Am J Manag Care. 2019;25:-S0
For author information and disclosures, see end of text.
Axial spondyloarthritis (axSpA) is a chronic, immune-mediated, inflammatory condition consisting of 2 subsets that have been clinically defined as ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (nr-axSpA). It is important to note that nr-axSpA is defined clinically by the absence of definitive x-ray evidence of structural damage to the sacroiliac (SI) joint by plain x-ray. Since the SI joint x-ray interpretation is subjective, the distinction between nr-axSpA and AS is not absolute. Sacroiliitis (inflammation of the SI joint) and inflammation of the spine are predominant features of axSpA, hence patients typically present with inflammatory back pain. Other manifestations, such as enthesitis, dactylitis, peripheral arthritis, anterior uveitis, psoriasis, and inflammatory bowel disease, are common. Despite an increased understanding of axSpA, unmet needs remain: most essentially, to improve the lengthy time to diagnosis after the onset of symptoms and to appropriate treatment. Patients and healthcare systems may incur substantial burden during the prolonged time to diagnosis or while patients are not receiving appropriate treatment for their axial disease. Prolonged time to diagnosis is related to difficulty in differentiating axSpA from common mechanical back pain, and absence of diagnostic criteria adversely affects the quality of care for axSpA. In addition, there are currently no diagnosis or billing codes for nr-axSpA, which poses an administrative challenge to identify and study patients affected. Patients with nr-axSpA have experienced a personal and societal disease burden similar to those of patients with rheumatoid arthritis and SpA conditions (AS and psoriatic arthritis). Healthcare costs of axSpA are substantial, and the costs of lost productivity due to illness are estimated to be even greater. More options are needed in the management of the disease to prevent possible conversion of nr-axSpA to AS; to avoid structural changes that limit spinal range of motion and increase the risk of fracture and spinal fusion; and to reduce the economic burden to patients, healthcare systems, payers, and society overall. Spondyloarthritis (SpA) represents a family of several heterogeneous and related chronic, immune-mediated, inflammatory conditions that share common clinical features. SpA can be classified as axial or peripheral, based on the predominant features of the clinical presentation, including anatomic distributions and manifestations.1-3
Peripheral SpA conditions, including psoriatic arthritis (PsA), reactive arthritis, inflammatory bowel disease (IBD)-related arthritis, and unspecified SpA, are marked by predominant peripheral joint manifestations. These include inflammatory arthritis in peripheral joints, enthesitis (inflammation of the sites where tendons, muscles, or ligaments insert into the bone), and dactylitis.1
Patients with axial spondyloarthritis (axSpA) have predominantly axial involvement, characterized by inflammation of 1 or both of the sacroiliac (SI) joints (sacroiliitis, where inflammation typically appears first), inflammation of the spine, or both.1,3 Other associated manifestations include inflammatory back pain (IBP), peripheral joint and entheseal manifestations, and extra-articular manifestations such as anterior uveitis (inflammation of the uvea), psoriasis, and IBD (Figure 11,2).1-3
Approximately 1.5 million Americans are affected by axSpA, with estimates of axSpA’s prevalence ranging from 0.9% to 1.4%.4,5 Typically, axSpA affects the younger SpA patient population, with an average age of symptom onset of 28 years.6 AxSpA consists of 2 subsets of patients: those with nonradiographic axial spondyloarthritis (nr-axSpA) and those with ankylosing spondylitis (AS), also known as radiographic axSpA.1,7 Results from current studies indicate that approximately half of all patients with axSpA are patients with nr-axSpA.8,9 Patients with AS are more likely to be male, whereas nr-axSpA is equally prevalent in both sexes.10
AxSpA is marked by a long diagnostic delay compared with other SpA conditions; on average, there is a 9-year period between symptom onset and diagnosis of AS compared with 9 months for rheumatoid arthritis.11,12
Modified New York Criteria
The modified New York criteria for AS (originally developed in 1984) include clinical and radiographic features for diagnosis.13 A diagnosis of AS requires the presence of 1 or more clinical criteria: These include low back pain and stiffness, lasting longer than 3 months, that improve with exercise but do not improve at rest; limited lumbar spinal movement (sagittal and frontal planes); and/or limited chest expansion for age and sex. The diagnosis also requires meeting one of the radiographic criteria: sacroiliitis on radiographic imaging of at least grade 2 bilaterally or grade 3 to 4 unilaterally or bilaterally.13 Sacroiliitis criteria present a barrier to early diagnosis because often the defined radiologic features of AS may not be evident for years after symptom onset.13 A substantial proportion of patients with nr-axSpA will not convert to AS; some, however, do.14
Radiologic and Imaging Assessments
The distinguishing characteristic of nr-axSpA is inflammation in the axial skeleton without definitive sacroiliitis on radiographic (x-ray) imaging, defined as a combination of erosive damage, joint space widening and narrowing, sclerosis, and bony fusions of the SI joint.2,13,15
X-rays may show structural/radiographic abnormalities from early stages of damage, such as indistinctness of the SI joint margins (widening and narrowing), that do not meet radiographic grading criteria (Table 116).13,16 In patients with nr-axSpA, inflammation and pain often precede evidence of radiographic sacroiliitis, which may reflect the consequences of inflammation rather than inflammation itself.13,17 As opposed to those with nr-axSpA, patients with AS present with definitive radiographic sacroiliitis representing irreversible structural damage.13,15,17
Advancements in imaging with magnetic resonance imaging (MRI) allow detection of early changes to the SI joints in patients with axSpA, including active inflammatory lesions and structural changes.13,15,17 Noting that not all nr-axSpA patients convert to AS, MRI abnormalities may often be detected years before the appearance of radiographic sacroiliitis. However, MRI is costlier than x-ray and may not always be available.3,13,18
Physicians consider multiple parameters, including a combination of clinical features, laboratory findings, and imaging assessments, as they look for patterns characteristic of nr-axSpA to establish diagnosis while eliminating other possible diagnoses. Although classification criteria have been established to assist in enrolling patients with axSpA in clinical trials, there are no diagnostic criteria or definitive diagnostic tests.13 In the absence of published diagnostic criteria, axSpA is diagnosed through a combination of specific symptoms (inflammatory back pain), extraspinal manifestations, laboratory abnormalities, genetic characteristics, and findings on imaging.
