Seronegative Spondyloarthropathy

Contributor: Nancy Liu, MD

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A 25 year old female is referred for evaluation of back pain.  She has had chronic back pain since high school and thought it was related to injuries since she was active in numerous sports,.  During college, she was less physically active in sports, but the back pain persisted.  She describes her back stiffness as most severe in the morning upon awakening and after prolonged inactivity, such as sitting in the classroom for an hour.  The symptoms last at least for 60 minutes and improve if she stretches, moves, or participates in physical exercise.  Her pain is mostly in the lower thoracic region and she describes muscle spasms.  She will awaken at night after 3-4 hours of sleep with back pain and will have to walk around.  Occasionally, she will have alternating buttock pain as well.  Naproxen OTC reduces her stiffness but she is afraid to take them regularly due to concern for toxicity.

  • Past Medical History: None.
  • Family and Social History: Unmarried elementary school teacher.  No family history of back pain; brother with psoriasis.
  • Medications:  None.
  • Review of Systems:  One episode of iritis in college that resolved with topical steroid eye drops.
  • General Physical Exam: Vital signs stable.  HEENT normal; skin without lesions; pulmonary, cardiac, GI and neurologic exams are all normal.
  • Musculoskeletal Exam:  Cervical spine with normal range of motion.  No evidence of peripheral arthritis or enthesitis; no point tenderness in thoracic or lumbar regions. There is loss of lumbar lordosis and the Schober's exam is 10 to 13 cm on full flexion (normal is >15 cm on full flexion).

What are the typical features of inflammatory back pain?

The characteristics features of  inflammatory back pain include: 1) onset of back pain before age 40; 2) insidious in onset; 3)pain that improves with exercise but 4) no improvement with rest; 5) nocturnal pain, especially the second half of the night.

What are other commonly associated features in this diagnosis that should be sought?

Aside from inflammatory back pain, other manifestations include: enthesitis, particularly in the Achilles tendonplantar fascia, anterior chest wall or iliac crest; shoulder or hip joint involvement; uveitis; aortitis; IgA nephropathy; rarely neurologic involvement; and apical pulmonary fibrosis.  

What is the best approach to classify and confirm the diagnosis?

Aside from the history and physical exam, laboratory data has limited utility. Although elevations in inflammatory markers such as erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) are often present, these are nonspecific.  Radiographic imaging in early disease can be normal but obtaining sacroiliac (SI) joint, thoracic and lumbar spine films can sometimes reveal characteristic changes (enthesitis at the vertebral bodysyndesmophytessacroiliac erosions or sclerosis) if symptoms have been of longer duration. MRI with STIR images of the axial spine and SI joints are more sensitive for early inflammatory changes and bone marrow edema.  HLA B27 testing is helpful in supporting the diagnosis in a patient with classic inflammatory back symptoms or other associated features (arthritis, dactylitis, heel enthesitis, uveitis, psoriasis, inflammatory bowel disease, elevated inflammatory markers, response to NSAIDs, or family history of spondyloarthropathy (SpA)  if radiographic changes are not yet present.

Spondyloarthropathy encompasses a group of diseases:  ankylosing spondylitis, non-radiographic axial SpA, undifferentiated SpA, reactive arthritis, SpA associated with psoriasis, inflammatory bowel disease, and juvenile onset SpA.

Another classification  proposed by the Assessment of Spondyloarthritis International Society (ASAS) separates this group of diseases into two main clinical classifications: predominantly axial spondyloarthritis or predominantly peripheral spondyloarthritis.

Thus, in this case, the patient would have axial spondyloarthritis or ankylosing spondylitis if there were radiographic changes, or non-radiographic axial SpA if her films Xrays were normal. 


A 40 year old male with longstanding psoriatic arthritis on adalimumab for management of skin and joint disease develops increasingly severe mid-back pain. The pain started after lifting a heavy box at work. He describes the pain as constant, unrelieved by positional change and worse with activity. He has tried ibuprofen 800mg three times daily without symptomatic relief. The pain has been increasing in severity. His psoriatic arthritis and skin disease have been in excellent control for the past 6 years on therapy. He denies any fevers but describes malaise for the past week and mild anorexia. He has no radicular symptoms.

