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Recognizing Axial Spondyloarthritis: A Guide for Primary Care

Open AccessPublished:July 29, 2020DOI:https://doi.org/10.1016/j.mayocp.2020.02.007

      Abstract

      Axial spondyloarthritis (axSpA) is an important cause of chronic low back pain and affects approximately 1% of the US population. The back pain associated with axSpA has a characteristic pattern referred to as inflammatory back pain (IBP). Features of IBP include insidious onset before age 45 years, association with morning stiffness, improvement with exercise but not rest, alternating buttock pain, and good response to treatment with nonsteroidal anti-inflammatory drugs. In patients with IBP, it is essential to look for other features associated with spondyloarthritis (SpA), such as enthesitis, dactylitis, peripheral arthritis, extra-articular manifestations (eg, psoriasis, uveitis, or inflammatory bowel disease), human leukocyte antigen B27 positivity, and a family history of SpA. Axial SpA is underrecognized, and a delay of several years between symptom onset and diagnosis is common. However, with new and effective therapies available for the treatment of active axSpA, early recognition and diagnosis are of critical importance. For this narrative review, we conducted a literature search of English-language articles using PubMed. Individual searches were performed to identify potential articles of interest related to axSpA (search terms: [“axSpA” OR “axial SpA” OR “axial spondyloarthritis” OR “ankylosing spondylitis”]) in combination with terms related to IBP (“inflammatory back pain” OR “IBP” OR “chronic back pain” OR “CBP” OR “lower back pain” OR “LBP”), diagnosis ([“diagn∗” OR “classification”] AND [“criteria” OR “recommend∗” OR “guidelines”]), and referral (“refer∗”). No date range was formally selected, as we were interested in providing an overview of the evolution of these concepts in clinical practice. We supplemented the review with insights based on our clinical expertise. Patients with chronic back pain should be screened for IBP and other SpA features; suspicion for axSpA should trigger referral to a rheumatologist for further evaluation.

      Abbreviations and Acronyms:

      AS (ankylosing spondylitis), ASAS (Assessment of SpondyloArthritis international Society), axSpA (axial spondyloarthritis), CRP (C-reactive protein), HLA-B27 (human leukocyte antigen B27), IBD (inflammatory bowel disease), IBP (inflammatory back pain), MRI (magnetic resonance imaging), nr-axSpA (nonradiographic axSpA), NSAID (nonsteroidal anti-inflammatory drug), PCP (primary care physician), r-axSpA (radiographic axSpA), SPA (spondyloarthritis)
      Article Highlights
      • Inflammatory back pain is a key clinical symptom of axial spondyloarthritis (axSpA).
      • Axial spondyloarthritis affects 1% of the US population but is widely underdiagnosed.
      • With advances in current therapies, axSpA can be treated effectively; early treatment is associated with improved symptoms, physical function, and quality of life.
      • Barriers to a timely diagnosis of axSpA include a lack of awareness about the disease, nonspecific findings on physical examination, and a lack of biomarkers for diagnosis.
      • Improved awareness of axSpA among primary care physicians will likely increase timely referral to rheumatologists for early diagnosis and effective management, which will improve long-term outcomes.
      Back pain is a common health problem, affecting 80% to 85% of people at some point during their lifetime
      • Hill J.C.
      • Whitehurst D.G.
      • Lewis M.
      • et al.
      Comparison of stratified primary care management for low back pain with current best practice (STarT Back): a randomised controlled trial.
      and is the second leading symptom prompting a visit to a primary care physician (PCP).
      • Cypress B.K.
      Characteristics of physician visits for back symptoms: a national perspective.
      Approximately 20% of people aged 20 to 59 years have chronic low back pain, and the prevalence increases with age.
      • Meucci R.D.
      • Fassa A.G.
      • Faria N.M.
      Prevalence of chronic low back pain: systematic review [published online ahead of print October 20, 2015].
      One important but underrecognized cause of chronic low back pain is axial spondyloarthritis (axSpA), an inflammatory rheumatic disease that predominantly involves the spine and sacroiliac joints.
      • Strand V.
      • Singh J.A.
      Evaluation and management of the patient with suspected inflammatory spine disease.
      ,
      • Proft F.
      • Poddubnyy D.
      Ankylosing spondylitis and axial spondyloarthritis: recent insights and impact of new classification criteria.
      Axial spondyloarthritis is associated with a characteristic pattern of back pain features referred to as inflammatory back pain (IBP). The aims of this review are to (1) introduce the concept of IBP and other features salient to early detection of axSpA and (2) discuss strategies to identify patients with axSpA among patients with chronic back pain in a primary care setting. We hope that this review will raise awareness of axSpA as a cause of chronic back pain, particularly in young adults, and facilitate the timely referral of patients who may have axSpA for evaluation in a rheumatology clinic.

      Material and Methods

      For this narrative review, we conducted a literature search of English-language articles using PubMed. Individual searches were performed to identify potential articles of interest related to axSpA (search terms: [“axSpA” OR “axial SpA” OR “axial spondyloarthritis” OR “ankylosing spondylitis”]) in combination with terms related to IBP (“inflammatory back pain” OR “IBP” OR “chronic back pain” OR “CBP” OR “lower back pain” OR “LBP”), diagnosis ([“diagn∗” OR “classification”] AND [“criteria” OR “recommend∗” OR “guidelines”]), and referral (“refer∗”). No date range was formally selected, as we were interested in providing an overview of the evolution of these concepts in clinical practice. After manually removing duplicates and articles deemed not relevant to the topic, the remaining articles of potential interest were reviewed and included for discussion and were supplemented with key insights from the authors as clinical experts in the field.

