Early Spondyloarthritis




Spondyloarthritis (SpA) is a large family of chronic inflammatory diseases characterized by inflammation of the axial skeleton, a typically asymmetric peripheral arthritis of the lower limbs, enthesitis, typical extra-articular manifestations, and shared genetic background. The prevalence in the general population is up to 2% for the entire group. SpA, particularly ankylosing spondylitis, has been associated with a diagnostic delay of up to 10 years. Important efforts toward shortening this delay have been made, including the development of new classification criteria. This article discusses the current concept of the disease, typical manifestations, advances in diagnosis, and current treatment recommendations.








  • Spondyloarthritis (SpA) is a common group of interrelated inflammatory rheumatic conditions with a prevalence of 1% to 2%.



  • MRI of the sacroiliac joints and the spine has substantially improved making an early diagnosis of nonradiographic axial SpA and ankylosing spondylitis.



  • New criteria developed by the Assessment of SpondyloArthritis international Society (ASAS) that include MRI help to better classify patients with early predominant axial disease or predominant peripheral disease.



  • Programs targeting chronic back patients with young age at onset and referral to the rheumatologists if either inflammatory back pain or HLA-B27 is present have been proven effective in identifying patients with axial SpA in primary care.



  • International recommendations for the management of ankylosing spondylitis and the use of anti-TNF agents have recently been updated by ASAS/European League Against Rheumatism (EULAR).



Key Points
The term spondyloarthritis (SpA) is an umbrella term for a group of diseases sharing common clinical and genetic features, including involvement of the axial skeleton (sacroiliac joints and spine), peripheral arthritis, enthesitis, dactylitis, acute anterior uveitis, associated psoriasis or inflammatory bowel disease, and presence of the HLA-B27 antigen. Depending on the predominant clinical manifestations, SpA can be classified either as axial SpA (characterized by predominant involvement of the spine and/or sacroiliac joints as in ankylosing spondylitis (AS) and nonradiographic axial SpA, or as peripheral SpA (peripheral arthritis, enthesitis, and/or dactylitis).


Nonradiographic (ie, without definite sacroiliitis on radiography) axial SpA and AS are now considered as different stages of one disease continuum referred to as axial SpA ( Fig. 1 ). The rate of progression from nonradiographic (without radiographic sacroiliitis) to radiographic (with definite radiographic sacroiliitis; ie, AS) stage was recently estimated to be about 12% over 2 years, yet there are probably patients who remain at the nonradiographic stage during the entire course of their disease without progression to established AS. Although in AS sacroiliac joints are normally involved ahead of the spine in an estimated 10% of patients with AS or axial SpA, syndesmophytes can be found in the absence of definite radiographic sacroiliitis.




Fig. 1


Continuum of axial spondyloarthritis. At the early disease stage no or very little radiographic damage of the sacroiliac joints and the spine can be visualized on radiograph (nonradiographic stage). The radiographic stage refers to the presence on radiographs of structural damage of the sacroiliac joints (radiographic sacroiliitis grade 2–4) and/or spine (syndesmophytes—bony bridges between vertebral bodies, spondylodiscitis, and arthritis-ankylosis of the facet joints).


How often is spondyloarthritis in the general population?


AS—the prototype disease of the SpA group—has an estimated prevalence of about 0.5% in the general white population (including the United States), while the estimated prevalence for the whole group of SpA is about 1.5% to 2%. The prevalence of AS and the whole group of SpA is related to the frequency of HLA-B27 in a given population. HLA-B27 is most prevalent in northern countries and is highest in the Haida Indian population (up to 50%), giving a high prevalence of AS of about 6%. In the central European population, the HLA-B27 is as common as 6% to 9% ; whereas, in Japanese or Central and South African antigen populations its prevalence is 1% or less with a resulting low SpA prevalence.


In most patients, the first symptoms of SpA (usually back pain) start in the third or fourth decade of life. Males are about 2.5 times more often affected than females and have, in general, more severe disease (more radiographic damage). In up to 40% of AS patients, significant functional impairment occurs with a close relationship between the grade of impairment and disease duration. The diagnosis of AS is commonly delayed by 8 to 10 years after the first symptom onset, which represents a major unsolved problem in this area.




What are the reasons for the late diagnosis in spondyloarthritis?