  • Past Medical History: Hypertension, mild asthma
  • Family and Social History: Brother with psoriasis and sister with Crohn’s disease; works full time in a factory’s shipping and receiving department. Non-smoker. Rare alcohol use on the weekend.
  • Medications: Adalimumab 40mg sc every 14 days; hydrochlorothiazide 25mg daily; albuterol inhaler as needed; topical steroids as needed.
  • Review of Systems: Weight loss of 4 lbs; no rash; minimal shortness of breath; no chest pain; no diarrhea or constipation; recent mild abrasion of elbow at work.
  • General Physical Exam: Temperature 99.7; pulse 100; normal respirations; blood pressure 100/60. Skin exam shows left olecranon abrasion with surrounding erythema. Heart with tachycardia but no murmurs. Lungs clear. Abdomen is normal without rebound or tenderness. Neurologic exam is normal.
  • Musculoskeletal exam: Prominent DIP enlargement; synovial thickening at left 3rd MCP; other peripheral joints are normal without tenderness. Percussion tenderness at T12 level.

What is your differential diagnosis?

Although psoriatic arthritis is one of the spondyloarthropathies that can have associated involvement in the axial spine, it is important to consider the entire history. The patient’s joint disease has been in very good control with adalimumab and it would be unusual to develop new inflammatory back pain on adequate therapy. The sudden onset of pain after lifting a box is concerning for possible mechanical injury or compression fracture. The latter would be unusual in this 40 year old male. However, he also has more generalized symptoms of fever, malaise and has low grade fever on ibuprofen. Given his immunosuppression with adalimumab and evidence of skin breakdown at his elbow, workup for possible infectious cause is strongly indicated.

How would you proceed in evaluating this patient?

General evaluation includes CBC with differential, electrolytes, creatinine, ESR, CRP, blood and urine cultures. If there is swelling of the olecranon bursa, an aspirate and culture can provide possible identification of organism.  Radiographs of area of point tenderness is the first imaging test but it is likelyfurther imaging with MRI or CT scan is needed to exclude vertebral osteomyelitis, discitis or paravertebral abcess. Cardiac echo should be ordered to exclude endocarditis.

Patient Care

  1. Learn the approach in evaluation of patients with axial or oligoarticular complaints through specific history, family information and physical exam details (aside from peripheral joint exam, review the back exam with Schober’s testing and other maneuvers).
  2. Distinguish characteristic features of inflammatory back pain; from mechanical back pain.
  3. Distinguish the symptoms and physical findings of spondyloarthritis patients from other inflammatory joint diseases or connective tissue disorders.
  4. Learn the appropriate approach for evaluation of the spondyloarthritis patient, including laboratory studies, imaging modalities and the utility of HLA B27 testing.
  5. Determine the need for further subspecialty evaluations with gastroenterology, dermatology or ophthalmology.
  6. Discuss the need for physical and occupational therapy (1) (2) and explore the impact of the specific diagnosis on the patient’s professional and personal lifestyle.
  7. Review the risks and benefits of various treatment modalities for each of the spondyloarthropathies and their limitations.
  8. Understand the potential complications [L4]  of the various spondylarthropathies.

Medical Knowledge

  1. Characterize the classification of spondyloarthropathy based on history, physical exam, laboratory and radiographic findings (see links above in case discussion).
  2. Differentiate the various forms of psoriatic arthritis (PsA) on physical exam: isolated DIP diseasedactylitissymmetrical polyarthritisarthritis mutilansasymmetrical sacroiliitis. Compare the different radiographic features of psoriatic arthritis: erosions similar to RAjoint ankylosis; arthritis mutilans with pencil-in-cup changes.
  3. Identify the common infectious organisms associated with reactive arthritis (ReA) and their role in pathogenesis.
  4. Compare the frequency and characteristics of axial versus peripheral arthritis associated with inflammatory bowel disease (IBD).
  5. Review the extra-articular manifestations of ankylosing spondylitis (AS), ReA, PsA and Inflammatory Bowel Disease (IBD) associated arthropathies (as discussed above) but also: onycholysisnail pitting; conjunctivitis; keratoderma blennorrhagicapalatal or oral ulcerscircinate balanitis; rare neurologic features. Understand the role of  HLA B27 in pathogenesis and the practical use of this genetic testing in patients with back pain or uveitis.
  6. Review the currently available drugs for treatment of AS, PsA, and IBD arthropathy and understand their mechanism of action, potential benefits, limitations and risks.

Interpersonal and Communication Skills

  1. Discuss the course of the specific spondyloarthropathies with the patient and designated family members and provide information from rheumatology resources and national organizations.
  2. Explain the potential complications of the arthritis and rationale for routine monitoring for disease status and drug toxicities.
  3. Discuss the importance of daily exercise and life style adaptations in patients with spondylitis and provide resources for the patient.
  4. Provide information to specialists or other providers regarding the reason for the consult/referral.


