Axial spondyloarthritis (axSpA) defines an immune-mediated inflammatory form of arthritis associated with the spine and sacroiliac joints, and it typically presents as chronic back pain. Available data estimate the prevalence of axSpA in up to 1% of adults in the United States.1 The diagnosis of axSpA is challenging and can take up to 10 years from initial symptom onset. Such delays can result in disability, irreversible joint fusion with a significant effect on the quality of life, missed time at work, and increased use of health care resources.2,3
Axial spondyloarthritis has been identified for decades as 2 subtypes of a disease with the same clinical features but different radiographic presentation. Patients with axSpA with an absence of radiographic changes are diagnosed with nonradiographic axSpA (nr-axSpA), and patients with radiographic changes are diagnosed with radiographic axSpA (r-axSpA) or ankylosing spondylitis (AS). However, the spectrum of clinical features on plain x-ray imaging may be considered “normal,” resulting in a subjective approach to diagnosis and the associated diagnostic delay. Part of the challenge with the accurate and timely diagnosis of axSpA may be inherent in the New York classification criteria, based on which diagnostic evaluations are made.4
Unlike peripheral spondyloarthritis, such as psoriatic arthritis, which has well-defined diagnostic criteria, axSpA is marked by longer diagnostic delays (9 months vs 9 years, respectively) due to its relatively less clear criteria.5.6
The availability of magnetic resonance imaging (MRI) imaging studies, genetic biomarkers such as human leukocyte antigen B27 (HLA-B27), and inflammatory markers such as C-reactive protein (CRP) has led to a re-examination of axSpA concepts and the publication of the Assessment of Spondyloarthritis International Society (ASAS) classification criteria. The ASAS criteria accommodate nr-axSpA as an earlier stage of AS and have the potential to reduce the lengthy time to diagnosis after symptom onset. Prompt treatment is essential to halt or to slow axSpA progression. However, in the absence of radiographic evidence of the disease, treating nr-axSpA with available biologic agents has been a clinical challenge.7
Have axSpA Classification Criteria Contributed to Diagnostic Delays?
Historically, diagnostic delays of axSpA were inherent in the criteria used in its classification, which was focused on the presence of radiographic sacroiliitis and defined clinical features in the setting of chronic low back pain.
Classification criteria for axSpA have evolved over the years since the initial Rome criteria of 1961. However, the New York criteria of 1968 and the modified New York criteria of 1984,7 required the presence of radiographic sacroiliitis, perpetuating the notion that radiographic evidence on plain radiographs was essential to diagnosis. Plain x-ray radiographic images can be difficult to read consistently. Consequently, there can be significant variability, and the interpretation of what is considered a “normal variation” can differ, introducing uncertainty in diagnostic evaluation. The lack of diagnostic certainty can result in diagnostic delays and a less than ideal approach to treatment. The New York classification criteria were then re-evaluated after studying first-degree relatives of HLA-B27-positive patients with AS, in whom researchers observed evidence of spondylotic disease in the absence of radiologic evidence of sacroiliitis.8
The New York classification criteria identifies axSpA as a condition with various clinical features associated with axial or nonaxial manifestations. The nonaxial manifestations
Subsequently, the presence of HLA-B27 and other clinical features, in addition to MRI studies, have contributed to the changing concept of axSpA from a disease requiring evidence of erosions in the sacroiliac joints to a spectrum of diseases with and without erosion.7
Interestingly, patients with r-axSpA and those with nr-axSpA or AS share, with nearly equal prevalence, common extra-spinal and peripheral manifestations. In a cross-sectional analysis of patients with axSpA, the researchers found that the frequency of the manifestation of the clinical features was similar between patients with r-axSpA and those with nr-axSpA (30.7% vs 30.4%, respectively).2,9 The lowest presenting clinical feature was inflammatory bowel disease (2.5% and 1.8%, respectively) and the highest was inflammatory back pain (97.5% and 100%, respectively).2
The Consortium of Rheumatology Researchers of North America (CORRONA) registry evaluated the relative disease burden and patient-reported outcomes for pain and fatigue. The findings were similar among patients with r-axSpA and those with nr-axSpA (disease burden and function, 3.3 vs 3.4; patient-reported outcomes [visual analog scale, 0-100], 45.9 vs 48.5, respectively).2,10 Results from this study suggested that irrespective of radiographic evidence, r-axSpA and nr-axSpA have a similar burden on function and quality of life.