A genetic marker, human leukocyte antigen-B27 (HLA-B27), has been useful in the classification of axSpA; however, its presence alone is not sufficient to make a diagnosis.18,19 HLA-B27 is a predictor of development of AS in patients with IBP and is also useful for identifying patients with nr-axSpA.19,20 Although most patients (between 70% and 95%) with AS have expression of HLA-B27, only 7% to 8% of HLA-B27 carriers in the general population develop AS.20,21 HLA-B27 is associated with the following disease features in patients with AS: (1) younger age at disease onset, (2) development of anterior uveitis, and (3) a positive family history of SpA.20
Additional features of axSpA used in the classification of disease include response to NSAIDs, family history of SpA, and elevated C-reactive protein (CRP).3 Notably, patients with AS more commonly have elevated CRP than those with nr-axSpA.22
Patients with nr-axSpA and AS share common extraspinal and peripheral manifestations, which can include psoriasis, uveitis, enthesitis, and Crohn disease.3,10,19,22,23 In a cross-sectional analysis of patients with axSpA in the German Spondyloarthritis Inception Cohort, the frequency of clinical manifestations (IBD, dactylitis, psoriasis, uveitis, enthesitis, peripheral arthritis, and IBP) were directly compared in patients with AS (n = 119) and nr-axSpA (n = 226) (Figure 2).24 IBP was the most common clinical manifestation observed in both axSpA populations, occurring in 100% and 97.5% of patients with nr-axSpA and AS, respectively.24
IBP and stiffness, hallmarks of axSpA, are caused by inflammation of the SI joint and spine.25 AxSpA occurs in up to 15% of patients with IBP.20 IBP is usually characterized by onset in late adolescence to early adulthood, improves with exercise and worsens at rest, and is associated with prolonged morning stiffness (more than 30 minutes).3 IBP contributes to disability and functional impairments in patients with axSpA.25
Assessment of Spondyloarthritis International Society (ASAS)
The ASAS classification criteria for axSpA were developed to facilitate earlier identification of patients with clinical manifestations of axSpA without definitive sacroiliitis on radiographic imaging.3,13 Unlike the modified New York classification criteria for AS, the ASAS classification includes MRI positivity for active inflammation in the SI joints; it also includes the presence of the HLA-B27 gene.
According to the ASAS criteria, patients with back pain lasting longer than 3 months and an age of onset of less than 45 years can be classified as having axSpA with either (1) the presence of HLA-B27 and 2 or more clinical features of SpA; or (2) definite sacroiliitis on imaging (x-ray or MRI) and 1 or more clinical features of SpA as follows: IBP, arthritis, enthesitis, uveitis, dactylitis, psoriasis, Crohn disease or ulcerative colitis, response to NSAIDs, family history of SpA, HLA-B27, or elevated CRP (Figure 3).3,13
These are classification criteria and are not diagnostic criteria. Use of the ASAS classification criteria for diagnosis could result in misdiagnosis due to the broad inclusion criteria. Objective signs of inflammation help to provide confidence in diagnosis; these include imaging, with no evidence of structural damage at the SI joints evident on x-ray (which, if present, would indicate an AS diagnosis) but evidence of active inflammation on MRI; laboratory tests indicating a high level of systemic inflammation (ie, elevated CRP); and associated extraspinal and peripheral manifestations such as active uveitis, psoriasis, IBD, dactylitis, peripheral arthritis, and enthesitis.14
AxSpA Disease Progression and Associated Risk Factors
Radiographic Progression of nr-axSpA
Prevention of inflammation is key in the management of axSpA. Ultimately, the prevention of progressive structural damage is the aspirational goal. Although both active inflammation and resulting structural damage may contribute to impaired spinal function and mobility, the component of disability due to structural damage is not reversible.17,25 Nr-axSpA may progress to AS in some patients; however, not all patients with nr-axSpA will show signs of progression with radiographic changes leading to development of AS.26
The rate of radiographic progression of nr-axSpA (ie, development of definitive structural changes of the SI joint) is variable. In a literature review of several longitudinal studies investigating radiographic progression in patients without structural damage in the SI joint, approximately 10% to 40% of patients with nr-axSpA converted to AS over 2 to 10 years.14
Risk Factors for Conversion From nr-axSpA to AS