      Clinical Picture

      Axial spondyloarthritis is a disease predominantly of the axial skeleton, but peripheral joints, entheses, and extra-articular organs such as skin, eyes, and intestines are also frequently affected. Axial spondyloarthritis typically develops in individuals younger than 45 years and has a peak age at onset of between 20 and 30 years.
      • Feldtkeller E.
      • Khan M.A.
      • 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.
      Chronic inflammation in the sacroiliac joints and the spine results in back pain and stiffness and can, over time, lead to pathologic new bone formation, structural damage, and, ultimately, fusion of sacroiliac joints and the spine in some patients—known as bamboo spine.
      • Braun J.
      • van der Heijde D.
      • Dougados M.
      • et al.
      Staging of patients with ankylosing spondylitis: a preliminary proposal.
      Patients with axSpA who have obvious structural changes on radiographs of the sacroiliac joints indicating sacroiliitis are classified as having radiographic axSpA (r-axSpA), which is, for all practical purposes, the same as ankylosing spondylitis (AS).
      • van der Linden S.
      • Valkenburg H.A.
      • Cats A.
      Evaluation of diagnostic criteria for ankylosing spondylitis: a proposal for modification of the New York criteria.
      • 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].
      • Boel A.
      • Molto A.
      • van der Heijde D.
      • et al.
      Do patients with axial spondyloarthritis with radiographic sacroiliitis fulfil both the modified New York criteria and the ASAS axial spondyloarthritis criteria? Results from eight cohorts.
      Patients who have axSpA based on symptoms and other clinical features but lack obvious radiographic changes of sacroiliitis have nonradiographic axSpA (nr-axSpA). Although patients with nr-axSpA do not have definitive changes indicating sacroiliitis on radiographs, sacroiliitis is typically evident on magnetic resonance imaging (MRI) in these patients. In approximately 5% to 10% of patients, nr-axSpA will evolve to r-axSpA over 2 years; this rate increases to 5% to 30% over 10 years.
      • Poddubnyy D.
      • Rudwaleit M.
      • Haibel H.
      • et al.
      Rates and predictors of radiographic sacroiliitis progression over 2 years in patients with axial spondyloarthritis.
      • Poddubnyy D.
      • Sieper J.
      Radiographic progression in ankylosing spondylitis/axial spondyloarthritis: how fast and how clinically meaningful?.
      • Sampaio-Barros P.D.
      • Bertolo M.B.
      • Kraemer M.H.
      • Marques-Neto J.F.
      • Samara A.M.
      Undifferentiated spondyloarthropathies: a 2-year follow-up study.
      Because AS was a well-recognized entity for decades before the concept of nr-axSpA was introduced, much of the axSpA literature is based on only the subset of patients with AS. No diagnostic criteria exist for AS or axSpA. For research purposes, AS populations are typically defined using the modified New York classification criteria.
      • van der Linden S.
      • Valkenburg H.A.
      • Cats A.
      Evaluation of diagnostic criteria for ankylosing spondylitis: a proposal for modification of the New York criteria.
      These criteria require definitive evidence of sacroiliitis on pelvic radiographs in combination with either IBP or limited range of motion in the spine, which typically occurs in later stages of the disease.
      • van der Linden S.
      • Valkenburg H.A.
      • Cats A.
      Evaluation of diagnostic criteria for ankylosing spondylitis: a proposal for modification of the New York criteria.
      ,
      • 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].
      The concept of axSpA (which includes AS) was first established by a set of classification criteria developed in 2009 by the Assessment of SpondyloArthritis international Society (ASAS)—a panel of rheumatology experts (Figure 1).
      • 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].
      According to the ASAS classification criteria, patients who experience chronic back pain before the age of 45 years have axSpA if they (1) have imaging evidence of sacroiliitis (by MRI or radiography) plus 1 or more spondyloarthritis (SpA) feature or (2) are positive for human leukocyte antigen B27 (HLA-B27) and have 2 or more other SpA features.
      • 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].
      The SpA features include IBP, peripheral inflammatory arthritis, enthesitis, uveitis, dactylitis, psoriasis, Crohn disease or ulcerative colitis, good response to nonsteroidal anti-inflammatory drugs (NSAIDs), family history of SpA, HLA-B27 positivity, and elevated C-reactive protein (CRP). Both AS (as determined by the modified New York criteria) and r-axSpA (as determined by the ASAS classification criteria) define the same patient population.
      • van der Linden S.
      • Valkenburg H.A.
      • Cats A.
      Evaluation of diagnostic criteria for ankylosing spondylitis: a proposal for modification of the New York criteria.
      • 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].
      • Boel A.
      • Molto A.
      • van der Heijde D.
      • et al.
      Do patients with axial spondyloarthritis with radiographic sacroiliitis fulfil both the modified New York criteria and the ASAS axial spondyloarthritis criteria? Results from eight cohorts.
      The modified New York criteria and ASAS classification criteria are mainly used for clinical research studies and should not be used as diagnostic criteria for AS or axSpA.
      • Proft F.
      • Poddubnyy D.
      Ankylosing spondylitis and axial spondyloarthritis: recent insights and impact of new classification criteria.
      ,
      • Aggarwal R.
      • Ringold S.
      • Khanna D.
      • et al.
      Distinctions between diagnostic and classification criteria?.
      Clinician judgment is considered the criterion standard for a diagnosis of AS and axSpA.
      Figure thumbnail gr1
      Figure 1Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (SpA). aImaging evidence of sacroiliitis includes active (acute) inflammation on magnetic resonance imaging highly suggestive of sacroiliitis associated with SpA or definite radiographic sacroiliitis according to the modified New York criteria for ankylosing spondylitis. CRP = C-reactive protein; HLA-B27 = human leukocyte antigen B27; NSAIDs = nonsteroidal anti-inflammatory drugs. Adapted from Ann Rheum Dis,
      • 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].
      with permission from BMJ Publishing Group Limited.

