Seronegative spondyloarthropathy

Author(s): Pritesh Patel, MD

Originally published:12/28/2012

Last updated:04/04/2017



Spondyloarthritides (SpAs), are a group of idiopathic inflammatory rheumatologic disorders first recognized in the 1970s with common defining phenotypic, genetic, and serologic features.1 They are characterized by inflammation of the spine, sacroiliac (SI) joints, peripheral joints, enthesitis, dactylitis, as well as extra-articular manifestations such as uveitis and skin rashes. Serologically, they are rheumatoid factor (RF) and antinuclear antibody (ANA) negative. Genetically, they are associated with human haplotype antigen, HLA-B27, which suggests a common pathologic mechanism. Early diagnosis is crucial to limit disease-related disability. Non-pharmacologic treatment is aimed at prevention of progression, compensation, and restoration of function. Pharmacologic therapies involve non-steroidal anti-inflammatory drugs (NSAIDs) and biologics agents such as tumor necrosis factor (TNF) antagonists.

Traditionally, there were four subtypes of spondyloarthritides: ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis (formerly Reiter Syndrome) (ReA), and spondyloarthropathy associated with inflammatory bowel disease (IBD). Recent developments have expanded the concept of SpA to include undifferentiated spondyloarthropathy (USpA). This category is for patients who are diagnosed with SpA, but do not fall into any specific subtype.2

Spondyloarthritis and spondyloarthropathy are often used interchangeably, but the term spondyloarthritis is more appropriate because it refers to joint inflammation whereas arthropathy is a more general term referring to any joint pathology.  Spondyloarthritides is the plural of spondyloarthritis.2,3 Spondyloarthritides are sometimes prefixed with the term seronegative in the literature; however, the prefix has been dropped because unlike rheumatoid arthritis (RA), SpAs are seronegative (rheumatoid factor (RF) and antinuclear antibody (ANA) negative)5,6,7.


The exact cause of SpAs is unknown. HLA-B27 is the biggest risk factor for the development of SpA.8 This antigen is strongly associated with the most widely recognized SpA, AS. The exact role that HLA-B27 plays in this group of diseases is not well understood. The pathogenesis appears to be a complicated interplay of genetic and environmental factors. In the ReA subtype, bacterial organisms precipitate the disease process.

Epidemiology including risk factors and primary prevention

As a group, the spondyloarthritides may be as common as RA with a prevalence of 0.5% to 1%.6,9,10 Worldwide, there are variations in the prevalence of SpA which correlate with the prevalence of HLA-B27.59 The prevalence of HLA-B27 varies among the different forms of spondyloarthropathies and ethnic groups.6,8-10 In the United States, HLA-B27 may be found in 7.5% of American whites and in less than 1% of African Americans.9 The SpA with the highest HLA-B27 association is AS with up to 95% of American whites and 50% of African Americans testing positive for the geneotype.6,10

Other than avoidance of reproduction among the genetically predisposed, there is no known method of prevention of SpAs.


The pathogenesis of SpA has not breen fully elucidated. The strong association of HLA-B27 with this group of diseases suggests it is a key contributor to the pathogenesis of SpAs. In humans, HLA-B27 is an allele of the MHC Class I molecule, found on all nucleated cells, which presents intracellular antigens to CD8+ T lymphocytes (cytotoxic T cells). Presentation of viral peptides bound to Class I MHC molecules found on infected cells results in their lysis11.

One theory, regarding the pathogenesis of ReA, is that this disease is triggered after the presentation of “arthritogenic” peptides to CD4+ and CD8+ T-cells, thus stimulating the associated inflammatory reactions.12 Certain bacteria, such as Yersinia, Salmonella, Shigella, and Campylobacter, have been clearly associated with ReA.13 Interestingly, bacterial DNA has been found in synovial fluid and synovial cells in those with ReA, suggesting a possible link between enteric infection and joint inflammation.12

New research is aimed at tumor necrosis factor (TNF), interleukin’s IL-23 and IL-17, their polymorphisms, and immunologic pathways in the pathogenesis of inflammatory arthritis. Cells expressing the IL-23 receptor have been shown to become pathogenic after exposure to IL-23. In tissues, IL-17A exacerbates the chronicity and severity of the disease process. Interaction of IL-23+ and IL-17+cells with different tissue specific cells leads to activation of cytokine-mediated pathways resulting in severe inflammation causing bone erosion and tissue modeling. Clinical trials specifically targeting TNF and IL-17 are promising a new treatment arm.14 But the question remains if diseases such as AS have a strong association with this pathogenesis model.

