Continuing Medical Education: Spondyloarthropathies.

Edited By: Gregory C. Gardner, M.D.
Last updated Friday, January 07, 2005

Introduction

Types of spondyloarthropathies

The spondyloarthropathies are a heterogeneous set of disorders characterized by axial skeletal involvement and an association with the HLA B27 antigen. Listed below are the entities included in this group of disorders.

• Ankylosing spondylitis
• Juvenile ankylosing spondylitis
• Late onset spondyloarthropathy
• Psoriatic arthritis
• Reiter's syndrome/reactive arthropathy
• Enteropathic spondylitis
• Undifferentiated spondyloarthropathy

HLA B27 antigen

Table II. HLA B27 and the Spondyloarthropathies

At least one family study suggests that up to 25% of HLA B27 positive relatives of patients with ankylosing spondylitis may have signs and symptoms of inflammatory back pain but do not meet full criteria for ankylosing spondylitis. The utility in ascertaining the B27 haplotype in individuals with inflammatory back symptoms is that it might be an impetus to proceed with further evaluation or try second line anti-inflammatory medications in equivocal cases.

Another important association of the HLA B27 antigen, not listed above, is in men with lone aortic incompetence in combination with pacemaker requiring bradycardia.

Recently, the HLA B27 gene was introduced into rats so that there is now an animal model to study these diseases.

What is AS?

Pathology

Clinical features

1. Axial Skeleton

   The symptoms of AS are typically insidious in nature. Patients complain of morning low back stiffness lasting 30 minutes to several hours. Pain and stiffness at night and with prolonged sitting is also characteristic. The discomfort is felt in the low back and buttock area and is improved with exercise. If the disease progresses, immobility occurs due to fibrosis and ossification of enthesis about the spine. The entire spine may be affected and in severe cases, patients may develop the so called "bamboo spine". The insertions of the ribs into the spine and intercostal enthesis can also be affected leading to pleuritic-like chest pain with deep breathing and with time fibrosis of these attachments may cause decreased inspiratory excursion of the chest. Sacroiliac joints are usually involved symmetrically but one side may be more involved than another. Sternoclavicular and tempromandibular joints can also be affected.

   Spinal mobility can be measured by the Schober test done by drawing a 10 cm line up from the midposterior iliac spines (the "dimples"). Have the patient bend forward and measure the distraction. Normal is greater than five cm.

2. Peripheral Joints

   AS can also affect the peripheral joints in particular the hips, the shoulders, and the ankles. Overall, 35 percent of patients may have peripheral joint manifestations. This is said to occur more frequently in females. Peripheral joint disease is usually asymmetric.

3. Enthesopathy

   The Achilles tendon and the plantar fascia are frequently affected causing considerable discomfort. The Achilles tendon may be quite swollen and tenderness and is usually at the insertion into the calcaneous. Dactylitis (diffuse swelling of the fingers or toes also called sausage digits) may also be present representing diffuse enthopathy.

4. Eye Disease

   As many as 25 percent of patients with AS may have this manifestation during the course of their illness. Anterior uveitis or iritis is typically episodic and unilateral. Blindness is rare but the uveitis may be severe enough to require local or even systemic corticosteroids. Eye involvement appears to be more common in patients with peripheral joint disease.

5. Cardiovascular Disease

   This complication usually occurs in patient with long standing severe AS with peripheral joint involvement. Aortic incompetence may be a combination of aortic valve cusp fibrosis and or aortitis distal to the valve itself. Complete atrioventricular block with Stokes-Adams attacks may occur. Cardiac involvement is found in up to 10 percent of patients after 10 years of disease.

6. Pulmonary Disease

   Patients with severe spondylitis may develop upper lobe fibrosis. Cysts formation may occur and these may be colonized by Aspergillus. Patients may succumb to massive hemoptysis. Restrictive lung disease may be present but is normally mild.