There are several factors contributing to the long diagnostic delay in AS. One of the most obvious is the usual application of the modified New York criteria for classification and diagnosis of AS, which require the presence of radiographic sacroiliitis for definite AS diagnosis ( Box 1 ). Published in 1984, these criteria still remain a basis for AS diagnosis in clinical practice in many countries. Because radiographic sacroiliitis usually develops rather late (after years) in AS, in many patients these criteria are obviously useless in patients with early disease.



Box 1





  • Clinical criteria



  • Low back pain and stiffness for more than 3 months that improves with exercise, but is not relieved by rest.



  • Limitation of motion of the lumbar spine in both the sagittal and frontal planes.



  • Limitation of chest expansion relative to normal values corrected for age and sex.




  • Radiological criterion



  • Sacroiliitis grade ≥2 bilaterally, or grade 3 to 4 unilaterally.



Definite AS is present if the radiological criterion is associated with at least one clinical criterion.


The modified New York criteria for AS

Data from van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum 1984;27(4):361–8.


In contrast to many other rheumatic diseases, early axial SpA with back pain as the most prominent clinical symptom often has no clinical manifestation that is readily recognizable by the clinician, such as swollen joints or skin rash, and that could aid in making a diagnosis. Lack of SpA-awareness among primary care physicians is another reason for the long diagnostic delay. Back pain is extremely prevalent in the general population and SpA accounts for only about 5% of causes of chronic back pain. A simple and effective screening strategy in primary care and subsequent referral to the rheumatologist of those back pain patients with a higher probability of axial SpA is needed to effectively diagnose patients earlier.




What are the reasons for the late diagnosis in spondyloarthritis?


There are several factors contributing to the long diagnostic delay in AS. One of the most obvious is the usual application of the modified New York criteria for classification and diagnosis of AS, which require the presence of radiographic sacroiliitis for definite AS diagnosis ( Box 1 ). Published in 1984, these criteria still remain a basis for AS diagnosis in clinical practice in many countries. Because radiographic sacroiliitis usually develops rather late (after years) in AS, in many patients these criteria are obviously useless in patients with early disease.



Box 1





  • Clinical criteria



  • Low back pain and stiffness for more than 3 months that improves with exercise, but is not relieved by rest.



  • Limitation of motion of the lumbar spine in both the sagittal and frontal planes.



  • Limitation of chest expansion relative to normal values corrected for age and sex.




  • Radiological criterion



  • Sacroiliitis grade ≥2 bilaterally, or grade 3 to 4 unilaterally.



Definite AS is present if the radiological criterion is associated with at least one clinical criterion.


The modified New York criteria for AS

Data from van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum 1984;27(4):361–8.


In contrast to many other rheumatic diseases, early axial SpA with back pain as the most prominent clinical symptom often has no clinical manifestation that is readily recognizable by the clinician, such as swollen joints or skin rash, and that could aid in making a diagnosis. Lack of SpA-awareness among primary care physicians is another reason for the long diagnostic delay. Back pain is extremely prevalent in the general population and SpA accounts for only about 5% of causes of chronic back pain. A simple and effective screening strategy in primary care and subsequent referral to the rheumatologist of those back pain patients with a higher probability of axial SpA is needed to effectively diagnose patients earlier.




Why is early diagnosis important?


Recent data from an early SpA cohort demonstrated that patients with early (nonradiographic) axial SpA have the same level of pain and stiffness in comparison with patients with more advanced disease (established AS) and, therefore, require also effective treatment. Early diagnosis would lead to early initiation of the most appropriate and effective therapy and reassures the patient. Moreover, short disease duration and a good functional status were among predictors of a good clinical response to the tumor necrosis factor α (TNF-α) blocking agents.




Which clinical manifestations are relevant for early diagnosis?


The principal features of SpA that are relevant for early diagnosis are presented in Fig. 2 .




Fig. 2


Clinical, laboratory and imaging manifestations of SpA, which are relevant for early diagnosis.

( Courtesy of ASAS: Assessment of Spondyloarthritis International Society, Maastricht, The Netherlands. Available at: www.asas-group.org ; with permission.)