Limited data are available to predict which patients with nr-axSpA will develop structural changes in the SI joints and experience progression to AS.14,23 Signs of active systemic inflammation, as indicated by elevated CRP levels, correlate with progression of radiographic damage to the spine.14 Additional risk factors for disease conversion include objective signs of inflammation on imaging (ie, presence of active or chronic inflammatory changes on MRI of the SI joints). The presence of low-grade structural damage on radiographs or MRI is also a risk factor.14
Irreversible Progression of AS
The progression of spinal damage of AS begins with bone inflammation, which may be visible as osteitis, typically seen on a short tau inversion recovery (STIR) image of the MRI.13,17 To repair the tissue, subchondral bone marrow is replaced with fatty metaplasia, which may present as a fatty lesion on a T1 weighted MRI scan.13,17 Presence of either inflammation or intermediate stage of fatty lesions may play an important role in the development of new bone formation (structural damage), highlighting the need for early abrogation of inflammation to reduce risk.17
Approximately 60% to 70% of patients with AS develop irreversible structural changes that result in spinal fusion and reduced spinal mobility.17,26 Although patients with AS usually present with compromised physical and spinal function due to structural damage and inflammation, in patients with nr-axSpA, this functional impairment is typically due to inflammation alone.15,27
Risk Factors for Radiographic Progression of AS
Risk factors for progression of spinal disease, in those patients already known to have AS, include male sex, presence of syndesmophytes at baseline, elevation of CRP, and smoking (in men).20,28
Clinical and Economic Burden of axSpA
Productivity Losses and Employment Limitations
AxSpA is associated with substantial clinical and economic burden for patients and healthcare systems. Patients with axSpA have physical limitations that can adversely affect employment, work productivity, leisure activities, mood, and interpersonal relationships.
Patients with axSpA and other inflammatory rheumatic diseases (PsA and RA) share a similar burden of disease on health-related quality of life, demonstrated by Short Form-36 physical and mental function scores (Figure 4).29 Results from a study that evaluated patients with axSpA (N = 324) according to ASAS criteria found that 42.1% (n = 178) of patients with AS and 35.4% (n = 146) of patients with nr-axSpA required help with their daily activities from relatives, friends, or paid caregivers, and those patients reported higher household and workplace activity losses than those who did not require assistance.30
It has been suggested that costs related to productivity losses constitute the largest part of the total cost of illness of AS.31 The economic impact of work limitations and lost productivity related to axSpA is likely compounded by the typically young age at diagnosis (28 years).31 A survey for the British Society for Rheumatology Biologics Register of patients with axSpA (N = 577) found that up to 41% of patients reported an at-work productivity loss due to their disease.32 A reason for the amount of work loss from axSpA is that back pain is the primary symptom31; this causes more disability than any other condition and is among the most common reasons that people miss work.33
The CORRONA registry evaluated the characteristics of patients with AS and nr-axSpA in the United States, and it demonstrated similar disease-related burdens in both groups of clinical pain and fatigue scores, disease activity, and function, with impacts on absenteeism, presenteeism, work productivity loss, and overall activity impairment (Figure 5).23 Patients with nr-axSpA, versus patients with AS, had a significantly greater mean percentage of presenteeism (32.6% vs 24.2%; P = .02) and overall activity impairment (36.6% vs 28.6%; P = .04). On average, patients with AS and nr-axSpA missed 6.3% of work time because of disease-related problems.23 In a phase 3 double-blind study evaluating the effects of axSpA on work productivity, patients with nr-axSpA reported approximately 8 days of paid work affected by their disease every month.31 Similar trends in absenteeism and presenteeism were observed in patients with AS and nr-axSpA (Figure 6).31
Patients may experience work instability, may be unable to meet the physical demands of a job, and may be forced into early retirement.34 The financial and clinical burden associated with axSpA is significant and affects patients, healthcare systems, and society overall.