7. Important Spinal Complications

   The immobile spine fractures easily with even minor trauma. The most common site is the cervical spine. Most fractures center around C5 and are transverse through the disc space. Gross instability can occur leading to impingement on the cord or vertebral arteries. Fracture may not be apparent on X-ray and may require CT scan or bone scan to localize. This is a true rheumatologic urgency.

   The cauda equina syndrome may cause insidious onset of pain in the buttocks or legs associated with bowel and bladder symptoms. This is due to spinal cord compression at the level of the cauda equina. Myelogram or MRI demonstrate lumbar diverticuli. Therapy, including surgery and high dose steroids, have not been satisfactory.

   Spinal stenosis can also occur due to bone over growth and nerve impingement. This may respond favorably to surgery.

   Spondylodiscitis occurs at a vertebral disc space (usually in the thoracic spine) that has become mobile. It is a source of mechanical-type back pain and although not usually unstable, can be a source of significant pain. On X-ray, there is usually erosion of the vertebral end plates and may mimic an infectious process. Treatment is by surgical fusion or trial of bracing to allow the segment to refuse on its own.

Radiographic features

1. Sacroilitis

   Initial changes include blurring of the joint margins and reactive sclerosis. With progression there may be complete fusion of the joints. Bilateral sacroilitis occurs in AS. Early changes at the sacroiliac joints are nicely demonstrated by CT scan.

2. Syndesmophytes

   These occur from ossification of the area of the annulus fibrosus and bridge adjacent vertebrae. With advancing disease, these can give the spine a bamboo appearance.

3. Vertebral Squaring

   Erosions at the vertebrae occur first at the anterosuperior anteroinferior corners. This leads to the appearance of squaring.

4. Reactive Sclerosis

   The anterior edges of the vertebrae can develop reactive sclerosis and have a so-called "shining corner" appearance. Reactive sclerosis/"fluffy" periostitis can also develop at the symphysis pubis and the ischium.

5. Calcaneal Spurs/Erosions

   Erosions can develop around the Achilles tendon insertion and calcaneal spurs are also common. Periostitis can occur at the calcaneus giving a "fluffy" appearance to the heel.

Treatment

1. Education

   Patients need to know the nature of their illness and its treatment. An extensive discussion is important for those who are recently diagnosed. There are educational materials available through the Arthritis Foundation, the Spondylitis Association of America, and on this web site.

2. Physical Therapy

   All patients should be sent to see a physical therapist when diagnosed to learn techniques for good posture and daily stretching. Patients should be encouraged to stay active! Swimming is an excellent activity for patients with arthritis.

3. Medication
   • NSAIDs are the mainstay of treatment. Patients usually have very immediate relief. Indomethicin or phenylbutazone (now under restricted use) are felt to be the most effective but most NSAIDs will work. Patients on these medication long term need to be monitored on a regular schedule (at one month then every three to twelve months thereafter).
   • Corticosteroids are useful for intra-articular use for peripheral joints but are not felt to be effective for spinal disease.
   • Sulfasalizine has recently been found useful for both the peripheral joint involvement but also shows promise in the spinal disease as well.
   • Other medications: Methotrexate is used by many rheumatologists but there are few studies. Of historic interest is the use of radiation which apparently did wonders for the spinal disease but lead to high a incidence of leukemia.
4. Surgery

   There is a limited role for surgery except in patients with severe hip or shoulder disease. A neurosurgeon or orthopaedic spine surgeon should be consulted early for spine fractures, cauda equina syndrome or spondylodiscitis.

Prognosis

About psoriatic arthritis

Clinical subgroups

There are five patterns of joint disease in psoriatic arthritis and are listed below. One pattern can evolve into another.

1. Asymmetric oligoarthritis

   This is the most common type and occurs in over one half of the patients with psoriatic arthritis. The DIPs PIPs of the hands and feet as well as the MTPs are frequently involved. In addition, the knees, hips, ankles, and wrists are commonly affected. A common finding is the whole digit to be swollen when the tendon sheath is involved and this gives the digit a sausage appearance.