The leading clinical symptom of AS or axial SpA is back pain. Back pain in general is extremely prevalent: at least two-thirds of the people in the world experience back pain during their lives. Back pain in SpA has several typical features distinguishing it to some degree from pain of other origin and has been termed inflammatory back pain. Inflammatory back pain is a chronic back pain (duration >3 months), that often starts insidiously and usually before 45 years of age, often has a peak intensity in the second half of the night and early morning hours, improves with exercise but does not improve (even worsens) at rest, and is accompanied by morning stiffness (usually lasting more than 30 minutes). A less frequent but more specific feature of inflammatory back pain is an alternating buttock pain ( Box 2 ).



Box 2





  • Insidious onset



  • Morning stiffness in the spine for more than 30 minutes



  • Improvement of pain and stiffness with exercise and not with rest



  • Pain at night, usually in the second half with improvement on getting up



  • Alternating buttock pain



The back pain in AS and nonradiographic axial SpA typically starts before 45 years of age and runs a chronic or relapsing course (duration of more than 3 months).


Typical clinical features of inflammatory back pain


Currently, three sets of criteria for inflammatory back pain exist (Calin criteria, Berlin criteria, and the most recent criteria by the Assessment of SpondyloArthritis international Society (ASAS) experts ), all combining the features listed in Box 2 .


Of note, inflammatory back pain can be observed in 20% to 25% of patients with noninflammatory (mechanical) causes of chronic back pain. Although the presence of inflammatory back pain alone does not suffice to make a diagnosis of axial SpA, the presence of inflammatory back pain is an important symptom that should prompt further diagnostic tests for axial SpA.


In addition to inflammatory back pain, other aspects of the patient’s medical history provide diagnostic clues in early SpA. These include (1) a major reduction in back pain within 48 hours in response to a full dose of a nonsteroidal antiinflammatory drug (NSAID), (2) a positive family history of spondyloarthritis, and (3) a history of psoriasis or inflammatory bowel disease, or uveitis.


Limitation of the spinal mobility is a feature of rather advanced SpA, and, on the other hand, pain-mediated reduction of mobility might occur also in other back pain conditions.


Other SpA manifestations (ie, peripheral arthritis, enthesitis, dactylitis, uveitis, psoriasis, and inflammatory bowel disease) may or may not be present at disease onset of axial SpA and may develop later. If present, these manifestations significantly increase the probability of axial SpA.


In peripheral SpA, the presence of peripheral arthritis plays a major role in the diagnosis. Of diagnostic importance is the pattern of joint involvement, which in SpA is usually asymmetric, oligoarticular (≤4 joints) and affects predominantly the lower limbs. Enthesitis (especially heel) and dactylitis are typical for peripheral SpA. The medical history regarding a urogenital or gastrointestinal infection within 1 to 4 weeks before symptom onset also has a diagnostic value in SpA (reactive arthritis, a subset of peripheral spondyloarthritis).




Are there any specific laboratory tests for SpA?


In contrast to rheumatoid arthritis or connective tissues disease, no disease-specific autoantibodies were found in SpA until now. However, there is a genetic marker (HLA-B27) that is strongly associated with this disease. More than 80% of the patients with AS and more than 70% of the patients with axial SpA are positive for HLA-B27 as opposed to about 8% in the general white population, which makes this marker relevant as a diagnostic tool. However, despite the strong association between AS and HLA-B27, AS develops only in a minority (about 5%) of HLA-B27 positive subjects. Twin studies demonstrated that HLA-B27 contributes less than 40% of the genetic susceptibility to AS. Therefore, attempts to identify other genes within and outside the major histocompatibility complex associated with AS and SpA are still ongoing. Recently, two new loci related to AS, ERAP1 (ARTS1) and IL23R, have been identified.


Acute phase reactants (C-reactive protein [CRP] and erythrocyte sedimentation rate) have a limited value in the early SpA diagnosis because about 50% of patients with SpA have normal values of these tests. Yet, CRP is relevant for disease assessment because it indicates active inflammation; correlates, albeit weakly, with clinical parameters such as spinal pain ; and predicts radiographic progression in the sacroiliac joints and in the spine.


In suspected reactive arthritis with a history of a preceding infection, bacterial serology and testing the morning urine for Chlamydia trachomatis by polymerase chain reaction or using a urethral or cervical swab can be of diagnostic value. In a preceding gastrointestinal infection, stool cultures are usually negative once the arthritis develops.




Can imaging help in the early SpA diagnosis?