Increased Prevalence of Comorbidities and Healthcare Costs
Patients with axSpA show an increased prevalence of comorbidities and extraspinal manifestations of their disease, driving axSpA-associated healthcare costs. In a retrospective observational study using a large US-based healthcare claims database, patients with AS had a higher prevalence of comorbidities compared with a matched population, including asthma, cardiovascular disease, depression, dyslipidemia, multiple sclerosis, osteoporosis, spinal fracture, IBD, and psoriasis.35
Patients with AS also have an increased risk of vascular mortality. An updated meta-analysis of 12 longitudinal studies demonstrated the risk of myocardial infarction (MI) to be significantly higher in patients with AS compared with a matched control population (risk ratio [RR], 1.44; 95% CI, 1.25-1.67; P <.00001).36,37 Similarly, a meta-analysis of 7 studies showed a significant increase in the risk of stroke (RR, 1.37; 95% CI, 1.08-1.73; P <.008).36 Patients with AS (n = 21,473) had a 43% higher risk of vascular death than those without AS (adjusted HR, 1.36; 95% CI, 1.13-1.65) in an analysis of administrative health data from a Canadian population-based retrospective cohort study.37
Increased comorbid conditions with AS contribute to higher healthcare costs, as shown in an analysis of a large US claims database. Patients with AS and comorbid conditions had higher rates of all-cause inpatient readmission, emergency department (ED) visits, and hospital-based outpatient visits than a matched population without AS (P <.001).35 Patients in the population with AS also had higher mean total all-cause healthcare costs than the matched control population ($33,285 vs $8310), with a mean healthcare cost of $16,337 per patient with AS. Total all-cause healthcare costs were driven by the increased use of outpatient medical services and pharmacy costs, and AS-specific costs were driven by the costs of AS medications.35
Because the clinical burden of nr-axSpA is similar to that of AS, healthcare costs associated with nr-axSpA and AS are likely similar.38 A retrospective cohort review of an administrative claims database assessed healthcare resource use and direct costs of AS. During the 12-month follow-up, 11.1% of all-cause healthcare resource use by patients with AS was due to hospitalizations and 22% was due to ED visits.39 Unadjusted mean annual all-cause direct costs during 12-month follow-up included $6514 for medical costs, $4185 for hospitalizations, and $11,214 for prescription drugs.39 Additionally, several factors may indirectly drive the healthcare costs and total economic burden of axSpA. As discussed previously, the long duration to axSpA accurate diagnosis from symptom onset (9 years) may be associated with increased costs and healthcare resource utilization prior to diagnosis, such as multiple follow-up visits and treatments.
Considerations in the Management of nr-axSpA
Opioid use is common among patients with axSpA. A retrospective analysis of commercial and Medicaid claims data from a US claims database evaluated opioid use among patients with AS. In this study, investigators defined “chronic” opioid use as 90 or more days of opioid use within a 12-month period. The study results showed that approximately two-thirds of patients who used opioids chronically had at least a 270-day supply during the 12-month evaluation period. Of the patients with axSpA who use opioids chronically to manage pain (26%), 44% use opioids exclusively, which fails to address underlying inflammation.40 Early diagnosis and appropriate management are important because most function loss occurs within the first 10 years of disease.33 Appropriate treatment of nr-axSpA can limit the impact of disease; however, treatment options for nr-axSpA are limited. Studies have shown a trend in the overtreatment (including opioids) of chronic back pain without an overall improvement in patient outcomes.33
2019 ACR/SAA/SPARTAN Recommendations
Evidence-based recommendations in 2015 from the American College of Rheumatology (ACR), Spondylitis Association of America (SAA), and Spondyloarthritis Research and Treatment Network (SPARTAN) provided treatment goals for AS and nr-axSpA, including preventing inflammation and progressive structural damage; reducing symptoms and decreasing disease complications; reducing functional limitations; maintaining spinal flexibility and normal posture; preserving/normalizing function and social participation; and restoring ability to work.26 In 2019, updated recommendations provided evidence-based guidance on the use of imaging, treat-to-target strategy, pharmacotherapy, and nonpharmacologic treatment options for the management of patients with AS and nr-axSpA.41
The ACR/SAA/SPARTAN guidance recommends MRI imaging for patients who have unclear disease activity, or if a patient’s MRI results could potentially change the course of their treatment. MRI imaging may focus on the spine or pelvis for patients with AS, and on the SI joints for those with nr-axSpA.41 The guidance also conditionally recommends against an MRI for patients with AS or nr-axSpA who have clearly clinically active or clinically stable disease, or if the results of the MRI do not have the potential to change treatment decisions. This recommendation was based on testing burdens, the potential for overtreatment, limitations in the detection of axSpA activity with MRI, and limited evidence that MRI results can help enhance clinical outcomes for stable patients. MRI imaging may be warranted if the patient and clinician disagree about whether the condition is stable.41
Radiographs may be limited to diagnosing axSpA, identifying the extent of spinal fusion, and exploring the possible cause of new spinal pain in patients with AS.41 The ACR/SAA/SPARTAN guidance recommends that regular radiographs be avoided, as no known clinical evidence indicates benefit that would offset the health risks to the patient that would come with repeated radiation exposure. The treat-to-target approach for active AS or active nr-axSpA, which places more importance on reaching a target Ankylosing Spondylitis Disease Activity Score of less than 1.3 (or 2.1) than physician assessment, is not endorsed.41
Nonsteroidal anti-inflammatory drugs (NSAIDs) and physical therapy are strongly recommended as first-line management strategies for patients with active axSpA.41 Although NSAIDs can effectively control pain and improve physical function,41,42 not all patients respond to or tolerate NSAIDs.43 Furthermore, treatment with NSAIDs does not always lead to adequate control of symptoms.44