2. DIP Arthritis

   This is a less common form and makes up five to ten percent of patients with psoriatic arthritis. The DIP joints are affected in a oligoarticular pattern in association with classic nail changes of psoriasis (pitting, hyperkeratosis, separation of the subungual bed).

3. Arthritis Mutilans

   This typically occurs in patients with wide spread severe psoriasis and there is often a spondylitis present. The affected digitis undergo significant osteolysis leading to so called "opera glass deformities."

4. Symmetric Polyarthritis

   This form has a pattern similar to rheumatoid arthritis but usually with less deforming disease. One characteristic is fusion of the wrist which does not typically occur in rheumatoid arthritis.

5. Psoriatic Spondylitis

   Twenty to 40 percent of patients with psoriatic arthritis may have some degree of sacroilitis often asymptomatic. The spondylitis is typically more asymmetric than with AS with paravertebral ossification between the vertebrae rather than syndesmophytes.

Radiographic features

1. Reactive Periostitis

   This "fluffy" appearing bony change at the enthesis is a hallmark for all of the spondyloarthropathies. Enthesitis occurs in psoriatic arthritis just as in AS with similar locations. In addition, reactive bony changes occur in the peripheral joints in association with erosions.

2. Marginal Erosions

   These occur in similar fashion to rheumatoid arthritis but the distribution of the involved joints along with the reactive bone changes help to distinguish it form rheumatoid arthritis. A characteristic lesion is the "pencil in a cup" deformity at the interphalangeal joints of the digits.

3. Sacroilitis

   As discussed above, it may be less symmetric in nature than AS.

4. Paravertebral Ossification

   Also called non-marginal syndesmophytes. These can be seen in the absence of sacroilitis and may be more asymmetric and sporadic than the syndesmophytes of AS.

Treatment

1. NSAIDs

   These are the mainstay of treatment but be aware that shunting of arachidonic acid to the lipoxygenase pathway may lead to a flare of the skin disease.

2. Corticosteroids

   Very useful for the peripheral joint disease. Both low dose orally or intra-articular corticosteroids in a fashion similar to rheumatoid arthritis can be used. The skin may also be benefited from oral corticosteroids.

3. Antimalarials (hydroxychloroquine, chloroquine)

   These agents have been used successfully for treatment of the peripheral joint disease but also may flare the skin especially chloroquine.

4. Gold Compounds

   Both oral and IM gold are effective in treating the peripheral joint disease. Given in a similar fashion to rheumatoid arthritis.

5. Sulfasalazine

   This agent has been shown to be effective in a variety of inflammatory forms of arthritis. Beneficial for both the peripheral and axial involvement.

6. Methotrexate

   Methotrexate has been in use for psoriasis for many years and is one agent that can treat skin, peripheral joint, and axial skeletal involvement. Dosed as per rheumatoid arthritis one time per week.

7. Miscellaneous

   Cyclosporin, PUVA, etretinate, azathioprine, have all been reported useful in small groups of patients.

History

Definition

The present criteria for defining Reiter's syndrome are listed below.

Table III. Definition of Reiter's Disease*

Reiter's syndrome affects men more often than women with the ratio of about 5:1. It can occur at any age but is principally seen among the 20 to 30 year old age group.

Reiter's syndrome has also been termed a reactive arthritis because it appears to be closely linked to various infectious agents. The notion has been that there is a molecular mimicry between antigens on the organism and the enthesis of the HLA B27 positive host leading to inflammation directed against the host as well as the organism. More recently, some investigators have felt that they have been able to identify chlamydia like organism in patients with Reiter' disease/reactive arthritis suggesting persistent synovial presence of organisms thought responsible for this disorder. Below is listed the agents presently recognized to be associated with Reiter's syndrome. The manifestations of Reiter's disease typically begin two to six weeks after such an infection.

Recently it has been recognized that Reiter's syndrome/psoriatic arthritis occur with an increased frequency in patients with HIV infection. This may be due to the various enteric infections that occur or to CD8 T cell activity.