On a macroscopic level, the pathologic inflammatory cascade disrupts the normal homeostasis of bone formation and bone resorption. The net result is pathologic endochondral bone formation known as osteoproliferation.15 Axial syndesmophytes and peripheral osteophytes form. The eventual fusion of syndesmophytes leads to ankylosis.

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

SpAs are characterized by a waxing and waning course of active inflammation alternating with periods of little to no inflammation. Symptoms correlate with sites of inflammation around peri-articulator and tendon insertion sites. Inflammatory back pain is a common manifestation of SpAs. It is characterized by morning stiffness lasting more than 30 minutes. Peripheral entheses occur at sites that bear greater physical stress such as plantar fascia and Achilles tendon. There is also asymmetric peripheral arthritis of the lower limbs most notably at the hips and knees. Dactylitis may be seen in reactive arthritis, psoriatic arthritis, and undifferentiated SpA.6,10,11

The natural history of SpAs depends on the particular subtypes. Even within subtypes, disease severity may vary. AS is the best studied SpA. The natural history of more severe forms of AS, if left unchecked, is fusion of the spine beginning with the sacroiliac joints and progressing caudally. This leads to limited lumbar flexion, limited chest expansion, and hyperkyphosis.6,10

Specific secondary or associated conditions and complications

The most common extra-articular finding is anterior uveitis which occurs in 20-30% of AS patients but less than 1% of PsA patients.6,10 Skin involvement is in the form of psoriasis.3 There also appears to be a relationship between SpAs and inflammatory bowel disease (IBD). Asymptomatic inflammation of the terminal illium and proximal colon may be found with serial colonoscopies in 60% of AS and USpA cases.10,11 About 10% of patients diagnosed with SpA develop IBD.16

Osteoporosis is commonly found in AS, and SpAs in general, and is responsible for loss of bone strength. Bone loss may be present early in the course of the disease and is predominantly found in the spine. It is associated with male gender, duration, severity of disease, and the presence of syndesmophytes in the spine. Low bone mineral density (BMD) increases the risk of vertebral fractures which contribute to kyphosis, vertebral deformity, and functional loss.16,17

Other associated conditions include diabetes, hyperlipidemia, obesity, hypertension, cardiovascular disease, urethritis, and, occasionally, increased mortality.12


Some studies indicate a 5 to 6-year delay between symptom onset and diagnosis.6,10 But, untreated SpAs can lead to considerable disease burden and disability. This makes early diagnosis and treatment crucial. The first step is to recognize inflammatory low back pain. The second step is prompt referral to a Rheumatologist. In the “Supplemental Assessment Tools” below, there are some materials which will help guide you. Note the criteria used to determine inflammatory low back pain.


Individuals with SpAs commonly relate morning stiffness and low back pain that improves with exercise and NSAIDs. Inflammatory low back is pain is the hallmark of SpAs and recognizing this is critical for early diagnosis. Morning stiffness lasts more than 30 minutes. Low back pain radiates into the buttocks and nocturnal back pain only occurs during the second half of the night.6,10,13 Chronic LBP lasting greater than 3 months with an age of onset before age 45 should raise suspicion of an autoimmune disorder.