  1. Recognize the importance of patient privacy, informed consent and equal care.
  2. Respect the patient’s decisions and opinions even when they are divergent with the standard of care.
  3. Recognize and address the patient’s concerns and fears when a diagnosis is uncertain or when the diagnosis is established.

Practice Based Learning

  1. Recognize the current classification of spondyloarthritis.
  2. Apply the information from the patient’s history, physical exam, laboratory and radiographic findings to make informed approach in further management of patients with different spondyloarthropathies.
  3. Set learning goals in comparing and contrasting the types of treatment and expected outcomes reported/recommended in the current literature for each of the spondyloarthropathies.
  4. Recognize current assessment tools for monitoring disease activity in AS and psoriatic arthritis.

System Based Practice

  1. Demonstrate the ability to work with consultants (dermatology, gastroenterology, ophthalmology, and orthopedics) and allied health professionals in the management of patients with inflammatory back disease or peripheral arthritis.
  2. Provide supporting information for patient’s health plan or employers when issues concerning medications, work accommodations or disability arise.
  3. Demonstrate an awareness of the impact of diagnostic and pharmacologic recommendations on the health care system, including insurance companies, physician and patient.
  4. Identify barriers to the delivery of optimal patient care for patients with spondyloarthritis and offer improved ideas for delivering care.

Key References

Key Resources


(Answer questions 1 – 5 on a piece a paper. Find Answer Key at the bottom on the page.)


A 25 year old male has a 6 months history of progressive lower back pain.  It began slowly without prior trauma and it is associated with stiffness and pain, particularly in the second portion of the night.  He will awaken and need to get up and move around for a period of time before he can return to bed.  In the morning, he has prolonged morning stiffness of his back, particularly in the buttock region.  The pain will sometimes radiate down towards the posterior knee but never below it and sometimes alternate from one side to the other.  He prefers to walk around at work rather than sit at his desk.

1) Which of the following is likely the source of his pain?

  1. Spinal stenosis
  2. Facet arthropathy
  3. Sacroiliac inflammation
  4. Sciatica
  5. Infectious disciitis


A 30 year old female has new onset joint pain and swelling in her right index finger, left wrist, and left ankle of 3 weeks duration.  There was no antecedent trauma.  She is in good health without any other medical problems.  She travelled to Central America for an extended period of time and just returned 2 months ago.  She developed an episode of what she presumed was traveler’s diarrhea that was associated with fevers, chills, crampy abdominal pain and loose stools.  Her symptoms resolved after a week.  Other companions on the same trip also developed similar symptoms.  She has tried naproxen 220mg BID with some improvement. 

On exam, she is afebrile with normal vital signs.  General exam is normal.  Joint exam reveals dactylitis of her right index finger, swelling in her left wrist, and medial left ankle which is   painful on inversion against resistance. 

Laboratories:  ESR of 45mm/hr; CRP of 30mg/L (normal <10mg/L); WBC of 13,000 cells/mm3; hgb of 14 gm/dL and hct of 40%. Creatinine, LFTs and urinalysis are normal.

2) What is the most appropriate next step in management of this patient?

  1. Switch to alternative nonsteroidal anti-inflammatory medication at high dose
  2. Obtain stool cultures
  3. Prescribe a course of Ciprofloxacin
  4. Order HLA B27
  5. Start methotrexate at 15mg po weekly


A 22 year old previously healthy male developed unilateral uveitis that was treated with topical steroids successfully. 3 months later, he develops onset of left knee pain and swelling that is associated with prolonged morning stiffness that gradually improves by noon. He also notes chest wall pain with inspiration and bilateral heel pain. He denies any rashes, diarrhea or mouth ulcers. There is family history of an uncle with Crohn’s disease.

Physical exam reveals normal vital signs.  The general exam is normal.   The chest wall is tender at the costochondral junctions. Musculoskeletal exam reveals moderate size left knee effusion that is warm and limited range of motion. The ankles are normal but there is point tenderness and swelling of bilateral Achilles insertion at the retrocalcaneal region.