Table IV. Organisms Associated with Reiter's Syndrome

Clinical features

1. Peripheral Arthritis

   The pattern seen with Reiter's syndrome is characteristically an asymmetric pauciarticular or polyarticular arthritis predominantly affecting the lower extremities. These patients may have very large effusions. "Sausage digits" may be seen at the fingers or toes similar to those in the other spondyloarthropathies.

2. Axial Arthritis

   Patients may complain of low back pain during the course of an attack but development of spondylitis usually occurs in patients with long standing persistent disease.

3. Enthesitis

   Similar in location to other spondyloarthropathies. Patients may have significant swelling of the Achilles tendons and the involvement at this location has been termed in the past "lovers heel" due to the association with venereal disease.

4. Eye Disease

   Conjunctivitis is the most common manifestation at the eye and may go unnoticed by the patient. Uveitis may occur and can be more serious than that seen in AS. Iridocyclitis and even optic neuritis have been described in Reiter's syndrome.

5. Urogenital Disease

   The urethritis seen in Reiter's can occur from postvenereal infection but also after infection from the enteric organisms. This has raised the question of the mechanism of urethritis in Reiter's syndrome. Prostatitis may occur in some degree in up to 80% of patients.

6. Mucocutaneous Disease

   There are several characteristic lesions that occur in Reiter's disease. Keratodermia blennorrhagicum occurs typically on the soles but may be seen on the palms, scalp, trunk, or scrotum. They begin as vesicles the form hyperkeratotic plaques that coalesce. Microscopically they are identical to psoriasis. Keratodermia is found in less than a third of patients. Ulcers and erosions can occur in the mouth and are typically not painful. Circinate balanitis is a superficial erosion on the glans penis and is seen in 20-50% of patients. Finally, nail changes can occur with accumulation of hyperkeratotic material beneath the nail.

7. Miscellaneous

   Cardiac involvement can occur in up to 10% of patients with either conduction problems or aortic insufficiency. Rarely, peripheral or cranial neuropathies can occur.

Radiographic features

Treatment

Medications used to treat Reiter's syndrome include NSAIDs, intra-articular steroids, occasionally oral steroids, sulfasalazine, methotrexate, and azathioprine. Methotrexate is presently felt to be contraindicated in patients with Reiter's syndrome and HIV infection due to data that suggests that methotrexate may hasten the progression of the HIV disease. All patients with Reiter's syndrome should be considered for HIV testing.

Antibiotics may have a role in preventing the development of a chronic disease state but this is presently not fully elucidated. One should consider a prolonged course (2-4 weeks ?) of tetracycline or another antichlamydia agent in patients with postvenereal Reiter's syndrome.

Prognosis

Juvenile ankylosing spondylitis

Late onset peripheral spondyloarthropathy

Enteropathic spondylitis

1. Inflammatory Bowel Disease
   • Peripheral arthritis: Both Crohn's disease and ulcerative colitis can be associated with a peripheral arthritis in about 20% of patients. The large joints of the lower extremities are typically affected and the arthritis waxes and wanes with the activity of the bowel disease. The peripheral arthritis is not a HLA B27 associated process.
   • Spondylitis: About 20% of patients may have evidence of sacroilitis and some 20% of these patients may progress on to actual ankylosing spondylitis. Only 50% of patients with sacroilitis carry the HLA B27 haplotype. The course of the spondylitis does not correlate with the bowel activity.
2. Whipple's Disease

   Arthritis is the presenting complaint in 60% and occurs at some time in 90% of patients with Whipple's disease. The arthritis is a migratory oligoarthritis. Patients also have an increased prevalence of sacroilitis and ankylosing spondylitis. Diagnosis is made by the history of persistent diarrhea and possibly protean other manifestations, along with PAS positive material in the lamina propria of the gut on biopsy. Treatment is with prolonged antibiotics.