      Epidemiology

      Worldwide estimates of axSpA prevalence range from 0.5% to 1.5%, which is comparable to that of rheumatoid arthritis.
      • Braun J.
      • Bollow M.
      • Remlinger G.
      • et al.
      Prevalence of spondylarthropathies in HLA-B27 positive and negative blood donors.
      • Helmick C.G.
      • Felson D.T.
      • Lawrence R.C.
      • et al.
      National Arthritis Data Workgroup. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States: part I.
      • Liao Z.T.
      • Pan Y.F.
      • Huang J.L.
      • et al.
      An epidemiological survey of low back pain and axial spondyloarthritis in a Chinese Han population.
      In the United States, the prevalence rates of axSpA and AS were found to be 1.4% and 0.55%, respectively.
      • Reveille J.D.
      • Weisman M.H.
      The epidemiology of back pain, axial spondyloarthritis and HLA-B27 in the United States.
      Ankylosing spondylitis is more common in men, with a male to female ratio of 2 to 3:1, but nr-axSpA is equally prevalent in men and women.
      • de Winter J.J.
      • van Mens L.J.
      • van der Heijde D.
      • Landewé R.
      • Baeten D.L.
      Prevalence of peripheral and extra-articular disease in ankylosing spondylitis versus non-radiographic axial spondyloarthritis: a meta-analysis.
      ,
      • Rudwaleit M.
      • Haibel H.
      • Baraliakos X.
      • et al.
      The early disease stage in axial spondylarthritis: results from the German Spondyloarthritis Inception Cohort.
      First-degree relatives of patients with AS have a 5.6- to 16-fold higher risk of development of AS. Ankylosing spondylitis is strongly associated with the genetic marker HLA-B27. Approximately 85% to 95% of white patients with AS are positive for HLA-B27.
      • Reveille J.D.
      Biomarkers for diagnosis, monitoring of progression, and treatment responses in ankylosing spondylitis and axial spondyloarthritis.
      Because HLA-B27 has a relatively high prevalence in the US population (6.1%) compared with the prevalence of axSpA (1.4%), the majority of HLA-B27–positive patients do not have axSpA.
      • Reveille J.D.
      • Hirsch R.
      • Dillon C.F.
      • Carroll M.D.
      • Weisman M.H.
      The prevalence of HLA-B27 in the US: data from the US National Health and Nutrition Examination Survey, 2009.
      The absolute risk of SpA in an HLA-B27–positive person is estimated to be between 2% and 10%.
      • Taurog J.D.
      • Chhabra A.
      • Colbert R.A.
      Ankylosing spondylitis and axial spondyloarthritis.
      Thus, HLA-B27 positivity has a moderate to high sensitivity but a low specificity for axSpA.