For patients with AS or nr-axSpA who do not respond to or tolerate at least 2 different NSAIDs at maximal doses over 1 month, or for patients who have partial response to 2 different NSAIDs over
2 months, treatment with a tumor necrosis factor (TNF) inhibitor (such as infliximab, etanercept, adalimumab, certolizumab, or golimumab) is strongly recommended.41 In patients with nr-axSpA, this recommendation was based on the evidence from several phase 3 clinical trials investigating the efficacy and safety of numerous TNF inhibitors (Table 2).45-53 TNF inhibitors are associated with global improvement in health-related quality of life by inhibiting the progression of disease; decreasing mean quarterly lost work days; improving function, spinal mobility, peripheral arthritis, enthesitis, bone density, and acute inflammation; and reducing pain and fatigue.33,42,54
Notably, at the time of publication, the TNF inhibitor certolizumab pegol is the sole FDA-approved treatment for nr-axSpA.55 The ACR/SAA/SPARTAN guidance does not recommend a specific TNF inhibitor for the treatment of AS or nr-axSpA.41 Given the limited evidence comparing the relative safety and efficacy of TNF inhibitors in patients with nr-axSpA,41 treatment recommendations for nr-axSpA were largely extrapolated from available evidence in the AS population; they were based on the results of indirect comparisons of network meta-analyses of short-term efficacy of different TNF inhibitors for active AS.41
A TNF inhibitor is recommended over an interleukin (IL)-17A as the first biologic treatment. For patients who do not experience symptom control with a TNF inhibitor, an IL-17A (secukinumab or ixekizumab) is recommended over switching to another TNF inhibitor. This recommendation is conditional, with the assumption that symptoms are unresponsive because TNF is not the key inflammatory mediator.41 In patients with AS, treatment with secukinumab or ixekizumab is strongly recommended over no treatment with secukinumab or ixekizumab; however, this is conditionally recommended in patients with nr-axSpA given that the trials for secukinumab and ixekizumab are currently being conducted and preliminary results have not been published (Table 245-53).41 For patients with active AS or nr-axSpA despite NSAID treatment who are contraindicated for treatment with TNF inhibitors, IL-17A inhibitors are conditionally recommended over certain conventional synthetic antirheumatic drugs.41
Unmet Needs in the Management of axSpA
The advent of advanced imaging with MRI scanning and the employment of genetic testing for HLA-B27 have contributed to the recognition of nr-axSpA in its earlier stages.13,19 However, prevalence of HLA-B27 is dependent on the racial background of the patients studied, and utility of advanced imaging is affected by operator experience.56,57 And, despite these advancements in detection, substantial unmet needs in the management of axSpA must be addressed, namely improving the delayed diagnosis of nr-axSpA with better identification of the disease at symptom onset and earlier treatment to prevent long-term suffering and to improve quality of life.6
One factor contributing to the delay in diagnosis is the difficulty in distinguishing patients with axSpA from patients with chronic low back pain of mechanical origin. Chronic low back pain is common and affects approximately 19% of the general population in the United States.58 Of those patients with chronic low back pain, just 5% have axSpA.21 A multicenter, single-visit study was conducted to determine the proportion of patients with nr-axSpA, AS, and axSpA among 751 patients who had had chronic back pain for at least 3 months, whose age of onset was less than 45 years, and who had at least 1 of the following features: HLA-B27 positivity, current IBP, and evidence of sacroiliitis on MRI or radiographic imaging. The age of onset of chronic low back pain in patients who received a diagnosis of axSpA from a rheumatologist for AS or nr-axSpa was reported to be 28.1 and 27.3 years, respectively, with a mean duration of back pain of 14 years prior to diagnosis.6
Early identification is important to prevent the incapacity the axSpA diseases can cause, with early treatment intervention.17,59,60 However, prolonged time to diagnosis invariably results in critical delays in these therapeutic interventions.61
Unlike AS and the other SpA conditions, nr-axSpA does not have an International Classification of Diseases, Version 10 (ICD-10) code, which is needed for its classification as a disease and for reimbursement of healthcare services. A specific ICD-10 code for nr-axSpA would address the administrative challenge of identifying patients and classifying disease, and would facilitate the generation of key research in real-world clinical databases.62,63
Increased awareness among patients, healthcare systems, and payers about axSpA is necessary to prevent delay in diagnosis, improve patient outcomes, prevent structural damage, and control direct and indirect costs for all stakeholders. Chronic back pain and reduced physical function cause substantial loss of productivity for patients with axSpA and contribute to its high associated healthcare costs. Special care should be taken to identify younger patients presenting with symptoms, because they bear a substantial part of the burden of this disease and represent a window of opportunity for treatment. It is important to understand that the healthcare burden of nr-axSpA is similar in terms of pain and disability to that of SpA conditions (AS and PsA) and of RA. Further complicating disease management is the fact that there are no diagnosis/billing codes for nr-axSpA, which poses an administrative challenge in identifying and classifying the disease and the patients affected.
Author Affiliation: Rheumatology Clinics, Division of Arthritis & Rheumatic Diseases, Oregon Health & Science University, Portland, OR.
Funding Source: This supplement was supported by UCB.
Author Disclosure: Dr Deodhar reports serving as a consultant or on a paid advisory board for AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Novartis, Pfizer, UCB. He reports grants received and pending from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly, Novartis, Pfizer, UCB. He reports receiving honorarium from AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Novartis, Pfizer, UCB. He also reports speaking fees on behalf of Eli Lilly, Janssen, Novartis, UCB, and attending conferences and meetings held by the European League Against Rheumatism, American College of Rheumatology, Brazilian, Turkish, and Korean Annual Rheumatology Societies.