Is There a Benefit in Broadening the axSpA Classification Criteria?
The revision of the New York classification criteria to the ASAS classification criteria in 2009 addressed the broadening concept of axSpA as a spectrum of diseases in which nonradiographic manifestations can progress to r-axSpA.11
The current ASAS criteria classify axSpA by active inflammation, based on MRI imaging or HLA-B27 positivity, with elevated CRP a feature of SpA in the presence of chronic back pain.12
Research has shown the features contributing to the classification of axSpA to include radiographic sacroiliitis (odds ratio [OR], 32.3) and active inflammation of the sacroiliac joints on MRI (OR, 66.7), with an OR of 1 to 7 for all other features of axSpA.11 These ORs suggest that inflammation of the sacroiliac joints and radiographic sacroiliitis are defining clinical features of axSpA. However, the fact that the ASAS criteria can help in the classification of axSpA according to HLA-B27 positivity without evidence of axial involvement question which criteria (sacroiliitis on imaging vs HLA-B27) should be adopted in the clinical setting, given that HLA-B27 positivity is present in more people without SpA than in those with SpA.11
The ASAS 2009 classification criteria have been used as a default diagnostic criteria, despite not being validated for sensitivity and specificity as a diagnostic tool.7
In light of that, the ongoing Classification of Axial Spondyloarthritis Inception Cohort study (CLASSIC; ClinicalTrials.gov Identifier: NCT03993847)13 aims to investigate the sensitivity and specificity of the 2009 criteria in 1000 patients aged 45 years and younger who were referred to a rheumatologist with back pain of more than 3 months. The study outcomes are a threshold specificity of at least 90% and sensitivity of at least 75%. If these endpoints are met, no changes will be made to the current ASAS criteria.13
Based on the current ASAS classification criteria, how can clinicians distinguish noninflammatory from inflammatory causes of back pain, which may be a warning sign of axSpA? Should axSpA be assigned to a patient with elevated CRP or MRI imaging within the definition of the “normal” range? If so, does the clinical presentation fit within the spectrum between early or mild nr-axSpA? The challenge with axSpA is the wide variation in its clinical manifestations. In the absence of a defined diagnostic tool for axSpA, it is challenging to determine where “normal” clinical presentation ends and “disease” begins, thus making the determination of mild and/or early disease also challenging In addition, some patients have spine-limited axSpA that does not affect the sacroiliac joints.15,16
Clinical experience and expert opinion have played a significant part in addressing these issues. Overall, the diagnostic evaluation of axSpA has been primarily based on a combination of clinical signs and symptoms, nonspecific biomarkers (HLA-B27 and CRP), and MRI results.17 However, inflammatory causes of low back pain respond to tumor necrosis factor inhibitors (TNFi).18 It has been shown that patients with axSpA, elevated CRP concentration, and/or sacroiliitis on MRI respond better to treatment with adalimumab, golimumab, and etanercept than patients with a normal CRP concentration and/or no sacroiliitis on MRI.19-22 These findings suggest that response to TNFis may help distinguish inflammatory from noninflammatory back pain or normal MRI variation from axSpA.
Expanded Definition of axSpA Reflects on Early Diagnosis and Treatment
The expansion of the definition of axSpA to include axial inflammation with no evidence of erosive damage on plain radiographs has increased the opportunity for the early diagnosis and treatment of patients with inflammatory back pain. Early diagnosis and appropriate management for this population are essential because most function loss occurs within the first 10 years of the disease.23
However, the updated axSpA definition has exposed a new set of challenges, including the identification of the patient population, treatment timing, and the appropriate treatment options, which are limited for axSpA.
Opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) effectively control pain, but they are not disease-modifying in nature and not all patients respond or can tolerate their treatment.2
The natural history, the risk factors for progression, and the spontaneous remission rate in nr-axSpA is currently unknown. Therefore, should treatment be initiated in the absence of an objective demonstration of inflammation? This is an important question, given that not all nr-axSpA progresses to r-axSpA and some patients undergo spontaneous remission.7
These treatment challenges also underlie the limited approval by regulators, such as the US Food and Drug Administration (FDA), of TNFi for nr-axSpA.7 Currently, certolizumab pegol is the only TNFi that is FDA-approved for nr-axSpA.24 In June 2020, the FDA approved 2 additional biologic medications – ixekizumab25 and secukinumab26 for treatment of active nr-axSpA. These FDA approvals were based on the reduced response to TNFis in patients in whom objective inflammation could not be demonstrated compared with those with evidence of inflammation. The argument was that treatment with TNFis in the absence of inflammation might result in overtreatment and its associated side effects.7 Overall, treating axSpA in the absence of inflammatory evidence of the disease may result in unnecessary treatment with unwarranted adverse effects and failure to treat may result in disease progression to r-axSpA.
Until recently, another challenge was the lack of an International Classification of Diseases, Tenth Revision (ICD-10) code for nr-axSpA. The specific ICD-10 code, M46.80, classifies nr-axSpA as a disease, addressing the administrative challenge of diagnosing patients and classifying their disease.27 The ICD-10 code for nr-axSpA also addresses reimbursement challenges for health care service to patients treated for nr-axSpA.
The ASAS classification criteria recognize axSpA as a spectrum of diseases in which nonradiographic manifestations can progress to r-axSpA. The use of MRI and biologic markers, including HLA-B27 and CRP levels, along with clinical features, have enabled earlier diagnosis of axSpA after the onset of the symptoms. However, differentiating axSpA from mechanical back pain, and r-axSpA from nr-axSpA, remains challenging. The treatment of nr-axSpA remains challenging, in part due to the limited treatment options and, until recently, the lack of a billing code specifically for the condition.
- Reveille JD, Witter JP, Weisman MH. Prevalence of axial spondylarthritis in the United States: estimates from a cross-sectional survey. Arthritis Care Res (Hoboken). 2012;64(6):905-910. doi:10.1002/acr.21621
- Deodhar AA. Supplements and featured publications, understanding axial spondyloarthritis: a primer for managed care. Am J Manag Care. 2019;25 (17):-S0.
- Barnett R, Ingram T, Sengupta R. Axial spondyloarthritis 10 years on: still looking for the lost tribe. Rheumatology (Oxford). 2020 Oct 1;59(Suppl4):iv25-iv37. doi: 10.1093/rheumatology/keaa472
- van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum. 1984;27(4):361-368
- Feldtkeller E, Khan MA, van der Heijde D, van der Linden S, Braun J. Age at disease onset and diagnosis delay in HLA-B27 negative vs. positive patients with ankylosing spondylitis. Rheumatol Int. 2003;23(2):61-66. doi:10.1007/s00296-002-0237-4
- Chan KW, Felson DT, Yood RA, Walker AM. The lag time between onset of symptoms and diagnosis of rheumatoid arthritis. Arthritis Rheum. 1994;37(6):814-820. doi:10.1002/art.1780370606
- Robinson PC, van der Linden S, Khan MA, Taylor WJ. Axial spondyloarthritis: concept, construct, classification and implications for therapy. Nat Rev Rheumatol. 2021;17(2):109-118. doi:10.1038/s41584-020-00552-4
- Khan MA, van der Linden SM, Kushner I, Valkenburg HA, Cats A. Spondylitic disease without radiologic evidence of sacroiliitis in relatives of HLA-B27 positive ankylosing spondylitis patients. Arthritis Rheum. 1985;28(1):40-43. doi:10.1002/art.1780280107
- Rudwaleit M, Haibel H, Baraliakos X, et al. The early disease stage in axial spondylarthritis: results from the German Spondylarthrosis Inception Cohort. Arthritis Rheum. 2009;60(3):717-727. doi:10.1002/art.24483
- Mease PJ, van der Heijde D, Karki C, et al. Characterization of patients with ankylosing spondylitis and non-radiographic axial spondyloarthritis in the US-based Corrona Registry. Arthritis Care Res (Hoboken). 2018;70(11):1661-1670. doi:10.1002/acr.23534
- 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;68(6):777-783. doi:10.1136/ard.2009.108233
- Ritchlin C, Adamopoulos IE. Axial spondyloarthritis: new advances in diagnosis and management. BMJ. 2021;372:m4447. doi:10.1136/bmj.m4447
- US National Library of Medicine. ClinicalTrials.gov. CLassification of axial spondyloarthritis inception cohort (CLASSIC). Accessed March 8, 2021. https://clinicaltrials.gov/ct2/show/NCT03993847.