      Disease Manifestations and Comorbidities

      The hallmark feature of axSpA is IBP, which is characterized by insidious onset of chronic (>3 months) back pain before the age of 40 to 45 years, waking up in the second half of the night due to back pain, improvement with physical activity but not with rest, morning stiffness persisting for more than 30 minutes, and a good response to NSAIDs (Table).
      • Strand V.
      • Singh J.A.
      Evaluation and management of the patient with suspected inflammatory spine disease.
      ,
      • Dillon C.F.
      • Hirsch R.
      The United States National Health and Nutrition Examination Survey and the epidemiology of ankylosing spondylitis.
      • Machado G.C.
      • Maher C.G.
      • Ferreira P.H.
      • Day R.O.
      • Pinheiro M.B.
      • Ferreira M.L.
      Non-steroidal anti-inflammatory drugs for spinal pain: a systematic review and meta-analysis.
      • van der Heijde D.
      • Ramiro S.
      • Landewé R.
      • et al.
      2016 Update of the ASAS-EULAR management recommendations for axial spondyloarthritis.
      When describing their symptoms, many patients with axSpA report alternating buttock pain or hip pain; neck pain can be an early symptom in up to 50% of the patients with axSpA.
      • Roussou E.
      • Sultana S.
      Spondyloarthritis in women: differences in disease onset, clinical presentation, and Bath Ankylosing Spondylitis Disease Activity and Functional indices (BASDAI and BASFI) between men and women with spondyloarthritides.
      Other common clinical features in patients with axSpA include peripheral inflammatory arthritis, enthesitis, and dactylitis.
      • de Winter J.J.
      • van Mens L.J.
      • van der Heijde D.
      • Landewé R.
      • Baeten D.L.
      Prevalence of peripheral and extra-articular disease in ankylosing spondylitis versus non-radiographic axial spondyloarthritis: a meta-analysis.
      ,
      • Yamamoto T.
      Optimal management of dactylitis in patients with psoriatic arthritis.
      ,
      • Kataria R.K.
      • Brent L.H.
      Spondyloarthropathies.
      Approximately 30% of patients with axSpA have inflammation in peripheral joints, which is typically an asymmetric oligoarthritis (involving 2-4 joints)
      • de Winter J.J.
      • van Mens L.J.
      • van der Heijde D.
      • Landewé R.
      • Baeten D.L.
      Prevalence of peripheral and extra-articular disease in ankylosing spondylitis versus non-radiographic axial spondyloarthritis: a meta-analysis.
      that disproportionately affects joints of the lower extremities, such as the ankle, knee, and hip; however, joints of the upper extremities and the sternoclavicular or temporomandibular joints may also be affected. Peripheral arthritis is slightly more common in women. Enthesitis refers to inflammation of the enthesis, the structure where a joint capsule, ligament, or tendon inserts into the bone. Enthesitis presents as pain or stiffness with tenderness to palpation. Visible swelling at the entheses is uncommon. Common sites for enthesitis include the Achilles tendon and plantar fascia insertions into the calcaneus and the patellar and quadriceps tendon insertions into the tibial tubercle and patella.
      • Kataria R.K.
      • Brent L.H.
      Spondyloarthropathies.
      Dactylitis is characterized by diffuse swelling of a whole finger or toe (“sausage digit”), which may be painful and is present in approximately 6% of patients with axSpA.
      • Ciurea A.
      • Scherer A.
      • Exer P.
      • et al.
      Rheumatologists of the Swiss Clinical Quality Management Program for Axial Spondyloarthritis. Tumor necrosis factor α inhibition in radiographic and nonradiographic axial spondyloarthritis: results from a large observational cohort.
      Dactylitis typically occurs in one or a few digits at a time. Diffuse swelling or puffiness of all digits in an extremity should trigger consideration of an alternative etiology.
      TableCharacteristics That Can Distinguish Inflammatory Back Pain From Mechanical Back Pain
      VariableInflammatory back painMechanical back pain
      Age at onset<40-45 yAny age
      Rapidity of onsetInsidiousVariable, may be acute
      Chronicity>3 moVariable duration
      Night painCommonly worse at night; may cause awakening in the second half of the night due to back painVariable
      Effect of physical activity or movementImprovement with activity, not rest; minimally affected by position changesWorsening with activity, improvement with rest; may improve or worsen with position changes
      Morning stiffnessPersisting for >30 min; may be severeShort-lived
      Response to NSAIDsGoodVariable
      Location and characteristics of painLow back pain common but may affect any area of the spine; may cause alternating buttock pain; does not radiate into legs; does not cause numbness, burning, or tinglingAnywhere in spine; may radiate into legs; may cause numbness, burning, or tingling
      NSAID = nonsteroidal anti-inflammatory drug.
      Data from references 4 and 24-26.
      Patients with axSpA frequently have extra-articular manifestations—including uveitis, psoriasis, and inflammatory bowel disease (IBD)—and additional comorbidities associated with axSpA such as fatigue, osteoporosis, cardiovascular disease, and sleep apnea.
      • de Winter J.J.
      • van Mens L.J.
      • van der Heijde D.
      • Landewé R.
      • Baeten D.L.
      Prevalence of peripheral and extra-articular disease in ankylosing spondylitis versus non-radiographic axial spondyloarthritis: a meta-analysis.
      ,
      • Harman L.E.
      • Margo C.E.
      • Roetzheim R.G.
      Uveitis: the collaborative diagnostic evaluation.
      • Bedaiwi M.
      • Sari I.
      • Thavaneswaran A.
      • Ayearst R.
      • Haroon N.
      • Inman R.D.
      Fatigue in ankylosing spondylitis and nonradiographic axial spondyloarthritis: analysis from a longitudinal observation cohort.
      • Erb N.
      • Karokis D.
      • Delamere J.P.
      • Cushley M.J.
      • Kitas G.D.
      Obstructive sleep apnoea as a cause of fatigue in ankylosing spondylitis [letter].
      • Moltó A.
      • Nikiphorou E.
      Comorbidities in spondyloarthritis.
      • Walsh J.A.
      • Song X.
      • Kim G.
      • Park Y.
      Evaluation of the comorbidity burden in patients with ankylosing spondylitis using a large US administrative claims data set.
      • Walsh J.A.
      • Song X.
      • Kim G.
      • Park Y.
      Evaluation of the comorbidity burden in patients with ankylosing spondylitis treated with tumour necrosis factor inhibitors using a large administrative claims data set.
      The most common extra-articular manifestation in axSpA is anterior uveitis, which affects 25% to 35% of patients. Uveitis in axSpA is typically acute and unilateral and can be self-limited; recurrence is common and may occur in the alternate eye.
      • Harman L.E.
      • Margo C.E.
      • Roetzheim R.G.
      Uveitis: the collaborative diagnostic evaluation.
      Patients present with acute unilateral eye pain, redness, photophobia, and blurred vision.
      • Rosenbaum J.T.
      Uveitis in spondyloarthritis including psoriatic arthritis, ankylosing spondylitis, and inflammatory bowel disease.
      Occasionally, uveitis is the first manifestation of axSpA, even before the onset of IBP. Symptomatic IBD occurs in 4% to 6% of patients with axSpA,
      • de Winter J.J.
      • van Mens L.J.
      • van der Heijde D.
      • Landewé R.
      • Baeten D.L.
      Prevalence of peripheral and extra-articular disease in ankylosing spondylitis versus non-radiographic axial spondyloarthritis: a meta-analysis.
      ,
      • Rudwaleit M.
      • Haibel H.
      • Baraliakos X.
      • et al.
      The early disease stage in axial spondylarthritis: results from the German Spondyloarthritis Inception Cohort.
      but asymptomatic ileal and colonic mucosal inflammation is found in up to 50% of patients.
      • Leirisalo-Repo M.
      • Turunen U.
      • Stenman S.
      • Helenius P.
      • Seppälä K.
      High frequency of silent inflammatory bowel disease in spondylarthropathy.
      ,
      • Van Praet L.
      • Van den Bosch F.E.
      • Jacques P.
      • et al.
      Microscopic gut inflammation in axial spondyloarthritis: a multiparametric predictive model.
      Psoriasis is seen in about 10% of patients with axSpA.
      • Stolwijk C.
      • van Tubergen A.
      • Castillo-Ortiz J.D.
      • Boonen A.
      Prevalence of extra-articular manifestations in patients with ankylosing spondylitis: a systematic review and meta-analysis.
      Patients with AS often have reduced mobility in the spine due to disease activity and later also from syndesmophyte formation and bony fusion of vertebrae. However, findings on physical examination of the spine may be completely normal in patients with nr-axSpA; therefore, it is important to look for other features of SpA on examination. Tender or swollen joints, a tender Achilles tendon or plantar fascia insertion, sausage digits, or psoriatic skin lesions, if present, support a diagnosis of axSpA. No specific diagnostic laboratory tests exist for axSpA. Human leukocyte antigen B27 testing plays an important role, but HLA-B27 positivity alone does not confirm a diagnosis of axSpA, and a negative HLA-B27 test result does not rule out an axSpA diagnosis. Serum CRP levels may be elevated in approximately 60% of patients with axSpA, but CRP elevation is neither sensitive nor specific for axSpA.
      • Landewé R.
      • Nurminen T.
      • Davies O.
      • Baeten D.
      A single determination of C-reactive protein does not suffice to declare a patient with a diagnosis of axial spondyloarthritis 'CRP-negative’.
      A single anterior-posterior radiograph of the pelvis is the recommended initial imaging study in a patient with suspected axSpA. Findings of sacroiliitis include joint space narrowing, sclerosis, erosive changes, and, in late stages, fusion of the joint. An MRI of the sacroiliac joints is valuable because it can demonstrate active inflammation in early stages, which may or may not progress to structural damage visible on radiography. Typical MRI lesions include bone marrow edema on short tau inversion recovery sequences in subchondral and periarticular areas and erosions, fatty lesions, sclerosis, or ankylosis on T1-weighted images. Magnetic resonance imaging is recommended when the findings on sacroiliac joint radiographs are normal or equivocal.
      • Mandl P.
      • Navarro-Compán V.
      • Terslev L.
      • et al.
      EULAR recommendations for the use of imaging in the diagnosis and management of spondyloarthritis in clinical practice.
      Although the availability of MRI has revolutionized the diagnosis of axSpA, the sensitivity and specificity of MRI for axSpA are imperfect, and MRI findings need to be interpreted in the context of the entire clinical picture to make a diagnosis of axSpA. In most situations, it is appropriate to refer patients to a rheumatologist for further work-up when the findings on sacroiliac joint radiographs are normal and the clinical suspicion for axSpA remains high.
      • Lukas C.
      • Cyteval C.
      • Dougados M.
      • Weber U.
      MRI for diagnosis of axial spondyloarthritis: major advance with critical limitations 'Not everything that glisters is gold (standard)’.

