THE SPONDYLARTHROPATHIES

ANKYLOSING SPONDYLITIS

Criteria for Diagnosis The criteria for diagnosing ankylosing spondylitis have been evolving in recent years. The New York criteria have limitations. A simpler approach defines ankylosing spondylitis as the presence of symptomatic sacroiliitis. A patient with back discomfort and radiologic evidence of sacroiliitis would be diagnosed as having ankylosing spondylitis.

Prevalence Once considered a rare disease, the illness is now known to have a prevalence comparable to that of rheumatoid arthritis. The distribution of ankylosing spondylitis follows the population frequency of HLA-B27 and is more common in whites than in blacks. Ankylosing spondylitis has often gone undiagnosed; inappropriate diagnostic procedures lead to erroneous diagnoses (i.e., mechanical back disease). Such patients often receive incorrect therapy. Although ankylosing spondylitis was formerly considered a predominantly male disease, several studies now suggest that there may be a more uniform sex distribution. Female patients are less frequently diagnosed, perhaps because physicians and radiologists may be reluctant to diagnose a disease that they consider to be rare in females. The disease may be milder in females and present with a greater number of peripheral joint manifestations. In the past, many women with ankylosing spondylitis were inappropriately diagnosed as having seronegative rheumatoid arthritis.

Clinical Presentation A history of several of the following five features is suggestive of inflammatory spinal disease: insidious onset of discomfort, age less than 40 years, persistence for more than three months, association with morning stiffness, and improvement with exercise. If this simple screening test is positive, radiologic evidence of sacroiliitis confirms ankylosing spondylitis. Many radiologists have been unfamiliar with rheurnatologic joint disease and have diagnosed ankylosing spondylitis only when there was evidence of major ankylosis of the sacroiliac joints and spine. Ankylosing spondylitis can be diagnosed, however, in the presence of only minimal sacroiliitis. What determines whether a patient will have only mild pelvic disease, ascending spinal disease, extraspinal articular disease, or extraarticular symptoms remains unknown. Presumably, phenotypic expression depends on numerous interrelating genes. Early change in the lumbar spine is manifested as squaring of the superior and inferior margins of the vertebral body. This phenomenon is caused by inflammatory disease at the site of insertion of the outer fibers of the anulus fibrosus (i.e., enthesopathy). Later changes result in the classic, though rare, bamboo spine. Comparable spinal changes are seen in primary ankylosing spondylitis and in the spondylitis associated with inflammatory bowel disease. In spondylitis associated with Reiter's syndrome and psoriatic arthropathy, however, the changes tend to be asymmetric and random. Radionuclide scans, computed tomography, and other advanced radiologic techniques are usually unnecessary. A simple anteroposterior radiograph suffices.

Physical Examination Examination of the spine may reveal muscle spasm and loss of the normal lordosis. The degree of restriction of forward flexion can be documented by measuring the distraction, on flexion, of two points-the lower point at the level of the lumbosacral junction and the upper point 10 cm above this level. In a normal individual, the distraction of this 10cm line is 5 to 12 cm, compared with 0 to 7 cm in an untreated spondylitis patient. Lateral spinal flexion is measured by the distraction, on contralateral flexion, of a 20-cm line drawn in the midaxillary plane. In this case, normal distraction varies from 5 to 12 cm, compared with 0 to 7 cm in spondylitis patients. Peripheral joint involvement, especially in the lower limb, occurs at some stage in approximately 20 to 30 per cent of cases; the frequency increases with the severity of the disease. Inflammatory disease of the hip and shoulder may produce progressive disability. Enthesopathic features include plantar fasciitis, costochondritis, and Achilles tendinitis.

Laboratory Findings HLA-B27 testing should not be used as a routine screening procedure; it is expensive and usually unnecessary. Other laboratory changes are less striking. Elevation of the erythrocyte sedimentation rate occurs in most patients but may be normal despite severe disease. Elevation of IgA levels and the presence of immune complexes suggest aberrant . munity. Serum creatine kinase and alkaline phosphatase activities may be elevated. Lymphocytes predominate in the synovial fluid, and synovial histologic findings are nonspecific.