Authorship Information: Concept and design, analysis and interpretation of data, and critical revision of the manuscript for important intellectual content.
Address Correspondence to: email@example.com.
1. Garg N, van den Bosch F, Deodhar A. The concept of spondyloarthritis: where are we now? Best Pract Res Clin Rheumatol. 2014;28(5):663-672. doi: 10.1016/j.berh.2014.10.007.
2. Raychaudhuri SP, Deodhar A. The classification and diagnostic criteria of ankylosing spondylitis. J Autoimmun. 2014;48-49:128-133. doi: 10.1016/j.jaut.2014.01.015.
3. 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 [published correction appears in Ann Rheum Dis. 2019;78(6):e59. doi: 10.1136/ard.2009.108233corr1]. Ann Rheum Dis. 2009;68(6):777-783. doi: 10.1136/ard.2009.108233.
4. Helmick CG, Felson DT, Lawrence RC, et al; National Arthritis Data Workgroup. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. part I. Arthritis Rheum. 2008;58(1):15-25. doi: 10.1002/art.23177.
5. 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.
6. Deodhar A, Mease PJ, Reveille JD, et al. Frequency of axial spondyloarthritis diagnosis among patients seen by US rheumatologists for evaluation of chronic back pain. Arthritis Rheumatol. 2016;68(7):1669-1676. doi: 10.1002/art.39612.
7. Baraliakos X, Sieper J, Chen S, Pangan AL, Anderson JK. Non-radiographic axial spondyloarthritis patients without initial evidence of inflammation may develop objective inflammation over time. Rheumatology (Oxford). 2017;56(7):1162-1166. doi: 10.1093/rheumatology/kex081.
8. Poddubnyy D, Brandt H, Vahldiek J, et al. The frequency of non-radiographic axial spondyloarthritis in relation to symptom duration in patients referred because of chronic back pain: results from the Berlin early spondyloarthritis clinic. Ann Rheum Dis. 2012;71(12):1998-2001. doi: 10.1136/annrheumdis-2012-201945.
9. Strand V, Rao SA, Shillington AC, Cifaldi MA, McGuire M, Ruderman EM. Prevalence of axial spondyloarthritis in United States rheumatology practices: assessment of SpondyloArthritis International Society criteria versus rheumatology expert clinical diagnosis. Arthritis Care Res (Hoboken). 2013;65(8):1299-1306. doi: 10.1002/acr.21994.
10. de Winter JJ, van Mens LJ, van der Heijde D, Landewé R, Baeten DL. Prevalence of peripheral and extra-articular disease in ankylosing spondylitis versus non-radiographic axial spondyloarthritis: a meta-analysis. Arthritis Res Ther. 2016;18:196. doi: 10.1186/s13075-016-1093-z.
11. 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.
12. 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.
13. Sieper J, Rudwaleit M, Baraliakos X, et al. The Assessment of SpondyloArthritis International Society (ASAS) handbook: a guide to assess spondyloarthritis. Ann Rheum Dis. 2009;68(suppl 2):ii1-ii44. doi: 10.1136/ard.2008.104018.
14. Protopopov M, Poddubnyy D. Radiographic progression in non-radiographic axial spondyloarthritis. Expert Rev Clin Immunol. 2018;14(6):525-533. doi: 10.1080/1744666X.2018.1477591.
15. Baraliakos X, Braun J. Non-radiographic axial spondyloarthritis and ankylosing spondylitis: what are the similarities and differences? RMD Open. 2015;1(suppl 1):e000053. doi: 10.1136/rmdopen-2015-000053.
16. Goie The HS, Steven MM, van der Linden SM, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis: a comparison of the Rome, New York and modified New York criteria in patients with a positive clinical history screening test for ankylosing spondylitis. Br J Rheumatol. 1985;24(3):242-249. doi: 10.1093/rheumatology/24.3.242.
17. Poddubnyy D, Sieper J. Mechanism of new bone formation in axial spondyloarthritis. Curr Rheumatol Rep. 2017;19(9):55. doi: 10.1007/s11926-017-0681-5.
18. Sieper J, van der Heijde D. Review: nonradiographic axial spondyloarthritis: new definition of an old disease? Arthritis Rheum. 2013;65(3):543-551. doi: 10.1002/art.37803.
19. Bennett AN, McGonagle D, O’Connor P, et al. Severity of baseline magnetic resonance imaging-evident sacroiliitis and HLA-B27 status in early inflammatory back pain predict radiographically evident ankylosing spondylitis at eight years. Arthritis Rheum. 2008;58(11):3413-3418. doi: 10.1002/art.24024.
20. Reveille JD. Biomarkers for diagnosis, monitoring of progression, and treatment responses in ankylosing spondylitis and axial spondyloarthritis. Clin Rheumatol. 2015;34(6):1009-1018. doi: 10.1007/s10067-015-2949-3.
21. Rudwaleit M, Sieper J. Referral strategies for early diagnosis of axial spondyloarthritis. Nat Rev Rheumatol. 2012;8(5):262-268. doi: 10.1038/nrrheum.2012.39.