      Barriers to a Timely Diagnosis of axSpA

      The true prevalence of axSpA is unknown, and large differences between diagnostic prevalence and population prevalence have been reported (2.6 vs 14 cases per 1000 US adults, respectively).
      • Reveille J.D.
      • Witter J.P.
      • Weisman M.H.
      Prevalence of axial spondylarthritis in the United States: estimates from a cross-sectional survey.
      ,
      • Curtis J.R.
      • Harrold L.R.
      • Asgari M.M.
      • et al.
      Diagnostic prevalence of ankylosing spondylitis using computerized health care data, 1996 to 2009: underrecognition in a US health care setting.
      This discrepancy may reflect substantial underdiagnosis in routine clinical practice; in many cases, patients with possible axSpA were not referred to a rheumatologist.
      • Curtis J.R.
      • Harrold L.R.
      • Asgari M.M.
      • et al.
      Diagnostic prevalence of ankylosing spondylitis using computerized health care data, 1996 to 2009: underrecognition in a US health care setting.
      The average delay between symptom onset and diagnosis of axSpA is estimated to be 5 to 7 years, with evidence that the delay can be significantly longer in women than in men.
      • Jones A.
      • Harrison N.
      • Jones T.
      • Rees J.D.
      • Bennett A.N.
      Time to diagnosis of axial spondylarthritis in clinical practice: signs of improving awareness?.
      • Jovani V.
      • Blasco-Blasco M.
      • Ruiz-Cantero M.T.
      • Pascual E.
      Understanding how the diagnostic delay of spondyloarthritis differs between women and men: a systematic review and metaanalysis.
      • Kiltz U.
      • Baraliakos X.
      • Karakostas P.
      • et al.
      The degree of spinal inflammation is similar in patients with axial spondyloarthritis who report high or low levels of disease activity: a cohort study.
      • Rusman T.
      • van Vollenhoven R.F.
      • van der Horst-Bruinsma I.E.
      Gender differences in axial spondyloarthritis: women are not so lucky.
      Several factors may contribute to the delay in diagnosis (Figure 2),
      • Danve A.
      • Deodhar A.
      Axial spondyloarthritis in the USA: diagnostic challenges and missed opportunities.
      including the high prevalence of back pain—most commonly due to mechanical etiologies—in the general population (19% based on National Health and Nutrition Examination Survey data
      • Weisman M.H.
      • Witter J.P.
      • Reveille J.D.
      The prevalence of inflammatory back pain: population-based estimates from the US National Health and Nutrition Examination Survey, 2009-10.
      ). The lack of specific physical examination findings in patients with early axSpA and absence of extraspinal manifestations has been reported to impair early diagnosis.
      • Poddubnyy D.
      • Rudwaleit M.
      Early spondyloarthritis.
      The lack of biomarkers unique to axSpA, younger age at onset, and gradual disease onset may also contribute to delayed referral for evaluation by a rheumatologist.
      • Reveille J.D.
      Biomarkers for diagnosis, monitoring of progression, and treatment responses in ankylosing spondylitis and axial spondyloarthritis.
      ,
      • Deodhar A.
      • Mittal M.
      • Reilly P.
      • et al.
      Ankylosing spondylitis diagnosis in US patients with back pain: identifying providers involved and factors associated with rheumatology referral delay.
      ,
      • Aggarwal R.
      • Malaviya A.N.
      Diagnosis delay in patients with ankylosing spondylitis: factors and outcomes—an Indian perspective.
      Instead, patients may be referred to and treated by orthopedists, physiatrists, chiropractors, and other providers in an attempt to relieve symptoms.
      • Deodhar A.
      • Mittal M.
      • Reilly P.
      • et al.
      Ankylosing spondylitis diagnosis in US patients with back pain: identifying providers involved and factors associated with rheumatology referral delay.
      Paradoxically, a good response to NSAIDs may contribute to a delay in diagnosis because further evaluation may not be pursued when patients report improved symptoms with NSAIDs. Lack of access to a rheumatologist and long waiting times may also contribute to diagnostic and therapeutic delays in some areas.
      • Deodhar A.
      • Mittal M.
      • Reilly P.
      • et al.
      Ankylosing spondylitis diagnosis in US patients with back pain: identifying providers involved and factors associated with rheumatology referral delay.
      Figure thumbnail gr2
      Figure 2Factors contributing to delay in diagnosis of axial spondyloarthritis. NSAID = nonsteroidal anti-inflammatory drug. Data from Clin Rheumatol.
      • Danve A.
      • Deodhar A.
      Axial spondyloarthritis in the USA: diagnostic challenges and missed opportunities.