Pathology The synovial lesions of ankylosing spondylitis and rheumatoid arthritis share identical histopathologic characteristics: intimal cell hyperplasia; a diffuse lymphocyte and plasma cell infiltrate; formation of lymphoid follicles; and plasma containing IgG, IgA, and IgM. IgM is found less frequently in ankylosing spondylitis than in rheumatoid disease. Synovitis per se, however, does not explain the propensity toward ligamentous ossification and widespread new bone formation observed in ankylosing spondylitis. Inflammation at the enthesis accounts for the unique pathology, or enthesopathy, of ankylosing spondylitis; new bone formation appears to be a specific reparative process occurring at the enthesopathic site. Complications of severe spinal disease include fractures and spondylodiskitis after minimal trauma.

Extraskeletal Involvement Extra-articular features include fatigue, weight loss, and low-grade fever. Cord compression resulting from spinal fractures or the cauda equina syndrome may cause neurologic symptoms. The negative effects of systemic involvement and of radiotherapy on the survival of patients with ankylosing spondylitis are well recognized.

EYE INVOLVEMENT. Uveitis develops in up to 25 per cent of patients during their illness. It occurs most often in HLA-1327-positive patients with peripheral joint disease but shows no correlation with the severity of the spondylitis. The visual episodes are usually self-limiting but may require local steroid therapy.

PULMONARY DISEASE. Patients with severe disease may exhibit chronic infiltrative and fibrotic changes in the upper lung fields that mimic tuberculosis. Pulmonary ventilation is usually well maintained by the diaphragm, despite the chest wall rigidity. The pulmonary fibrosis is occasionally clinically silent, but most affected patients present with cough, sputum, and dyspnea. Cyst formation and subsequent Aspergillus invasion may cause hemoptysis.

CARDIOVASCULAR DISEASE. Aortic incompetence, cardiornegaly, and persistent conduction defects occur in 3.5 to 10.0 per cent of patients with severe spondylitic disease. Cardiac involvement may be clinically silent or may dominate the clinical picture. Thickened aortic valve cusps and scar tissue in the root of the aorta represent the major histologic changes.

AMYLOIDOSIS. Amyloid deposition is an occasional complication of ankylosing spondylitis, particularly in Europe. KIDNEY. In contrast to patients with rheumatoid arthritis who may show renal impairment as an expression of disease, renal glomerular function is apparently unimpaired in ankylosing spondylitis, despite recognized pathologic changes. An IgA nephropathy, however, has been described in patients with seronegative spondylarthropathy.

Treatment and Prognosis Ankylosing spondylitis may be a mild or severe disease. We have recently shown that the younger the age at onset, the more severe the outcome. For example, in an analysis of 1500 cases, 15 per cent of those with onset between 15 and 16 years of age needed a total hip replacement within 15 years, compared to 10 per cent of those between 19 and 20 years and less than 1 per cent of patients with onset over 40 years of age (all cohorts followed for a similar period). Ankylosing spondylitis is a gratifying condition to recognize and treat early: Much can be accomplished toward ameliorating symptoms and, perhaps, preventing spinal deformity. The primary objectives are to relieve pain, decrease inflammation, begin remedial strengthening exercises, and maintain good posture and function. Anti-inflammatory agents relieve inflammation, pain, and spasm and permit patients to follow an adequate exercise program. There is some evidence that phenylbutazone decreases the rate of spinal fusion. Nevertheless, indomethacin is the drug of choice. Phenylbutazone, although more efficacious, may be more toxic. Indomethacin, started at a dosage of 25 mg three times a day, may be increased to a maximum of 150 mg daily. The dose should be titrated against response and side effects. Possible side effects include headache, vertigo, and depression, especially in older patients, and nausea, gastric discomfort, and diarrhea in all age groups. Phenylbutazone (100 mg t.i.d. or cl.i.d.) is remarkably effective but must be used with caution. Dangerous side effects include agranulocytosis and aplastic anemia. Agranulocytosis is an idiosyncratic response, developing chiefly in young individuals within three to six weeks of the start of therapy. Aplastic anemia appears to be dose-related and occurs primarily in individuals more than 60 years of age. Nonsteroidal anti-inflammatory drugs (NSAIDs) include ibuprofen, naproxen, fenoprofen, tolmetin, sulindac, meclofenamate sodium, and piroxicam. If indomethacin is efficacious but not tolerated, one of these NSAIDs may be given. In general, these agents play a minor role in the management of the spondylarthritides. Phenylbutazone should be tried when indomethacin is ineffective. Gold and penicillamine have no role to play, but sulfasalazine may be effective. Radiotherapy, once the treatment of choice, is no longer practiced in view of the high risk of inducing leukemia. The patient also needs remedial strengthening exercises and postural training. A firm mattress and small pillow are ideal when resting; attention to posture at work and at rest must be stressed. The best exercise regimen includes extension exercises and hydrotherapy; swimming is highly recommended. In those few patients who, despite optimal management, develop an irreversible deformity, wedge osteotomy may be indicated. For those with destructive arthropathy of the hip, arthroplasty is useful.