22. Burgos-Vargas R, Wei JC, Rahman MU, et al. The prevalence and clinical characteristics of nonradiographic axial spondyloarthritis among patients with inflammatory back pain in rheumatology practices: a multinational, multicenter study [published correction appears in Arthritis Res Ther. 2016;18(1):154. doi: 10.1186/s13075-016-1066-2]. Arthritis Res Ther. 2016;18(1):132. doi: 10.1186/s13075-016-1027-9.
23. 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.
24. 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.
25. Smolen JS, Schöls M, Braun J, et al. Treating axial spondyloarthritis and peripheral spondyloarthritis, especially psoriatic arthritis, to target: 2017 update of recommendations by an international task force [published correction appears in Ann Rheum Dis. 2018;77(3):472. doi: 10.1136/annrheumdis-2017-211734corr1]. Ann Rheum Dis. 2018;77(1):3-17. doi: 10.1136/annrheumdis-2017-211734.
26. Ward MM, Deodhar A, Akl EA, et al. American College of Rheumatology/Sponylitis Association of America/Spondyloarthritis Research and Treatment Network 2015 recommendations for the treatment of ankylosing spondylitis and nonradiographic axial spondyloarthritis. Arthritis Rheumatol. 2016;68(2):282-298. doi: 10.1002/art.39298.
27. Kiltz U, Baraliakos X, Karakostas P, et al. Do patients with non-radiographic axial spondylarthritis differ from patients with ankylosing spondylitis? Arthritis Care Res (Hoboken). 2012;64(9):1415-1422. doi: 10.1002/acr.21688.
28. Deminger A, Klingberg E, Geijer M, et al. A five-year prospective study of spinal radiographic progression and its predictors in men and women with ankylosing spondylitis. Arthritis Res Ther. 2018;20(1):162. doi: 10.1186/s13075-018-1665-1.
29. Mease PJ, van Tubergen A, Deodhar A, Coteur G, Nurminen T, van der Heijde. SAT0545: comparing health-related quality of life across rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis: analyses from certolizumab pegol clinical trial baseline data. Ann Rheum Dis. 2013;72(3 suppl):A766-A767. doi: 10.1136/annrheumdis-2013-eular.2269.
30. van der Heijde D, Purcaru O, Kavanaugh A. FRI0439: high economic burden of axial spondyloarthritis related to paid work and household productivity at baseline in the RAPID-axSpa study: differences and similarities between ankylosing spondylitis and non-radiographic axial spondyloarthritis. Ann Rheum Dis. 2013;72(suppl 3):523-524. doi: 10.1136/annrheumdis-2013-eular.1566.
31. van der Heijde D, Braun J, Rudwaleit M, Purcaru O, Kavanaugh AF. Improvements in workplace and household productivity with certolizumab pegol treatment in axial spondyloarthritis: results to week 96 of a phase III study. RMD Open. 2018;4(1):e000659. doi: 10.1136/rmdopen-2018-000659.
32. Shim J, Jones GT, Pathan EMI, Macfarlane GJ. Impact of biological therapy on work outcomes in patients with axial spondyloarthritis: results from the British Society for Rheumatology Biologics Register (BSRBR-AS) and meta-analysis. Ann Rheum Dis. 2018;77(11):1578-1584. doi: 10.1136/annrheumdis-2018-213590.
33. 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.
34. Fabreguet I, Koumakis E, Burki V, et al. Assessment of work instability in spondyloarthritis: a cross-sectional study using the Ankylosing Spondylitis Work Instability Scale. Rheumatology (Oxford). 2012;51(2):333-337. doi: 10.1093/rheumatology/ker319.
35. Walsh JA, Song X, Kim G, Park Y. Healthcare utilization and direct costs in patients with ankylosing spondylitis using a large US administrative claims database. Rheumatol Ther. 2018;5(2):463-474. doi: 10.1007/s40744-018-0124-4.
36. Mathieu S, Soubrier M. Cardiovascular events in ankylosing spondylitis: a 2018 meta-analysis. Ann Rheum Dis. 2019;78(6):e57. doi: 10.1136/annrheumdis-2018-213317.
37. Haroon NN, Paterson JM, Li P, Inman RD, Haroon N. Patients with ankylosing spondylitis have increased cardiovascular and cerebrovascular mortality: a population-based study. Ann Intern Med. 2015;163(6):409-416. doi: 10.7326/M14-2470.
38. Boonen A, Sieper J, van der Heijde D, et al. The burden of non-radiographic axial spondyloarthritis. Semin Arthritis Rheum. 2015;44(5):556-562. doi: 10.1016/j.semarthrit.2014.10.009.
39. Greenberg JD, Palmer JB, Li Y, Herrera V, Tsang Y, Liao M. Healthcare resource use and direct costs in patients with ankylosing spondylitis and psoriatic arthritis in a large US cohort. J Rheumatol. 2016;43(1):88-96. doi: 10.3899/jrheum.150540.
40. Sloan VS, Sheahan A, Stark JL, Suruki RY. Opioid use in patients with ankylosing spondylitis is common in the United States: outcomes of a retrospective cohort study [published online January 15, 2019]. J Rheumatol. doi: 10.3899/jrheum.180972.
41. 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 Rheumatol. 2019;71(10):1599-1613. doi: 10.1002/art.41042.