In addition, other common symptoms to look for are those that include enthesitis (e.g. of the heel or ischial tuberosity), unilateral or symmetrical arthritic-type pain, along with the common extra-articular manifestations of SpA such as uveitis, iritis, skin rash, constitutional symptoms, dactylitis, and aortitis. ReA usually presents 2-4 weeks after a urogenital (including sexually transmitted diseases) or gastrointestinal infection.13

Physical examination

Findings on physical examination in patients with SpA include: restricted spinal range of motion, tenderness of the sacroiliac and peripheral joints to palpation, swelling, warmth and erythema (synovitis) in the peripheral joints, enthesitis (edema, warmth, tenderness, erythema at tendon insertion points), dactylitis, and pertinent skin rashes (such as psoriasis). Patients with moderate to severe AS typically have a positive Schober’s test (very limited lumbar intersegmental flexion range of motion – see below).

Functional assessment

Functional difficulties due to spine pain and peripheral joint arthritis should be assessed in patients suspected of SpA. Functional assessment should be tailored to the individual’s disease. All patients with AS should have their cervical spine range of motion assessed. This group of patients is at risk of developing a progressive spinal flexion deformity which can be measured with the occiput to wall test. Involvement of a patient’s thoracic spine can be measured by the degree of chest expansion. Lumbar spine range of motion is measured in the sagittal and coronal planes. Lumbar flexion is assessed using the modified Schober test.18,19 Functional assessment tool such as the Bath Ankylosing Spondylitis Functional Index (BASFI) should be used.20

Laboratory studies

There are no specific lab tests to confirm a suspected diagnosis of SpA. Rather, a diagnosis is made through the combination of clinical, radiological, and laboratory findings. Most patients with SpAs have a positive HLA-B27, elevated C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR), and negative RF and antinuclear antibody (ANA) tests. Ninety to 95% of AS patients and 81% of ReA patients are HLA-B27 positive. CRP or ESR is elevated in 72%-90% of AS and ReA patients.21


Each of the SpAs has some degree of sacroiliac and spinal inflammation. Although plain radiographs are the imaging modality of choice, they detect bony changes approximately 6 months from the onset of clinical symptoms, leading to a delay in diagnosis. MRI is the most sensitive imaging modality for detecting active inflammation of the SI joints using fat-saturated T2-weighted turbo spin-echo sequence or short tau inversion recovery (STIR) sequences with high resolution settings.22 Ultrasonography (US) is also better than plain radiographs in detecting inflammatory changes early, and it is better than MRI in detecting and treating enthesitis. Computerized axial tomography (CT) scans may be useful in assessing the spine for occult fractures.2,6,10,22,23

Radiographs are also helpful in differentiating the SpA sub-types while ruling out similar diseases. Sacroiliitis in AS is bilateral and symmetrical, whereas in ReA and PsA it is often unilateral or asymmetrical. SpA- related sacroiliitis must be distinguished from other causes such as infection and osteitis condensans ilii. The absence of sacroiliitis is typical of diffuse idiopathic skeletal hyperosteosis (DISH) syndrome which can be confused with AS23.  DISH syndrome usually occurs in older patients and its spinal manifestations progress craniocaudally with paravertebral and paradiscal ossification and osteophytes with ligamentous calcification particularly of the anterior longitudinal ligament.23 In contrast, AS begins in the SI joints and progresses up the spine.2,5,6,7

In more severe and advanced cases, the spinal inflammation of AS leads to attrition and squaring of vertebrae followed by osteoproliferation and the formation of syndesmophytes. Fusion of these bony outgrowths is known as ankylosis and gives the appearance of a “bamboo spine” on plain radiography.23 The classic “pencil-in-cup” radiographic finding which occurs in arthritis mutilans, the most severe form of PsA, is a manifestation of the severe destruction and proliferation of bone resulting in shortening of the phalanges.6,10

Dual energy x-ray absorptiometry (DEXA) scans should be considered as osteoporosis is commonly found in AS and SpAs in general. Low BMD will increase the risk of vertebral fractures which contribute to kyphosis, vertebral deformity, and functional loss.17 Measurements of the spine may be normal or even high because the bridging syndesmophytes found in AS may mask osteoporosis. Measurements of the femoral neck may be more accurate.23

Supplemental Assessment Tools

The Assessment of SpondyloArthritis International Society (ASAS) Criteria for Inflammatory Back Pain:18 need at least 4 out of 5