REITER'S SYNDROME

The most common cause of an inflammatory oligoarthropathy in a young male is Reiter's syndrome. This classic triad of urethritis, conjunctivitis, and arthritis represents the one chronic rheumatic disorder related to both a specific genetic background (HLA-B27) and a specific infection. Reiter's syndrome is often not self-limiting. Progressive disease may result in major disability. The disease may be defined as "an episode of arthropathy within one month of urethritis or cervicitis." Whether a dysenteric (epidemic) or a venereal (endemic) infection is the most common precipitating event is unclear. In young children, the former is the rule. In many cases, the distinction between urethritis as a precipitating factor and urethritis as an integral manifestation of the syndrome remains unclear. In postvenereal Reiter's syndrome both Chlamydia and Mycoplasma have been implicated. In a patient with a specific predisposing genetic background, a variety of different organisms may be responsible.

Prevalence Reiter's syndrome develops in at least 1 per cent of patients with nonspecific urethritis. Shigella dysentery is followed by Reiter's syndrome in 1 to 2 per cent of cases (i.e., 20 per cent of B27-positive patients). The sex distribution of Reiter's syndrome is difficult to define because the syndrome is diagnosed only with difficulty in females, in whom urethritis is often clinically inapparent. Formes frustes of the syndrome are now being recognized. A woman presenting with uveitis and an inflammatory arthropathy of the knee in association with the HLA-1327 antigen may have Reiter's syndrome. Similarly, the disorder is difficult to recognize in children; a diagnosis is usually made only if an epidemic of dysentery is present and Reiter's syndrome has been recognized in other family members. Postclysenteric Reiter's syndrome almost certainly has an equal sex distribution.

Clinical Picture Reiter's syndrome should be considered a symptom complex rather than the association of three specific features. The syndrome may present as a tetrad (i.e., with the addition of buccal ulceration or balanitis to the classic triad); alternatively, only two of the three cardinal features may be present. Several of the classic features may appear insignificant and be overlooked. For example, the urethritis may be mild, perhaps forgotten; the discharge may be minimal and remembered by the patient only after direct questioning. Balanitis may not be evident unless the prepuce is retracted and the glans penis closely inspected. Buccal ulceration is usually painless and apparent only after close inspection. A red eye may be forgotten or considered irrelevant, and the various skin lesions typified by keratoderma blennorrhagicurn may be misdiagnosed. Rheumatologic features include arthralgias, tenosynovitic episodes, plantar fasciitis, and other enthesopathies, as well as frank arthritis. The typical sausage-shaped digit is a frequent occurrence related to the disorder's enthesopathic nature. Some 20 per cent of patients with Reiter's syndrome develop sacroiliitis and ascending spinal disease. Other radiologic evidence of Reiter's syndrome includes plantar spurs and periosteal new bone formation. Cardiac complications similar to those in ankylosing spondylitis occur late in Reiter's syndrome. The hyperkeratotic skin lesions seen in Reiter's syndrome cannot be distinguished from those in psoriasis. Formerly considered a self-limited process, Reiter's syndrome is now known to be a more or less persistent disease in many patients. About 80 per cent of patients have evidence of disease activity when they are re-examined after a five-year period.

Laboratory Evaluation It is unclear whether the presence of HLA-1327 correlates with increased severity of Reiter's syndrome. A patient with severe Reiter's syndrome may have an erythrocyte sedimena on rate in the normal range or one as high as 100 mm per hour or more. Synovial fluid analysis is rarely diagnostic, apart from the fact that it reveals a relatively high complement level (reflecting a nonspecific inflammatory reaction), rather than the low level seen in rheumatoid arthritis (reflecting immune complex disease). Occasionally, the diagnoses of ankylosing spondylitis and Reiter's syndrome may prove difficult to disentangle. Some patients who are diagnosed as having ankylosing spondylitis may have presented originally with Reiter's syndrome, but the episodes of urethritis have subsequently been forgotten by the physician and patient. Similarly, patients diagnosed as having Reiter's syndrome may actually have ankylosing spondylitis with peripheral joint disease and a chance occurrence of urethritis.

