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Seronegative spondyloarthropathies share certain clinical characteristics (eg, back pain, uveitis, GI symptoms, rashes). Some are strongly associated with the HLA-B27 allele. Clinical and genetic similarities suggest that they also share similar causes or pathophysiologies. Rheumatoid factor (RF) is negative in the spondyloarthropathies (hence, why they are called seronegative spondyloarthropathies). They include ankylosing spondylitis, reactive arthritis, psoriatic arthritis, and other disorders.
Ankylosing Spondylitis
Ankylosing spondylitis (AS) is a systemic disorder characterized by inflammation of the axial skeleton, large peripheral joints, and digits; nocturnal back pain; back stiffness; accentuated kyphosis; constitutional symptoms; aortitis; cardiac conduction abnormalities; and anterior uveitis. Diagnosis requires showing sacroiliitis on x-ray. Treatment is with NSAIDs or tumor necrosis factor antagonists and physical measures that maintain joint flexibility.
AS is 3 times more frequent in men than in women and begins most often between ages 20 and 40. It is 10 to 20 times more common among 1st-degree relatives of AS patients than in the general population. The risk of AS in 1st-degree relatives with the HLA-B27 allele is about 20%. Increased prevalence of HLA-B27 in whites or HLA-B7 in blacks supports a genetic predisposition. However, the concordance rate in identical twins is only about 50%, suggesting that environmental factors contribute. The pathophysiology probably involves immune-mediated inflammation.
Symptoms and Signs
The most frequent manifestation is back pain, but disease can begin in peripheral joints, especially in children and women, and rarely with acute iridocyclitis (iritis or anterior uveitis). Other early symptoms and signs are diminished chest expansion from diffuse costovertebral involvement, low-grade fever, fatigue, anorexia, weight loss, and anemia.
Back pain—often nocturnal and of varying intensity—eventually becomes recurrent. Morning stiffness, typically relieved by activity, and paraspinal muscle spasm develop. A flexed or bent-over posture eases back pain and paraspinal muscle spasm; thus, kyphosis is common in untreated patients. Severe hip arthritis can eventually develop. In late stages, the patient has accentuated kyphosis, loss of lumbar lordosis, and fixed bent-forward posturing, with compromised pulmonary function and inability to lie flat. There may be peripheral potentially deforming joint involvement, sometimes involving the digits (dactylitis). Achilles tendinitis can occur.
Systemic manifestations occur in one third of patients. Recurrent, acute anterior uveitis is common but usually self-limited; uncommonly it becomes protracted and severe enough to impair vision. Neurologic signs occasionally result from compression radiculitis or sciatica, vertebral fracture or subluxation, or cauda equina syndrome (see Spinal Cord Disorders: Symptoms and Signs). Cardiovascular manifestations can include aortic insufficiency, aortitis, angina, pericarditis, and cardiac conduction abnormalities (which may be asymptomatic). Dyspnea, cough, or hemoptysis can result from nontuberculous fibrosis or cavitation of an upper lobe of the lung; secondary infection with Aspergillus can develop. Rarely, AS results in secondary amyloidosis. Subcutaneous nodules do not develop.
Diagnosis
AS should be suspected in patients, particularly young men, with nocturnal back pain and kyphosis, diminished chest expansion, Achilles tendinitis, or unexplained anterior uveitis. A 1st-degree relative with AS should heighten suspicion. Patients should generally be tested with ESR, C-reactive protein, and CBC. IgM, RF, and antinuclear antibodies are needed only if peripheral arthritis suggests other diagnoses. No laboratory test is diagnostic, but results can increase suspicion for the disorder or rule out other disorders than can simulate AS. If, after these tests, AS is still suspected, patients should undergo imaging of the lumbosacral spine; demonstration of sacroiliitis on x-ray strongly supports the diagnosis.
Alternatively, AS can be diagnosed by the modified New York criteria. Using these criteria, the patient must have imaging study evidence of sacroiliitis and one of the following:
Historical features that distinguish inflammatory back pain from noninflammatory back pain include onset at ≤ 40 yr, gradual onset, morning stiffness, improvement with activity, and duration ≥ 3 mo before seeking medical attention.
ESR and other acute-phase reactants (eg, C-reactive protein) are inconsistently elevated in patients with active AS. Tests for RF and antinuclear antibodies are negative. The HLA-B27 genetic marker is not of diagnostic value.