  • Greater than 3 months of LBP
  • Age of onset before 40 years
  • Insidious onset
  • Improvement with exercise
  • Pain at night (with improvement upon getting up)

Bath Ankylosing Spondylitis Functional Index (BASFI)20

The BASFI is the mean of 10 item scores completed on a numerical rating scale. Items to be scored by the patient: 

  • Putting on your socks or tights without help or aids (eg, sock aid).
  • Bending forward from the waist to pick up a pen from the floor without an aid.
  • Reaching up to a high shelf without help or aids (eg, helping hand).
  • Getting up out of an armless dining room chair without using your hands or any other help.
  • Getting up off the floor without help from lying on your back.
  • Standing unsupported for 10 min without discomfort.
  • Climbing 12 to 15 steps without using a handrail or walking aid. One foot at each step.
  • Looking over your shoulder without turning your body.
  • Doing physically demanding activities (eg, physiotherapy, exercises, gardening or sports).
  • Doing a full day’s activities, whether it be at home or at work.

Modified Scober test17 Patient must be standing erect.

  • Mark an imaginary line connecting both posterior superior iliac spines (close to the dimples of Venus) (A).
  • The next mark is placed 10 cm above (B).
  • The patient bends forward maximally: measure the difference (C).
  • Report the increase (in cm to the nearest 0.1 cm).
  • The better of two tries is recorded.

Assessment of SpondyloArthritis International Society (ASAS) Classification Criteria for axial spondyloarthritis and spondyloarthritis in general:24

Currently, there are no diagnostic criteria for the spondyloarthritides. Rather, there are classification criteria developed by ASAS with the goal of early identification and treatment. ASAS divides SpAs into predominantly axial (axSpA) or predominantly peripheral (pSpA). A patient may be classified as axSpA either through a pathway beginning with the presence of HLA-B27 or radiographic evidence of sacroiliitis.

In order to identify patients with SpAs, symptoms of LBP lasting ≥ 3months should be present, and occur before age 45 years. In addition, the following criteria should be met: Sacroiliitis on imaging plus one or more of the SpA features listed below. Or, alternatively, HLA-B27 positivity plus two or more of the following SpA features listed below:

  • Inflammatory back pain
  • Arthritis
  • Enthesitis (e.g., heel)
  • Uveitis
  • Dactylitis
  • Psoriasis
  • Crohn’s/colitis
  • Good response to NSAIDs
  • Family history of SpA
  • HLA-B27
  • Elevated c-reactive protein (CRP)

In patients with only peripheral symptoms, arthritis, enthesitis or dactylitis must be present plus one or more SpA feature listed below:

  • Uveitis
  • Psoriasis
  • Crohn’s/ ulcerative colitis
  • Preceding infection
  • HLA-B27
  • Sacroiliitis on imaging


Two or more other SpA features:

  • Arthritis
  • Enthesitis
  • Dactylitis
  • Inflammatory back pain history
  • Family history of SpA

Early predictions of outcomes

Poor prognostic indicators include a younger age of onset, greater peripheral than axial joint involvement, uveitis, and elevated erythrocyte sedimentation rate (ESR), and poor response to non-steroidal anti-inflammatory drugs (NSAIDs).12


As with rheumatoid arthritis, changes in barometric pressure can affect spine or joint pain associated with SpAs. Repetitive work environments can provoke pain and may increase risk of disability. Functional barriers at home or work should be addressed.

Social role and social support system

As SpAs progress, disability can occur, affecting a patient’s role at home or work and potentially adversely affecting their relationships. Formal support groups, both in person and online do exist. There are numerous ones and should be screened by practitioners before their patient joins. One place to find a list of support groups in through the Spondylitis Association of America.


Available or current treatment guidelines

Treatment is directed at preventing progression of disease, preservation of joint architecture and function, and individual symptom management. The approach to treatment is multimodal involving education, referral to specialists, lifestyle and workplace modifications, prevention, occupational and physical therapy, regular exercise, and medication.