3) The most likely diagnosis is:

  1. Rheumatoid arthritis
  2. Ankylosing spondylitis
  3. Undifferentiated  spondyloarthritis
  4. Psoriatic arthropathy
  5. Sarcoidosis

4) Psoriatic arthritis has a wide range of clinical features that are clinically present in other spondyloarthropathies. The one feature that is unique and characteristic in psoriatic arthritis is:

  1. Spondylitis
  2. Arthritis mutilans
  3. Dactylitis
  4. Enthesopathy
  5. Asymmetric arthritis

Tumor necrosis factor alpha inhibitors (TNFi) are the predominant class of biologic medications used to treat ankylosing spondylitis, psoriatic arthritis, and inflammatory bowel disease when more traditional medications are ineffective.  The decision to use these medications includes assessing risk factors.

5) Which of the following would be a contraindication to starting a TNFi?

  1. Well controlled diabetes mellitus
  2. Latent tuberculosis treated with isoniazid
  3. Chronic Hepatitis B
  4. Chronic renal insufficiency
  5. Angina pectoris

Answer Key

  1. The correct is C. The patient’s back symptoms are classic for inflammatory back pain (IBP).  These characteristic features include:  1) insidious onset over 3 months; 2) pain improving with activity but not with rest; 3) nocturnal pain, particularly in the second half of the night; and 4) alternating buttock pain suggesting SI joint involvement.  Usually mechanical pain is worse with activity and improves with rest.  Spinal stenosis and sciatica have pain radiating from the low back down the legs and extend past the knee but again, the pain is more problematic with activity.  Spinal stenosis and facet arthropathy would be highly unusual given his age.    Nocturnal pain is often a worrisome sign of infection or malignant disease within or near the spine.  In this patient, given his age, duration of symptoms and lack of systemic complaints, these two considerations are less likely but should remain in the differential. 
  2. The correct answer is A. This patient has acute post-enteric reactive arthritis.  By the time she presented, usually 2-6 weeks after the gastrointestinal infection, there is low likelihood that stool culture will be positive.  Antibiotics have not been proven to be effective for post-enteric reactive arthritis while there is still some suggestion that prolonged antibiotics for post-chlamydial reactive arthritis might benefit from prolonged antibiotics such as lymecycline, ciprofloxacin, or azithromycin.  The prevalence of HLA B27 is estimated to be anywhere from 30-50% in reactive arthritis and not likely to predict susceptibility but perhaps predictor of more severe disease.  Since this patient is in the acute phase of reactive arthritis, a trial of different NSAIDs is most appropriate as initial therapy and use of corticosteroids if NSAIDs are ineffective may provide short term relief.  If the patient evolves into more chronic reactive arthritis, then sulfasalazine, methotrexate may be necessary.
  3. The correct answer is C. The term undifferentiated spondyloarthritis is sometimes very useful in a patient who presents with feature of spondyloarthritis but without associated features of psoriasis, inflammatory bowel disease, or features of true ankylosing spondylitis. Sometimes, the joint manifestations present prior to the onset of skin disease (psoriasis) or bowel symptoms (inflammatory bowel disease).  The unifying features of this group of diseases include uveitis, enthesitis, asymmetrical arthritis, tendonitis, and/or inflammatory back pain.  This patient’s symptoms would also fit into the proposed ASAS classification of peripheral spondyloarthritis since most of his clinical features are peripheral but there are patients who have component of both.  Rheumatoid arthritis can present in asymmetrical fashion but is not usually associated with uveitis or enthesopathy.  Sarcoid is associated with uveitis and arthritis /periarthritis but the enthesopathic features of the chest wall is uncommon.  
  4. The correct answer is B. Arthritis mutilans is a rare but destructive form of psoriatic arthritis that is associated with progressive loss of bone in the affected joint.  This results in progressive changes and on radiograph, the findings of “pencil cup “deformities.  This subset of arthritis is very suggestive of psoriatic arthritis even if the patient has no skin manifestations.   All the other listed clinical features above are also seen in reactive arthritis, ankylosing spondylitis, and arthropathy associated with inflammatory bowel disease.
  5. The correct answer is C. TNF alpha inhibitors have multiple potential side effects and before initiation of these drugs, risk assessment should be carefully weighed.  The most important exclusion would be the presence of active infection or presence of latent tuberculosis.  Reactivation of tuberculosis has been observed in initial clinical trials and other fungal infections including histoplasmosis and coccidiomycosis have also been reported.  All patients should have PPD or interferon-gamma release assay for latent TB and treatment should be initiated before start of TNFi.  Other infections include untreated hepatitis B or C.  Patients with heart failure, NYHA functioparnal class III/IV should avoid these drugs due to potential worsening of congestive heart failure.  Other relative contraindications to these drugs include prior or current history of demyelinating disease, history of melanoma, or pregnancy.

Last updated February 2015

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