The earliest x‑ray abnormalities are pseudowidening from subchondral erosions, followed by sclerosis or later narrowing and eventually fusion in the sacroiliac joints. Changes are symmetric. Early changes in the spine are upper lumbar vertebral squaring with sclerosis at the corners; spotty ligamentous calcification; and one or two evolving syndesmophytes. Late changes result in a “bamboo spine” appearance, resulting from prominent syndesmophytes, diffuse paraspinal ligamentous calcification, and osteoporosis; these changes develop in some patients on average over 10 yr.
Changes typical of AS may not become visible on plain x‑rays for years. CT and MRI show changes earlier, but there is no consensus regarding their role in routine diagnosis.
A herniated intervertebral disk can cause back pain and radiculopathy similar to AS, but the pain is limited to the spine, usually causes more sudden symptoms, and causes no systemic manifestations or laboratory test abnormalities. If necessary, CT or MRI can differentiate it from AS. Involvement of a single sacroiliac joint suggests a different spondyloarthropathy, possibly infection. Tuberculous spondylitis can simulate AS (see Mycobacteria: TB of bones and joints).
Diffuse idiopathic skeletal hyperostosis (DISH) occurs primarily in men > 50 yr and may resemble AS clinically and on x-ray. Patients uncommonly have spinal pain, stiffness, and insidious loss of motion. X-ray findings in DISH include large ossifications anterior to spinal ligaments (the calcification appears as if someone poured candle wax in front and on the sides of the vertebrae), bridging several vertebrae and usually starting at the lower thoracic spine, eventually affecting the cervical and lumbar spine. There is often subperiosteal bone growth along the pelvic brim and at insertion of tendons (such as the Achilles tendon insertion). However, the anterior spinal ligament is intact and frequently bulging, and sacroiliac and spinal apophyseal joints are not eroded. Additional differentiating features are stiffness that is not accentuated in the morning and a normal ESR.
Prognosis
AS is characterized by mild or moderate flares of active inflammation alternating with periods of little or no inflammation. Proper treatment in most patients results in minimal or no disability and in a full, productive life despite back stiffness. Occasionally, the course is severe and progressive, resulting in pronounced incapacitating deformities.
Treatment
The goals of treatment are relieving pain, maintaining joint range of motion, and preventing end-organ damage. Because the condition may cause lung fibrosis, cigarette smoking is discouraged.
NSAIDs reduce pain and suppress joint inflammation and muscle spasm, thereby increasing range of motion, which facilitates exercise and prevents contractures. Most NSAIDs work in AS, and tolerance and toxicity dictate drug choice. The daily dose of NSAIDs should be as low as possible, but maximum doses may be needed with active disease. Drug withdrawal should be attempted only slowly, after systemic and joint signs of active disease have been suppressed for several months.
Sulfasalazine may help reduce peripheral joint symptoms and laboratory markers of inflammation. Dosage should be started at 500 mg/day and increased by 500 mg/day at 1-wk intervals to 1 to 1.5 g bid maintenance. Peripheral joint symptoms may also abate with methotrexate (see Joint Disorders: Traditional DMARDs). Systemic corticosteroids, immunosuppressants, and most disease-modifying antirheumatic drugs have no proven benefit and should generally not be used. TNF-α antagonists (eg, etanercept, infliximab, adalimumab) are effective treatments for inflammatory back pain.
For proper posture and joint motion, daily exercise and other supportive measures (eg, postural training, therapeutic exercise) are vital to strengthen muscle groups that oppose the direction of potential deformities (ie, the extensor rather than flexor muscles). Reading while lying prone and pushing up on the elbows or pillows and thus extending the back may help keep the back flexible. Because chest wall motion can be restricted, which impairs lung function, cigarette smoking, which also impairs lung function, is strongly discouraged.
Intra-articular depot corticosteroids may be beneficial, particularly when one or two peripheral joints are more severely inflamed than others, thereby compromising exercise and rehabilitation. They may also help if systemic drugs are ineffective. Corticosteroids injected into the sacroiliac joints may occasionally help severe sacroiliitis.
For acute uveitis, topical corticosteroids and mydriatics are usually adequate. If severe hip arthritis develops, total hip arthroplasty may lessen pain and improve flexibility dramatically.
Reactive Arthritis
Reactive arthritis is an acute spondyloarthropathy that often seems precipitated by an infection, usually GU or GI. Common manifestations include asymmetric arthritis of variable severity that tends to affect the lower extremities, sausage-shaped deformities of fingers or toes or both, constitutional symptoms, enthesitis, tendinitis, and mucocutaneous ulcers, including hyperkeratotic or crusted vesicular lesions (keratoderma blennorrhagicum). Diagnosis is clinical. Treatment involves NSAIDs and sometimes sulfasalazine or immunosuppressants.