The American College of Rheumatology, Spondylitis Association of America, and Spondylitis Research and Treatment Network collaborated to develop treatment guidelines in 2015.25 These guidelines encompass the spectrum of both pharmacologic and non-pharmacologic treatments. Separately, in 2015, members of an AS special interest group in Australia developed the first comprehensive exercise recommendations for AS patients.26 These recommendations are extrapolated for all SpAs and are incorporated below.

There are no functional measures specific for SpAs. However, the Bath Ankylosing Spondylitis Metrology Index (BASMI), is categorical for AS18. It is an axial mobility measure and is associated with quality of life, physical function and psychological status. Hip involvement may be assessed with tape-based hip internal rotation. Strength, balance, and cardiopulmonary status should be evaluated.

Lifestyle modifications are directed at minimizing repetitive mechanical stress. For those who smoke, cessation should be a priority to prevent worse outcomes and spinal damage. Dietary consults may be appropriate and obesity should be addressed as it places more stress on the spine and contributes to low back pain. Adaptations and modifications to home and work-space may be necessary. A firm but not hard mattress may be preferred. Similarly, preference should be given to office chairs which promote good posture. 23

While the exact benefit of exercise to SpAs remains to be appraised, exercise should be a part of the non-pharmacologic treatment approach.23,25,27 SpA patients should strive for a life-long exercise program. In general, exercises prescriptions best focus on low impact exercises. Pilates, Tai Chi and certain forms of yoga may be beneficial and may be done in a group setting. Patients wishing to engage in more aggressive types of activities should be assessed on a case by case basis. Careful consideration needs to be given before permitting high impact exercise or physical activity such as martial arts or theme park rides. High velocity or strongly resistance exercises place a lot of pressure on joints. Exercises which place excessive challenges to balance, postural stability or cardiopulmonary function may need to be toned down. Excessive spinal or peripheral joint mobility where there are ankyloses are to be avoided.26 Bony change, balance, mobility, osteoporosis, and cardiopulmonary status should be taken into consideration while writing an exercise prescription.

The prescription should cater to maintaining posture, flexibility and strengthening the core and cardiopulmonary system.27 After a complete musculoskeletal assessment, an exercise prescription may address specific muscle groups to correct posture. For example, in patients with excessive cervical kyphosis the cervical flexors are stretched while the cervical extensors are strengthened.27

Occupational and physical therapy play an important role in the multi-modal approach to care. Occupation therapists may survey home dwellings and work-places to make recommendations for adaptive equipment and ergonomic modifications. Both occupation and physical therapy are useful in treating enthesitis with modalities and custom-made orthotics. For Achilles tendonitis and plantar fasciitis, custom-made insoles may be ordered. Night time resting splints may be used for tendonitis and tenosynovitis of the hands, wrists, ankles and feet to help prevent joint contractures. Physical and occupational therapists may help with active and passive range of motion of the joints and more importantly educate patients on doing this at home.

Pharmacologic options for SpAs are non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoid injections, and tumor necrosis factor (TNF) inhibitors. NSAIDs are the first line pharmacologic agents in treating SpAs, and may have disease modifying activity and reduce radiographic spinal progression of the disease. They should be prescribed scheduled.25,28, A good response to NSAIDs strongly supports the diagnosis of a spondyloarthropathy and is actually a part of the classification criteria for SpA.28 Long term use of glucocorticoids is not recommended; however, short-term glucocorticoids with rapidly tapering doses may be considered in severe arthritic flares. Glucocorticoid injections are beneficial for entheses and inflamed joints, but peri-tendon injections to the Achilles, patellar, or quadriceps should be avoided. Topical glucocorticoids may be prescribed for prompt home use in the event of acute iritis.23,25 Traditional disease modifying antirheumatic agents (DMARDs) such as methotrexate should be avoided due to lack of evidence in their favor. Tumor necrosis factor (TNF) α blockers, in contrast, have shown significant benefit in the treatment of AS and SpAs. All manifestations of disease including synovitis, joint inflammation, enthesitis, dactylitis, axial disease, and skin and nail changes respond to TNF blockers. They are recommended for patients with insufficient response to NSAIDs. 22,25

Coordination of care

Rheumatologists are usually directors of care for SpA patients. The approach to care is multimodal and may require other specialties. Dermatologists should be consulted in those with psoriatic manifestations or PsA. Gastroenterologist referral may be helpful as gastrointestinal involvement is often found in SpAs. Any patient with uveitis should be evaluated by an ophthalmologist.

