and monitoring disease may prove useful in the clinical care of patients.

Conclusion
Dr. Reveille concluded by noting how far rheumatologists have come in better understanding such conditions as nr-axSpA, but he also indicated that much remains to be done to best care for patients with this condition.

As in many other areas of rheumatology, patient-reported outcomes are, and will be, essential in understanding the patient’s experience with their disease, and allowing clinicians to have a reliable and validated tool to measure disease activity and change treatment plans accordingly.

The lecture was stimulating and helped demonstrate the importance of recognizing disease symptoms and signs early and not reflexively misattributing symptoms of inflammatory back pain to other etiologies. It is only by honing in on the inflammatory underpinnings of spondyloarthritis that clinicians will be able to help these patients, with the goal of getting them back to a higher quality of life.

Jason Liebowitz, MD, completed his fellowship in rheumatology at Johns Hopkins University, Baltimore, where he also earned his medical degree. He is currently in practice with Skylands Medical Group, N.J.

References

1. Rudwaleit M, Landewé R, van der Heijde D, et al. The development of Assessment of SpondyloArthritis International Society classification criteria for axial spondyloarthritis (part I): Classification of paper patients by expert opinion including uncertainty appraisal. Ann Rheum Dis. 2009 Jun;68(6):770–776.
2. Rudwaleit M, van der Heijde D, Landewé R, et al. The development of Assessment of SpondyloArthritis International Society classification criteria for axial spondyloarthritis (part II): Validation and final selection. Ann Rheum Dis. 2009 Jun;68(6):777–783.
3. Deodhar A, Reveille JD, van den Bosch F, et al. The concept of axial spondyloarthritis: Joint statement of the Spondyloarthritis Research and Treatment Network and the Assessment of SpondyloArthritis International Society in response to the U.S. Food and Drug Administration’s comments and concerns. Arthritis Rheumatol. 2014 Oct;66(10):2649–2656.
4. Weisman MH, Witter JP, Reveille JD. The prevalence of inflammatory back pain: Population-based estimates from the U.S. national health and nutrition examination survey, 2009–10. Ann Rheum Dis. 2013 Mar;72(3):369–373.
5. Redeker I, Callhoff J, Hoffmann F, et al. Determinants of diagnostic delay in axial spondyloarthritis: An analysis based on linked claims and patient-reported survey data. Rheumatology (Oxford). 2019 Sep 1;58(9):1634–1638.
6. Protopopov M, Poddubnyy D. Radiographic progression in non-radiographic axial spondyloarthritis. Expert Rev Clin Immunol. 2018 Jun;14(6):525–533.
7. Laloo F, Herregods N, Jaremko JL, et al. MRI of the axial skeleton in spondyloarthritis: The many faces of new bone formation. Insights Imaging. 2019 Jul 24;10(1):67.
8. Ward MM, Deodhar A, Gensler LS, et al. 2019 update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network recommendations for the treatment of ankylosing spondylitis and nonradiographic axial spondyloarthritis. Arthritis Care Res (Hoboken). 2019 Oct;71(10):1285–1299.
9. Michelena X, Marzo-Ortega H. Axial spondyloarthritis: Time to stop the split 10 years on. Nat Rev Rheumatol. 2020 Jan;16(1):5–6.