Imaging is essential for early SpA diagnosis. A diagnosis of definite AS requires the presence of definite sacroiliitis (at least grade 2 bilaterally or grade 3 unilaterally) on the radiographs ( Fig. 3 ). Radiographs of sacroiliac joints are still the first imaging procedure in suspected axial SpA. In case of unequivocal sacroiliitis on radiographs (see Fig. 3 ), no further diagnostic imaging is needed. However, normal radiographs or suspicious abnormalities only require further diagnostic imaging in the context of suggestive clinical symptoms or findings because structural change visible on radiographs can take months or years to occur. Moreover, the interpretation of radiographs of the sacroiliac joints can be challenging and depends on many factors, including quality of the image, chosen radiograph technique, individual variation of the sacroiliac anatomy, and the reader’s experience. These all decrease the reliability of this method. Spinal radiographs should normally not be considered as a first diagnostic procedure in case of suspicion of early SpA, because structural changes in the spine (eg, syndesmophytes) develop usually later than radiographic sacroiliitis.




Fig. 3


Radiograph of the sacroiliac joints of a 26-year-old male patient with a history of back pain over the previous 6 years. Subchondral sclerosis and multiple erosions are evident, corresponding to definite bilateral radiographic sacroiliitis of grade 2.


CT scan of sacroiliac joints detects structural changes (sclerosis, erosions, joint space width alteration, and ankylosis) more reliably than conventional radiography and is, therefore, considered the gold standard of detection of bony damage ( Fig. 4 ). However, CT cannot visualize active inflammation and is associated with relatively high radiation exposure and costs. As mentioned previously, structural damage cannot be considered as an early sign, which also limits the diagnostic value of CT scan in early SpA, Thus, CT scan is indicated rather in cases of differential diagnosis of SpA with degenerative changes, osteitis condensans ilii, fractures, and so forth.




Fig. 4


Sacroiliac joints of a 31-year-old male patient with a history of back pain over the previous 8 years. ( A ) Radiograph: definite subchondral sclerosis of both sacroiliac joints with suspicious erosions and possible joint space narrowing on the left side and definite erosions on the right side. ( B ) CT scan: the structural changes (erosions and sclerosis) are clearly visualized and better seen as compared with plain radiograph.


Recently, MRI became almost the standard imaging method for the early identification of patients with sacroiliitis due to axial SpA. The main reason for this is the ability of MRI to visualize not only structural damage of sacroiliac joints (eg, erosions, sclerosis, and ankylosis) but also active inflammatory lesions occurring before any structural changes visible on radiographs or CT scan. MRI has both an estimated sensitivity and specificity of about 90%, is not associated with ionizing radiation, and has very few contraindications. However, MRI is not available in all places in the world and is associated with relatively high costs in comparison to conventional radiographs, for instance. The diagnostic value of MRI in the detection of structural damage lesions (erosions, sclerosis, joint space changes, and ankylosis) is not entirely clear and needs further studies.


For the diagnosis of axial SpA, two MRI sequences are of importance: short tau inversion recovery (STIR) and T1-weighted sequences. T2-weighted sequence (with or without fat suppression) and T1-weighted postcontrast fat-suppressed sequence are supplementary and usually do not provide additional information to the previously mentioned sequences. STIR is a method of visualization of active inflammatory lesions ( Fig. 5 B), which is important for early SpA diagnosis. In T1-weighted images, several kinds of postinflammatory changes providing supportive information (eg, relevant for the differential diagnosis), can be recognized: fatty lesions (fat depositions), erosions, and, to a lesser extent, sclerosis and ankylosis (see Fig. 5 C).




Fig. 5


Sacroiliac joints of a 27-year-old male patient with a history of inflammatory back pain over the previous 12 months. ( A ) Conventional radiograph: no definite structural changes on the right side and only suspicious changes (small localized area with subchondral sclerosis) on the left side ( arrow ) without clear erosions or joint space width changes; sacroiliitis grade I left side. ( B ) MRI (STIR sequence): large area of hyperintense signals ( arrow ) corresponding to bone marrow edema located subchondrally and highly compatible with active sacroiliitis. ( C ) MRI (T1-weighted sequence): erosions ( arrowheads ), fatty lesion and fat deposition ( thick arrow ), and subchondral sclerosis (hypointense in both STIR and T1 sequences, thin arrows ).

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Oct 1, 2017 | Posted by in RHEUMATOLOGY | Comments Off on Early Spondyloarthritis

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