      Referral Strategy for axSpA

      Axial spondyloarthritis can easily be missed in a primary care setting because no specific physical examination findings or diagnostic tests exist that easily differentiate axSpA from other chronic back pain syndromes.
      • Reveille J.D.
      Biomarkers for diagnosis, monitoring of progression, and treatment responses in ankylosing spondylitis and axial spondyloarthritis.
      Screening and referral strategies have been developed to help PCPs determine when axSpA should be considered and to guide the initial evaluation for suspected axSpA, including support in making the decision whether to refer patients to a rheumatologist.
      • Braun A.
      • Saracbasi E.
      • Grifka J.
      • Schnitker J.
      • Braun J.
      Identifying patients with axial spondyloarthritis in primary care: how useful are items indicative of inflammatory back pain?.
      • Hermann J.
      • Giessauf H.
      • Schaffler G.
      • Ofner P.
      • Graninger W.
      Early spondyloarthritis: usefulness of clinical screening.
      • Poddubnyy D.
      • Vahldiek J.
      • Spiller I.
      • et al.
      Evaluation of 2 screening strategies for early identification of patients with axial spondyloarthritis in primary care.
      • Sieper J.
      • Srinivasan S.
      • Zamani O.
      • et al.
      Comparison of two referral strategies for diagnosis of axial spondyloarthritis: the Recognising and Diagnosing Ankylosing Spondylitis Reliably (RADAR) study.
      • van Hoeven L.
      • Luime J.
      • Han H.
      • Vergouwe Y.
      • Weel A.
      Identifying axial spondyloarthritis in Dutch primary care patients, ages 20-45 years, with chronic low back pain.
      • Poddubnyy D.
      • van Tubergen A.
      • Landewé R.
      • Sieper J.
      • van der Heijde D.
      Assessment of SpondyloArthritis international Society (ASAS)
      Development of an ASAS-endorsed recommendation for the early referral of patients with a suspicion of axial spondyloarthritis.
      Inflammatory back pain usually develops before age 45 years and is characterized by insidious onset of chronic (≥3 months) back pain. Thus, referral strategies are designed to be applied to patients with back pain for 3 months or longer and onset age younger than 45 years, who we subsequently refer to as “at-risk” patients.
      • Braun A.
      • Saracbasi E.
      • Grifka J.
      • Schnitker J.
      • Braun J.
      Identifying patients with axial spondyloarthritis in primary care: how useful are items indicative of inflammatory back pain?.
      • Hermann J.
      • Giessauf H.
      • Schaffler G.
      • Ofner P.
      • Graninger W.
      Early spondyloarthritis: usefulness of clinical screening.
      • Poddubnyy D.
      • Vahldiek J.
      • Spiller I.
      • et al.
      Evaluation of 2 screening strategies for early identification of patients with axial spondyloarthritis in primary care.
      • Sieper J.
      • Srinivasan S.
      • Zamani O.
      • et al.
      Comparison of two referral strategies for diagnosis of axial spondyloarthritis: the Recognising and Diagnosing Ankylosing Spondylitis Reliably (RADAR) study.
      • van Hoeven L.
      • Luime J.
      • Han H.
      • Vergouwe Y.
      • Weel A.
      Identifying axial spondyloarthritis in Dutch primary care patients, ages 20-45 years, with chronic low back pain.
      • Poddubnyy D.
      • van Tubergen A.
      • Landewé R.
      • Sieper J.
      • van der Heijde D.
      Assessment of SpondyloArthritis international Society (ASAS)
      Development of an ASAS-endorsed recommendation for the early referral of patients with a suspicion of axial spondyloarthritis.
      Because IBP is the most common symptom in patients with axSpA, IBP has been used as a key component of screening tools for axSpA. In studies in which physicians were asked to refer at-risk patients (back pain ≥3 months with onset age <45 years) with IBP to a rheumatologist, a diagnosis of axSpA was made in 17% to 33% of these patients.
      • Hermann J.
      • Giessauf H.
      • Schaffler G.
      • Ofner P.
      • Graninger W.
      Early spondyloarthritis: usefulness of clinical screening.
      • Poddubnyy D.
      • Vahldiek J.
      • Spiller I.
      • et al.
      Evaluation of 2 screening strategies for early identification of patients with axial spondyloarthritis in primary care.
      • Sieper J.
      • Srinivasan S.
      • Zamani O.
      • et al.
      Comparison of two referral strategies for diagnosis of axial spondyloarthritis: the Recognising and Diagnosing Ankylosing Spondylitis Reliably (RADAR) study.
      ,
      • Brandt H.C.
      • Spiller I.
      • Song I.H.
      • Vahldiek J.L.
      • Rudwaleit M.
      • Sieper J.
      Performance of referral recommendations in patients with chronic back pain and suspected axial spondyloarthritis.
      The relatively high sensitivity of IBP for axSpA in at-risk patients (≈77%) makes it useful in screening for axSpA, but nearly one-quarter of patients with axSpA would be missed if screening relied on the presence of IBP alone.
      • Solmaz D.
      • Akar S.
      • Soysal O.
      • et al.
      Performance of different criteria sets for inflammatory back pain in patients with axial spondyloarthritis with and without radiographic sacroiliitis.
      Several studies have therefore evaluated and validated axSpA screening strategies in patients with chronic low back pain using IBP in combination with other SpA features.
      • Poddubnyy D.
      • Vahldiek J.
      • Spiller I.
      • et al.
      Evaluation of 2 screening strategies for early identification of patients with axial spondyloarthritis in primary care.
      • Sieper J.
      • Srinivasan S.
      • Zamani O.
      • et al.
      Comparison of two referral strategies for diagnosis of axial spondyloarthritis: the Recognising and Diagnosing Ankylosing Spondylitis Reliably (RADAR) study.
      • van Hoeven L.
      • Luime J.
      • Han H.
      • Vergouwe Y.
      • Weel A.
      Identifying axial spondyloarthritis in Dutch primary care patients, ages 20-45 years, with chronic low back pain.
      • Poddubnyy D.