Spondyloarthropathy associated with urethritis or cervicitis, conjunctivitis, and mucocutaneous lesions (previously called Reiter's syndrome) is one type of reactive arthritis.
Etiology
Two forms of reactive arthritis are common: sexually transmitted and dysenteric. The sexually transmitted form occurs primarily in men aged 20 to 40. Genital infections with Chlamydia trachomatis are most often implicated. Men or women can acquire the dysenteric form after enteric infections, primarily Shigella, Salmonella, Yersinia, or Campylobacter. Reactive arthritis probably results from joint infection or postinfectious inflammation. Although there is evidence of microbial antigens in the synovium, organisms cannot be cultured from joint fluid.
Epidemiology
The prevalence of the HLA-B27 allele in patients is 63 to 96% vs 6 to 15% in healthy white controls, thus supporting a genetic predisposition.
Symptoms and Signs
Reactive arthritis can range from transient monarticular arthritis to a severe, multisystem disorder. Constitutional symptoms may include fever, fatigue, and weight loss. Arthritis may be mild or severe. Joint involvement is generally asymmetric and oligoarticular or polyarticular, occurring predominantly in the large joints of the lower extremities and in the toes. Back pain may occur, usually with severe disease. Enthesopathy (inflammation at tendinous insertion into bone—eg, plantar fasciitis, digital periostitis, Achilles tendinitis) is common and characteristic. Mucocutaneous lesions—small, transient, relatively painless, superficial ulcers—commonly occur on the oral mucosa, tongue, and glans penis (balanitis circinata). Particularly characteristic are vesicles (sometimes identical to pustular psoriasis) of the palms and soles and around the nails that become hyperkeratotic and form crusts (keratoderma blennorrhagicum). Rarely, cardiovascular complications (eg, aortitis, aortic insufficiency, cardiac conduction defects), pleuritis, and CNS or peripheral nervous system symptoms develop.
Urethritis may develop 7 to 14 days after sexual contact (or occasionally after dysentery); low-grade fever, conjunctivitis, and arthritis develop over the next few weeks. Not all features may occur, so incomplete forms need to be considered. In men, the urethritis is less painful and productive of purulent discharge than acute gonococcal urethritis and may be associated with hemorrhagic cystitis or prostatitis. In women, urethritis and cervicitis may be mild (with dysuria or slight vaginal discharge) or asymptomatic. Conjunctivitis is the most common eye lesion. It usually causes eye redness and grittiness, but keratitis and anterior uveitis can develop also, causing eye pain, photophobia, and tearing.
Diagnosis
Reactive arthritis should be suspected in patients with acute, asymmetric arthritis affecting the large joints of the lower extremities or toes, particularly if there is tendinitis or a history of an antecedent diarrhea or dysuria. Diagnosis is ultimately clinical and requires the typical peripheral arthritis with symptoms of GU or GI infection or one of the other extra-articular features. Because these features may manifest at different times, definitive diagnosis may require several months. Serum and synovial fluid complement levels are high, but these findings are not usually diagnostic and need not be measured.
Disseminated gonococcal infection can closely simulate reactive arthritis (see Sexually Transmitted Diseases (STDs): Symptoms and Signs). Arthrocentesis may fail to differentiate them, owing to inflammatory characteristics of synovial fluid in both disorders and the difficulty of culturing gonococci from this fluid. Clinical characteristics may help; disseminated gonococcal infection tends to involve upper and lower extremities equally, be more migratory, and not produce back pain, and vesicles tend not to be hyperkeratotic. A positive gonococcal culture from blood or skin lesions helps differentiate the two disorders, but a positive culture from the urethra or cervix does not. If differentiation is still difficult, ceftriaxone may be required for simultaneous diagnosis and treatment.
Psoriatic arthritis can simulate reactive arthritis, causing similar skin lesions, uveitis, and asymmetric arthritis. However, psoriatic arthritis often affects mostly the upper extremities and especially the distal interphalangeal joints, may be abrupt in onset but may also develop gradually, causes less enthesopathy, and tends not to cause mouth ulcers or symptoms of GU or GI infection.
Prognosis
Reactive arthritis often resolves in 3 to 4 mo, but up to 50% of patients experience recurrent or prolonged symptoms over several years. Joint, spinal, or sacroiliac inflammation or deformity may occur with chronic or recurrent disease. Some patients are disabled.