Management There is no cure for Reiter's syndrome. The patient's feelings of guilt and anxiety about sexual misconduct must be allayed. Although anecdotal evidence suggests that individuals with postvenereal Reiter's syndrome may develop a relapse following sexual activity, many individuals have spontaneous exacerbations. An explanation of allergic response may help the patient: Asthma may develop on exposure to a known or unknown allergen in sensitive individuals; in the same way, Reiter's syndrome may flare up following an unknown allergic event. Symptomatic management includes the use of indomethacin, phenylbutazone, or other NSAIDs. Antibiotic therapy is too late and unnecessary. Patients with severe recurrent uveitis may require steroid eye drops or subconjunctival preparations. The syndrome may remit, recur, or continue unabated despite steroid or even cytotoxic therapy. For patients with progressive disease, azathioprine or methotrexate is effective.

THE REACTIVE ARTHROPATHIES Reactive arthropathy refers to an inflammatory arthritis that follows an infection in which there is no microbial invasion of the synovial space. The B27-linked arthropathies following Shigella, Salmonella, Yersinia, and Campylobacterjejuni infections are in this group. Why some patients develop only an arthropathy whereas others have the full spectrum of Reiter's disease after exposure to one of these agents is unknown. Yersinia Infection Yersinia enterocolitica infection may produce the following: fever, mild gastrointestinal illness, and, after a latent period, polyarthropathy and erythema nodosum, especially in B27positive individuals. The symptom complex may mimic acute rheumatic fever. The arthropathy may last for weeks or months, and in HLA-1327-positive individuals, sacroiliitis may occur.

Salmonellosis An arthropathy associated with Salmonella infection mimics that caused by Yersinia. Treatment of these disorders is the same as that of Reiter's syndrome.

JUVENILE CHRONIC ARTHROPATHY

Chronic arthritis in a child or teenager often persists into adulthood; therefore, an awareness of juvenile chronic arthropathy is relevant when attending adult patients. Until recently, the term juvenile rheumatoid arthritis was used, inappropriately, to describe all forms of childhood arthritis. As in adults, arthritis in children may be associated with psoriasis, inflammatory bowel disease, and other conditions. The acute systemic form, Still's disease, presents with fever, rash, and toxicity in young children who are negative for B27 and rheumatoid factor (IgM-anti-IgG). Still's disease is also recognized in adults. Another subset (in the spondylarthropathy group) consists largely of adolescent males who predominantly exhibit oligoarthropathy affecting the large joints of the lower limbs: Such individuals are frequently positive for HLA-1327. This group may develop sacroiliitis or ankylosing spondylitis; the presence of B27 is associated with spinal disease involvement. Another group includes B27-negative individuals (usually females less than five years of age) presenting with an oligoarthropathy characterized by a positive fluorescent antinuclear antibody (FANA) test. These subjects are at risk for developing asymptornatic chronic iridocyclitis, in contrast with FANA-negative and 1327-positive patients, who develop clinically obvious acute uveitis. A few older children (preponderantly females) develop a seropositive, nodular, and erosive disease that resembles adult rheumatoid arthritis. A 1327-related syndrome known as seronegative enthesopathy and arthropathy (SEA syndrome) is now also recognized in children.

THE ENTEROPATHIC ARTHROPATHIES

Two major clinical patterns of arthopathy associated with inflammatory bowel disease (ulcerative colitis and Crohn's disease) are peripheral arthropathy and spondylarthropathy.

Peripheral Arthropathy Approximately 20 per cent of individuals with severe Crohn's disease or ulcerative colitis develop an acute migratory inflammatory polyarthritis, often of abrupt onset and involving the larger joints of the lower extremities. The arthritis resolves in weeks or months. Arthritis flare-ups usually parallel exacerbations of the underlying disorder. The pathogenesis of the joint complication is unknown. B27 antigen is not present. Treatment is directed at the primary disorder and is more effective in ulcerative colitis than in Crohn's disease.