      • van Tubergen A.
      • Landewé R.
      • Sieper J.
      • van der Heijde D.
      Assessment of SpondyloArthritis international Society (ASAS)
      Development of an ASAS-endorsed recommendation for the early referral of patients with a suspicion of axial spondyloarthritis.
      ,
      • Deodhar A.
      • Mease P.J.
      • Reveille J.D.
      • et al.
      Frequency of axial spondyloarthritis diagnosis among patients seen by US rheumatologists for evaluation of chronic back pain.
      ,
      • van Hoeven L.
      • Vergouwe Y.
      • de Buck P.D.
      • Luime J.J.
      • Hazes J.M.
      • Weel A.E.
      External validation of a referral rule for axial spondyloarthritis in primary care patients with chronic low back pain.
      In the German Multicenter Ankylosing Spondylitis Survey Trial to Evaluate and Compare Referral Parameters in Early SpA (MASTER) study, 2 referral strategies were compared in at-risk patients (those with low back pain of ≥3 months’ duration; age at onset ≤45 years).
      • Poddubnyy D.
      • Vahldiek J.
      • Spiller I.
      • et al.
      Evaluation of 2 screening strategies for early identification of patients with axial spondyloarthritis in primary care.
      These referral strategies were further tested in an international study—Recognising and Diagnosing Ankylosing Spondylitis Reliably (RADAR)—that included additional extra-articular manifestations (ie, uveitis, psoriasis, IBD) in strategy 2.
      • Sieper J.
      • Srinivasan S.
      • Zamani O.
      • et al.
      Comparison of two referral strategies for diagnosis of axial spondyloarthritis: the Recognising and Diagnosing Ankylosing Spondylitis Reliably (RADAR) study.
      Here, axSpA was diagnosed in 35.6% of patients referred per strategy 1 and in 39.8% of patients referred per strategy 2; IBP was the most frequently used referral parameter across both strategies (93% and 96%, respectively). Findings from the RADAR study suggested that a more complicated referral strategy was not more advantageous than the simpler strategy, which required the presence of only one SpA parameter in at-risk patients. In the United States, the Prevalence of Axial Spondyloarthritis (PROSpA) study confirmed that referral of at-risk patients (chronic back pain for >3 months that started before 45 years of age) with IBP, HLA-B27 positivity, or imaging evidence of sacroiliitis was an effective strategy for identifying patients with possible axSpA (Figure 3).
      • Deodhar A.
      • Mease P.J.
      • Reveille J.D.
      • et al.
      Frequency of axial spondyloarthritis diagnosis among patients seen by US rheumatologists for evaluation of chronic back pain.
      ,
      • Rudwaleit M.
      • Sieper J.
      Referral strategies for early diagnosis of axial spondyloarthritis.
      Figure thumbnail gr3
      Figure 3Referral strategies for axial spondyloarthritis evaluated in the Prevalence of Axial Spondyloarthritis (PROSpA) and Multicenter Ankylosing Spondylitis Survey Trial to Evaluate and Compare Referral Parameters in Early SpA (MASTER)/Recognising and Diagnosing Ankylosing Spondylitis Reliably (RADAR) studies.
      • Deodhar A.
      • Mease P.J.
      • Reveille J.D.
      • et al.
      Frequency of axial spondyloarthritis diagnosis among patients seen by US rheumatologists for evaluation of chronic back pain.
      ,
      • Rudwaleit M.
      • Sieper J.
      Referral strategies for early diagnosis of axial spondyloarthritis.
      CT = computed tomography; HLA-B27 = human leukocyte antigen B27; IBP = inflammatory back pain; MRI = magnetic resonance imaging. Adapted from Nat Rev Rheumatol,
      • Rudwaleit M.
      • Sieper J.
      Referral strategies for early diagnosis of axial spondyloarthritis.
      with permission from Springer Nature.
      The ASAS additionally proposed a slightly longer referral algorithm, with the intention of maximizing sensitivity.
      • Poddubnyy D.
      • van Tubergen A.
      • Landewé R.
      • Sieper J.
      • van der Heijde D.
      Assessment of SpondyloArthritis international Society (ASAS)
      Development of an ASAS-endorsed recommendation for the early referral of patients with a suspicion of axial spondyloarthritis.
      According to the ASAS strategy, patients with chronic back pain for 3 months or more and onset at age 45 years or younger should be referred to a rheumatologist for further evaluation if they have any of the following parameters: IBP, HLA-B27 positivity, imaging evidence of sacroiliitis (on radiography or MRI), peripheral manifestations (arthritis, enthesitis, and/or dactylitis), extra-articular manifestations (psoriasis, IBD, and/or uveitis), family history of SpA, good response to NSAIDs, or elevated acute-phase reactants.
      • Poddubnyy D.
      • van Tubergen A.
      • Landewé R.
      • Sieper J.
      • van der Heijde D.
      Assessment of SpondyloArthritis international Society (ASAS)
      Development of an ASAS-endorsed recommendation for the early referral of patients with a suspicion of axial spondyloarthritis.
      A recent study retrospectively compared 13 referral strategies in the Spondyloarthritis Caught Early (SPACE) cohort.
      • Abawi O.
      • van den Berg R.
      • van der Heijde D.
      • van Gaalen F.A.
      Evaluation of multiple referral strategies for axial spondyloarthritis in the SPondyloArthritis Caught Early (SPACE) cohort.
      This study showed that the ASAS strategy was indeed most effective at ensuring that no patients with axSpA were missed; however, increased sensitivity came at the expense of lower specificity. Implementing the ASAS strategy may be challenging in locations that are underserved by rheumatologists because those few rheumatologists could be overwhelmed by the volume of referrals. Although the optimum referral strategy may depend on details of the health care environment, axSpA should always be considered in the differential diagnosis of chronic back pain, particularly in younger patients. It is critical that PCPs screen for IBP and other SpA features and refer patients with suspicion for axSpA to a rheumatologist for further evaluation.