3. Bowel Bypass Arthritis-Dermatitis Syndrome

   Intestinal bypass for obesity has been associated with a interesting syndrome of arthritis and dermatitis occurring in 8-36% of patients. The arthritis in typically oligoarticular in nature and very painful. The etiology is felt to be due to immune complexes containing bacterial products from the gut. Dermatitis is also present in up to 80%. Treatment is with NSAIDs, antibiotics to reduce bacterial load, or reanastomosis of the bowel.

Undifferentiated spondyloarthropathy

This category is used to include those patients who do not fit any particular category of disease or may have a combination of features. Many of these patients may have a chronic inflammatory monoarthritis in the setting of B27 haplotype, heel pain caused by calcaneal periosititis, or recurrent dactylitis (sausage digits).

Uveitis is a feature of almost all of the spondyloarthropathies to one degree or another. Any young male who presents to an ophthalmologist with uveitis should be evaluated for a spondyloarthropathy.

Bibliography

1. Schumacher HR, Klippel JH, Robinson DR (eds): Primer on the Rheumatic Diseases, Tenth Edition. Arthritis Foundation, Atlanta, Georgia, 1993.

   Excellent source for quick information on the rheumatic diseases. Generally more detailed than medicine textbooks.

2. Kahn MA (ed): Ankylosing spondylitis and related spondyloarthropathies. Spine. State of the Art Reviews 1990;4:497-688.

   A more detailed source of information on this subject.

3. Kahn MA, van der Linden SM: A wider spectrum of spondyloarthropathies. Semin Arthritis Rheum 1990; 20:107-113.

   Discusses the continuum of disease associated with the HLA-B27 antigen.

4. Kahn MA, van der Linden SM, Kushner I, et al: Spondylitic disease without radiologic evidence of sacroilitis in relatives of HLA-B27 positive ankylosing spondylitis patients. Arthritis Rheum 1985; 28:40-43.


5. Calabrese LH: Human immunodeficiency virus infection and arthritis. Rheum Dis Clin N Am 1993; 19:477-489.


6. Blocha KLN, Sibley JT: Undiagnosed chronic monoarthritis. Arthritis Rheum 1987; 30:1357-1361.

   Discusses the etiology of chronic inflammatory monoarthritis on long term follow-up. Sixty-five percent were still undiagnosed at 2 years but approximately 15% ended up with the diagnosis of spondyloarthropathy and 8% with rheumatoid arthritis.

Review questions

1. A 27 year old male with severe ankylosing spondylitis was involved in a minor car accident. He complains about neck pain but routine films demonstrate only changes of the spondylitis including ankylosis of multiple cervical segments. A likely cause of this patients neck pain is: (one best answer)
   1. Muscle strain from the accident.
   2. Flare of the ankylosing spondylitis from the trauma.
   3. Fracture through an ankylosed cervical disc space.
   4. Insufficiency fracture through a cervical vertebrae.
   5. Desire for large insurance settlement.
2. A 38 year old male comes to your office with a 3 week history of swelling and pain in the right ankle as well as several the toes of both feet. In addition, the left heel is very painful. Associated with these is a history of a urethral discharge and frequent loose stools. Diagnostic considerations include: (may be more than one right answer)
   1. Whipple's disease
   2. Reiter's syndrome
   3. HIV infection
   4. Inflammatory bowel disease
   5. Early rheumatoid arthritis
3. A 24 year old female comes to the office with a 3 month history of low back pain particularly bad in the morning and better with activity. There is tenderness over both sacroiliac joints. X-rays of the pelvis show a question of right sided sacroilitis. The next choice for diagnostic testing to evaluate the possibility of ankylosing spondylitis might be: (one best answer)
   1. HLA-B27 antigen
   2. Sedimentation rate
   3. CT scan of sacroiliac joints
   4. X-rays of the lumbar spine
   5. Repeat AP pelvis in 6 months
4. Radiographic features of ankylosing spondylitis include all of the following except: (one best answer)
   1. Syndesmophytes
   2. Facet joint fusion
   3. Reactive periostitis
   4. Disc space narrowing
   5. Sacroilitis

Surgery for arthritis at the University of Washington