Spondylarthropathy About one patient in five with inflammatory bowel disease develops sacroiliitis and, occasionally, severe ankylosing spondylitis. The spinal disease may precede the bowel disease or follow it. There is no correlation between the severity of the bowel disorder and the spondylitis, which mimics primary ankylosing spondylitis rather than the spondylitis associated with psoriasis or Reiter's syndrome. Therapy is the same as for classic ankylosing spondylitis. Despite the bowel disease, the NSAIDs are usually well tolerated. About 50 per cent of individuals with both inflammatory bowel disease and ankylosing spondylitis are B27-positive, a percentage lower than that found in patients with primary ankylosing spondylitis. A post-intestinal-bypass syndrome consisting of arthropathy and occasionally dermatitis is well recognized. Immune alterations have been described in these patients, and B27 is occasionally associated with this syndrome.

PSORIATIC ARTHROPATHY Different subsets of psoriatic arthropathy are recognized, several forms of which appear to be enthesopathic rather than purely synovitic. Uveitis, sacroiliitis, and ascending spinal disease occur in up to 20 per cent of cases. Patients are seronegative for rheumatoid factor and exhibit sausage digits and characteristic radiologic changes. The disease may be markedly destructive. Psoriasis itself is a genetically determined disease, associated with HLA-1313, HLA-Bw17, and HLA-Cw6. Moreover, HLA-1327 is present in approximately 20 per cent of individuals with psoriatic arthropathy even in the absence of sacroiliitis. HLA-Bw38, HLA-DR4, and HLA-DR7 appear to be genetic markers for patients with peripheral arthropathy. About 50 per cent of psoriatic spondylitis patients are B27-negative; thus, as with inflammatory bowel disease, other genetic or environmental factors are relevant. Psoriatic arthropathy is a common disease, occurring in about 20 per cent of individuals with psoriasis, particularly in those patients with psoriatic nail disease. Women are affected only slightly more commonly than men, in contrast to the more marked sex distribution in rheumatoid disease. Several forms of psoriatic arthropathy, separated by indistinct boundaries, have been described.

1. Asymmetric oligoarthropathy. In general, there is little relationship between joint and skin activity. Patients with this common form of psoriatic arthropathy remain seronegative for rheumatoid factor. Asymmetric involvement of both large and small joints is seen; the sausage-shaped digit is common. A disparity is often observed between the clinical appearance and subjective symptoms. Any patient presenting with this form of arthropathy should be carefully examined for signs of psoriasis (scalp, umbilicus, gluteal region, and nails). In the past; many such individuals were considered to have seronegative rheumatoid arthritis.

2. Symmetric polyarthropathy resembling rheumatoid arthritis. Rarely, the pattern of arthritis may be indistinguishable from that seen in rheumatoid disease. This form may represent coincidental rheumatoid arthritis in a patient with psoriasis.

3. Arthritis mutilans. A resorptive arthropathy, arthritis mutilans is the severest form of destructive arthritis. The telescoping digits appear as the so-called opera-glass hand.

4. Psoriatic spondylitis. Approximately 20 per cent of subjects with psoriatic arthropathy have radiologic sacroiliitis (ankylosing spondylitis).

5. Psoriatic nail disease and distal interphalangeal joint involvement. Nail pitting, transverse depressions, and subungual hyperkeratosis often occur in association with dista interphalangeal joint disease. The relationship between the psoriasis and the arthritis remains unclear.

Laboratory Features An elevated erythrocyte sedimentation rate, anemia, and rarely, hyperuricernia may occur. The frequency of positive tests for rheumatoid factor is the same as that found in the general population. The synovial tissue and fluid changes are nonspecific.

Radiologic Findings Characteristic changes in this sometimes highly destructive disease include whittling of the distal ends of the phalanges, giving the joints a "pencil-and-cup" appearance; extensive bone resorption can result in an opera-glass hand. Erosions, ankylosis, periostitis, sacroiliitis, and ankylosing spondylitis are other typical radiologic findings.

Therapy The skin and joints are treated separately. Improvement of the skin disease may be associated with amelioration of the joint inflammation. For mild arthropathy, indomethacin (25 to 50 mg t.i.d.) is the drug of choice. If this fails, phenylbutazone may be given. Gold and penicillamine may be useful, but few controlled studies have been done. Methotrexate is helpful in resistant cases.