Physiatrists play a critical role in the care of SpA patients, and may even have more exposure to them than other specialties. Pain is a common presenting symptom, and SpA patients would greatly benefit from a PM&R pharmacologic and non-pharmacologic approach to pain. Furthermore, Physiatrists can assess the musculoskeletal system and write individualized therapy prescriptions.

Patient & family education

Education may be in the setting of a formal support group or individual self-management program.23,25 While there are numerous websites for learning, the practitioner should guide the patient to use reputable evidence-based ones.

Patients should be educated regarding the genetic implications of SpAs. For instance, if an individual under 40 years old has a family member with AS that is HLA-B27 positive, that individual has a 20% chance of developing AS.12

Emerging/unique Interventions

Treatment result outcomes can be measured using blood work (CRP > ESR),12 imaging (x-ray and MRI of joints), physical examination (including Schober test), and functional performance examinations (observed activities of daily living) and surveys (Oswestry Disability Index, Short Form-36, Visual Analog Pain Scale). An outcome measure specifically designed for AS is the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI).18

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

Early diagnosis and treatment is a critical concept in SpAs. In order to achieve that, physiatrists must recognize signs and symptoms of SpAs and then promptly refer to rheumatologists. Seiper and Rudwaleit published an algorithm to assist with this. The steps are outlined below.62

If the patient has ≥ 3 months of LBP occurring before age 45 years, proceed to step 1.

  1. Do not order any new imaging, but rather review imaging (MRI/X-ray) which is already present. If there evidence of sacroilitis then refer to rheumatologist. Otherwise proceed to step 2.
  1. Do the patient’s symptoms suggest inflammatory LBP? These symptoms are
    • morning stiffness lasting greater than 30mins
    • LBP occurs mostly late night/early morning
    • Pain improves with exercises
    • If patient’s symptoms do not suggest inflammatory LBP, proceed to step 3
  2. Check HLA-B27, if positive, refer to rheumatologist.

Other clinical pearls to note:

SpAs are usually very responsive to NSAIDs and unless there are any contraindications, NSAIDs should be scheduled.  Refrain from using oral glucocorticoids. Physiatrists can play a crucial role in the care of SpA patients. Physiatrists may well see these patients on a chronic basis more often than other specialties. As a result, we should be aware of the complications of this group of disease and make referral and coordinate with rheumatologists.


Cutting edge concepts and practice

As mentioned above, this is an exciting time in the research field for SpAs. More light is being shed on TNF blockers, the role of IL-23 and IL-17 and the interplay of genetics and environmental factors. This offers the hope of promising therapies and novel treatment strategies.

In September 2016, the International Congress on Spondyloarthritides (SPA) studied the effectiveness of IL-17, IL-17A inhibitors. Topics on genetic research explored the functional role of HLA-B27. They also discussed the concept of treat-to-target which is well established in RA but not in SpAs. Fibromyalgia was also addressed as a possible hindrance to treatment goals. Other areas of discussion were on the treatment of SpAs with predominantly axial symptoms (known as axial SpAs or ax-SpAs).30


Gaps in the evidence-based knowledge

As discussed above, the role of HLA-B27 in this group of disease needs a deeper understanding. Further investigation is needed regarding the pathophysiologic processes of the subtypes of SpAs to determine if they are different phenotypes of the same pathological process or if there are different processes involved.


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Original Version of the Topic 

David S Fitch, DO, MS, PT. Seronegative spondyloarthropathy. 02/05/2013.

Author Disclosure

Pritesh Patel, MD
Nothing to Disclose

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