42. Strand V, Singh JA. Patient burden of axial spondyloarthritis. J Clin Rheumatol. 2017;23(7):383-391. doi: 10.1097/RHU.0000000000000589.
43. Cinar M, Dinc A, Simsek I, et al. Evaluation of the short-term efficacy of NSAIDs on patients with active ankylosing spondylitis in daily practice: a 3-month, longitudinal, observational study [published correction appears in Rheumatol Int. 2010;30(8):1141]. Rheumatol Int. 2010;30(3):331-340. doi: 10.1007/s00296-009-0963-y.
44. van der Heijde D, Baraf HS, Ramos-Remus C, et al. Evaluation of the efficacy of etoricoxib in ankylosing spondylitis: results of a fifty-two-week, randomized, controlled study. Arthritis Rheum. 2005;52(4):1205-1215. doi: 10.1002/art.20985.
45. 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.
46. van der Heijde D, Sieper J, Maksymowych WP, et al. Clinical and MRI remission in patients with nonradiographic axial spondyloarthritis who received long-term open-label adalimumab treatment: 3-year results of the ABILITY-1 trial. Arthritis Res Ther. 2018;20(1):61. doi: 10.1186/s13075-018-1556-5.
47. Deodhar A, Gensler LS, Sieper J, et al. Three multicenter, randomized, double-blind, placebo-controlled studies evaluating the efficacy and safety of ustekinumab in axial spondyloarthritis. Arthritis Rheumatol. 2019;71(2):258-270. doi: 10.1002/art.40728.
48. 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.
49. Dougados M, van der Heijde D, Sieper J, et al. Effects of long-term etanercept treatment on clinical outcomes and objective signs of inflammation in early nonradiographic axial spondyloarthritis: 104-week results from a randomized, placebo-controlled study. Arthritis Care Res (Hoboken). 2017;69(10):1590-1598. doi: 10.1002/acr.23276.
50. 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.
51. Deodhar A, Gensler LS, Kay J, et al. A fifty-two-week, randomized, placebo-controlled trial of certolizumab pegol in nonradiographic axial spondyloarthritis. Arthritis Rheumatol. 2019;71(7):1101-1111. doi: 10.1002/art.40866.
52. CliA Study of ixekizumab (LY2439821) in participants with nonradiographic axial spondyloarthritis (COAST-X). clinicaltrials.gov/ct2/show/NCT02757352. Updated August 27, 2019. Accessed October 3, 2019.
53. Study of efficacy and safety of secukinumab in patients with non-radiographic axial spondyloarthritis. clinicaltrials.gov/ct2/show/NCT02696031. Updated January 9, 2019. Accessed October 3, 2019.
54. Wallman JK, Jöud A, Olofsson T, Jacobsson LTH, Bliddal H, Kristensen LE. Work disability in non-radiographic axial spondyloarthritis patients before and after start of anti-TNF therapy: a population-based regional cohort study from southern Sweden. Rheumatology (Oxford). 2017;56(5):716-724. doi: 10.1093/rheumatology/kew473.
55. Cimzia [prescribing information]. Smyrna, GA: UCB, Inc; 2019. www.cimzia.com/themes/custom/cimzia/docs/CIMZIA_full_prescribing_information.pdf. Accessed October 11, 2019.
56. Reveille JD, Hirsch R, Dillon CF, Carroll MD, Weisman MH. The prevalence of HLA-B27 in the US: data from the US National Health and Nutrition Examination Survey, 2009. Arthritis Rheum. 2012;64(5):1407-1411. doi: 10.1002/art.33503.
57. Herzog R, Elgort DR, Flanders AE, Moley PJ. Variability in diagnostic error rates of 10 MRI centers performing lumbar spine MRI examinations on the same patient within a 3-week period. Spine J. 2017;17(4):554-561. doi: 10.1016/j.spinee.2016.11.009.
58. Reveille JD, Weisman MH. The epidemiology of back pain, axial spondyloarthritis and HLA-B27 in the United States. Am J Med Sci. 2013;345(6):431-436. doi: 10.1097/maj.0b013e318294457f.
59. Robinson PC, Brown MA. The window of opportunity: a relevant concept for axial spondyloarthritis. Arthritis Res Ther. 2014;16(3):109. doi: 10.1186/ar4561.
60. Haroon N, Inman RD, Learch TJ, et al. The impact of tumor necrosis factor α inhibitors on radiographic progression in ankylosing spondylitis. Arthritis Rheum. 2013;65(10):2645-2654. doi: 10.1002/art.38070.
61. Seo MR, Baek HL, Yoon HH, et al. Delayed diagnosis is linked to worse outcomes and unfavourable treatment responses in patients with axial spondyloarthritis. Clin Rheumatol. 2015;34(8):1397-1405. doi: 10.1007/s10067-014-2768-y.
62. International Classification of Diseases, (ICD-10-CM/PCS) transition — background. CDC website. cdc.gov/nchs/icd/icd10cm_pcs_background.htm. Updated November 6, 2015. Accessed October 9, 2019.
63. Spondylopathies. IDC10data website. icd10data.com/ICD10CM/Codes/M00-M99/M45-M49. Accessed October 9, 2019.