- Weber U, Jurik AG, Zejden A, et al. Frequency and anatomic distribution of magnetic resonance imaging features in the sacroiliac joints of young athletes: exploring “background noise” toward a data-driven definition of sacroiliitis in early spondyloarthritis. Arthritis Rheumatol. 2018;70(5):736-745. doi:10.1002/art.40429
- Dimitroulas T, Lambe T, Raphael JH, Kitas GD, Duarte RV. Biologic drugs as analgesics for the management of low back pain and sciatica. Pain Med. 2019;20(9):1678-1686. doi:10.1093/pm/pny214
- Sieper J, van der Heijde D, Dougados M, et al. A randomized, double-blind, placebo-controlled, sixteen-week study of subcutaneous golimumab in patients with active nonradiographic axial spondyloarthritis. Arthritis Rheumatol. 2015;67(10):2702-2712. doi:10.1002/art.39257
- 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(6):815-822. doi:10.1136/annrheumdis-2012-201766
- Dougados M, van der Heijde D, Sieper J, et al. Symptomatic efficacy of etanercept and its effects on objective signs of inflammation in early nonradiographic axial spondyloarthritis: a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol. 2014;66(8):2091-2102. doi:10.1002/art.38721
- Brown MA, Bird PA, Robinson PC, et al. Evaluation of the effect of baseline MRI sacroiliitis and C reactive protein status on etanercept treatment response in non-radiographic axial spondyloarthritis: a post hoc analysis of the EMBARK study. Ann Rheum Dis. 2018;77(7):1091-1093. doi:10.1136/annrheumdis-2017-211313
- van der Heijde D, Sieper J, Maksymowych WP, et al. Spinal inflammation in the absence of sacroiliac joint inflammation on magnetic resonance imaging in patients with active nonradiographic axial spondyloarthritis. Arthritis Rheumatol. 2014;66(3):667-673. doi:10.1002/art.38283
- Weber U, Zubler V, Zhao Z, al. Does spinal MRI add incremental diagnostic value to MRI of the sacroiliac joints alone in patients with non-radiographic axial spondyloarthritis? Ann Rheum Dis. 2015;74(6):985-992. doi:10.1136/annrheumdis-2013-203887
- Weber U, Zhao Z, Rufibach K, Zubler V, Lambert RG, Chan SM, Østergaard M, Pedersen SJ, Maksymowych WP. Diagnostic utility of candidate definitions for demonstrating axial spondyloarthritis on magnetic resonance imaging of the spine. Arthritis Rheumatol. 2015;67(4):924-933. doi:10.1002/art.39001
- Barnes MC, Worthy S, Simon K. A call for differential diagnosis of non-specific low back pain to reduce opioid abuse. J Med Regul. 2015;101(2):39-47. doi:10.30770/2572-1852-101.2.39
- Cimzia [prescribing information]. Accessed March 9, 2021. www.cimzia.com/themes/custom/cimzia/docs/CIMZIA_full_prescribing_information.pdf.
- Ixekizumab [prescribing information]. Accessed March 9, 2021. https://uspl.lilly.com/taltz/taltz.html#pi
- Secukinumab [prescribing information]. Accessed March 9, 2021. https://www.novartis.us/sites/www.novartis.us/files/cosentyx.pdf
- ICD-10 Codes. ICD-10-CM Code M46.80. Accessed March 9, 2021. https://icd.codes/icd10cm/M4680#:~:text=80%20is%20a%20billable%20ICD,specified%20inflammatory%20spondylopathies%2C%20site%20unspecified