Treatment
NSAIDs (eg, indomethacin 25 to 50 mg po tid) usually help relieve symptoms. If induced by infection with C. trachomatis, doxycycline 100 mg po bid for up to 3 mo may accelerate recovery, but this is controversial. Sulfasalazine as used to treat RA may also be helpful (see Joint Disorders: Traditional DMARDs). If symptoms are severe despite NSAIDs and sulfasalazine, azathioprine or methotrexate may be considered. Systemic corticosteroids have no proven value.
Local injection of depot corticosteroids for enthesopathy or resistant oligoarthritis may relieve symptoms. Physical therapy aimed at maintaining joint mobility is helpful during the recovery phase. Anterior uveitis is treated as usual, with corticosteroid and mydriatic eye drops to prevent scarring. Conjunctivitis and mucocutaneous lesions require only symptomatic treatment.
Psoriatic Arthritis
Psoriatic arthritis is a chronic inflammatory arthritis that occurs in people with psoriasis of the skin or nails. The arthritis is often asymmetric, and some forms involve the distal interphalangeal joints. Diagnosis is clinical. Treatment is usually similar to that of RA but can also involve phototherapy.
Psoriatic arthritis develops in 5 to 40% of patients with psoriasis. Prevalence is increased in patients with AIDS. Risk of some involvement is increased in patients with HLA-B27 or some other specific alleles and in family members. Etiology and pathophysiology are unknown.
Symptoms and Signs
Psoriasis of the skin or nails may precede or follow joint involvement. Skin lesions may be hidden in the scalp, gluteal folds, or umbilicus and go unrecognized by the patient.
The distal interphalangeal (DIP) joints of fingers and toes are especially affected. Asymmetric involvement of large and small joints, including the sacroiliacs and spine, is common. Joint and skin symptoms may lessen or worsen simultaneously. Inflammation of the fingers, toes, or both may lead to sausage-shaped deformities. Rheumatoid nodules are absent. Arthritic remissions tend to be more frequent, rapid, and complete than in RA, but progression to chronic arthritis and crippling may occur. There may be arthritis mutilans (destruction of multiple hand joints with telescoping of the digits).
Back pain may be present. It is often accompanied by asymmetric syndesmophytes of the spine.
Diagnosis
Psoriatic arthritis should be suspected in patients with both psoriasis and arthritis. Because psoriasis may be overlooked or hidden or develop only after arthritis occurs, psoriatic arthritis should be considered in any patient with seronegative inflammatory arthritis; these patients should be examined for psoriasis and nail pitting and should be questioned about a family history of psoriasis. Patients suspected of having psoriatic arthritis should be tested for rheumatoid factor, which can coexist. Psoriatic arthritis is diagnosed clinically and by excluding other disorders that can cause such similar manifestations. X-ray findings common in psoriatic arthritis include DIP involvement; resorption of terminal phalanges; arthritis mutilans; and extensive destruction, proliferative bone reaction, and dislocation of large and small joints.
Treatment
Treatment is directed at control of skin lesions (see Psoriasis and Scaling Diseases: Treatment) and at joint inflammation. Drug therapy is similar to that for RA, particularly methotrexate. Hydroxychloroquine is inconsistently of benefit and may cause exfoliative dermatitis or aggravate underlying psoriasis. Benefit may be gained from NSAIDs, cyclosporine, and TNF antagonists (see Joint Disorders: Drugs for RA under Drugs for RA); TNF antagonists have been particularly effective.
Phototherapy using long-wave psoralen plus ultraviolet A (PUVA) combined with oral methoxsalen 600 µg/kg po 2 h before PUVA twice/wk seems to be highly effective for psoriatic lesions and somewhat effective for peripheral arthritis, but not for spine involvement.
Other Spondyloarthropathies
Spondyloarthropathy can develop in association with GI conditions (sometimes called enteropathic arthritis) such as inflammatory bowel disease, intestinal bypass surgery, or Whipple's disease.
Juvenile-onset spondyloarthropathy is an asymmetric, mostly lower extremity spondyloarthropathy that begins most commonly in boys aged 7 to 16.
Spondyloarthropathy can also develop in people without characteristics of other specific spondyloarthropathy (undifferentiated spondyloarthropathy). Treatment of the arthritis of these other spondyloarthropathies is similar to that of treatment of reactive arthritis (see Joint Disorders: Prognosis).
Last full review/revision February 2008 by Roy D. Altman, MD
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