      Treatment Approaches

      The goals of treatment for axSpA include alleviating symptoms, optimizing function, and preventing structural damage to the spine.
      • van der Heijde D.
      • Ramiro S.
      • Landewé R.
      • et al.
      2016 Update of the ASAS-EULAR management recommendations for axial spondyloarthritis.
      ,
      • Ward M.M.
      • Deodhar A.
      • Gensler L.S.
      • 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.
      Although currently available therapies improve symptoms and physical function,
      • Maxwell L.J.
      • Zochling J.
      • Boonen A.
      • et al.
      TNF-alpha inhibitors for ankylosing spondylitis.
      the impact of treatment on long-term structural damage remains uncertain, with conflicting data from imaging studies.
      • Boers N.
      • Michielsens C.A.J.
      • van der Heijde D.
      • den Broeder A.A.
      • Welsing P.M.J.
      The effect of tumour necrosis factor inhibitors on radiographic progression in axial spondyloarthritis: a systematic literature review.
      ,
      • Wang R.
      • Bathon J.M.
      • Ward M.M.
      Nonsteroidal antiinflammatory drugs as potential disease-modifying medications in axial spondyloarthritis [published online ahead of print November 9, 2019].
      Recommendations/guidelines for the management of axSpA include pharmacological and nonpharmacological interventions, such as education, physical therapy/exercise, and cessation of smoking.
      • van der Heijde D.
      • Ramiro S.
      • Landewé R.
      • et al.
      2016 Update of the ASAS-EULAR management recommendations for axial spondyloarthritis.
      ,
      • Ward M.M.
      • Deodhar A.
      • Gensler L.S.
      • 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.
      The initial medication class for treatment of active axSpA is NSAIDs. A Cochrane review of 39 studies of NSAIDs found high- to moderate-quality evidence suggesting that both traditional and cyclooxygenase 2–selective NSAIDs are efficacious for treating axSpA and moderate- to low-quality evidence that any harms with NSAIDs may not be different from placebo in the short term.
      • Kroon F.P.
      • van der Burg L.R.
      • Ramiro S.
      • et al.
      Non-steroidal anti-inflammatory drugs (NSAIDs) for axial spondyloarthritis (ankylosing spondylitis and non-radiographic axial spondyloarthritis).
      Various NSAIDs are equally effective, and longer-acting drugs may be preferable because they are more convenient.
      • Ward M.M.
      • Deodhar A.
      • Gensler L.S.
      • 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.
      ,
      • Droste U.
      • Siemens P.
      Treatment of ankylosing spondylitis with slow-release diclofenac sodium in a single daily dose [in German].
      Treatment with a biologic drug is indicated for active axSpA if a patient is intolerant of NSAIDs or has an inadequate response to 2 or more NSAIDs at therapeutic doses for 2 weeks each.
      • van der Heijde D.
      • Ramiro S.
      • Landewé R.
      • et al.
      2016 Update of the ASAS-EULAR management recommendations for axial spondyloarthritis.
      ,
      • Ward M.M.
      • Deodhar A.
      • Gensler L.S.
      • 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.
      Several tumor necrosis factor and interleukin 17A inhibitors are available for the treatment of axSpA. The selection of biologic therapies may be influenced by comorbidities, availability (eg, insurance formularies), response to prior treatment, patient preference, and other factors. Neither traditional disease-modifying drugs (eg, methotrexate, sulfasalazine) or systemic glucocorticoids are recommended for axial manifestations because there is little evidence of their clinical benefit, although these agents may be appropriate for some patients who have axSpA with peripheral SpA manifestations.
      • Ward M.M.
      • Deodhar A.
      • Gensler L.S.
      • 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.
      When axSpA is initially diagnosed or suspected, patients should be given a prescription for NSAIDs—up to the maximum dose unless there are contraindications—as an interim first-line treatment while rheumatology consultation is being arranged.
      • van der Heijde D.
      • Ramiro S.
      • Landewé R.
      • et al.
      2016 Update of the ASAS-EULAR management recommendations for axial spondyloarthritis.
      ,
      • Terenzi R.
      • Monti S.
      • Tesei G.
      • Carli L.
      One year in review 2017: spondyloarthritis.
      Early initiation of physical therapy is also recommended. It is usually appropriate to defer the decision to start treatment with a biologic to a rheumatologist to confirm the diagnosis, to assess the risks and benefits of biologic therapy, and to develop a monitoring plan, in conjunction with the patient.

      Conclusion

      Axial spondyloarthritis is a chronic inflammatory disease that causes back pain and stiffness, reduces mobility, and decreases quality of life. It is thought to affect about 1% of the US population, but it is currently underdiagnosed. Patients without a diagnosis are unlikely to receive appropriate treatment and may therefore experience more severe symptoms and unfavorable long-term outcomes. Primary care physicians are the first-line providers of care for patients with back pain and need to be aware of the clinical features that suggest axSpA, particularly in younger patients. Raising awareness of axSpA, including both AS and nr-axSpA, among PCPs should improve recognition of the disease in the primary care setting and facilitate the timely referral of appropriate patients to rheumatologists for early diagnosis and effective management.

      Acknowledgments

      Support for third-party writing assistance for the submitted manuscript, furnished by Victoria Kinsley, PhD, of SciMentum and Eric Deutsch, PhD, CMPP, of Health Interactions, Inc, was provided by Novartis Pharmaceuticals Corporation .

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