Seronegative Spondyloarthropathy: Epidemiology, Etiology, Pathogenesis, Clinical Features, Treatment, Animal Models

SERONEGATIVE SPONDYLOARTHROPATHY

Introduction and Epidemiology

Ankylosing spondylitis (AS) and related spondyloarthropathies are characterized by sacroiliitis and inflammation of the intervertebral discs in the lumbar spine, as well as an enthesitis at sites of ligamentous insertions into bone. Patients with AS develop calcification of the ligamentous insertions, back stiffness, and pain. The immunologic basis of the specific loca-tions of inflammation in this disorder is not understood, but a strong association of the disease with particular HLA alleles, particularly HLA-B27, suggests a possible role for antigen presentation to T cells in the immunopathogenesis. The prevalence of AS closely parallels the frequency of HLA-B27. Among whites, the estimated prevalence rate of AS is 197 per 100,000 in the United States. AS, in general, is diag-nosed more frequently in males. Females, however, may have milder or subclinical disease. AS is more common in males with a male to female ratio of 3:1. The age of onset of AS is usually from the late teens to age 40.

Etiology and Pathogenesis

The exact etiology of AS is unclear. The strong association with most subtypes of HLA-B27 supports the hypothesis that the disease is due to a genetically determined immune response to environmental fac-tors in susceptible individuals. HLA-B27 is present in 80 to 98 percent of white patients with AS, in contrast to only about 8 percent of the general population. The arthritogenic peptide hypothesis postulates that AS results when external antigenic challenge activates autoreactive T cells that recognize

endogenous peptides presented by HLA-B27. In normal situations, the HLA-B27 molecule on the surface of the antigen-presenting cells presents endogenously derived peptides to CD8+ T cells. These peptides, which are usually nine amino acids long and have arginine in position 2, are mostly self-derived, but they may also be of viral or bacterial origin. Recent studies also suggest that the intracellu-lar handling of molecular complexes that include HLA-B27 molecules may activate an inflammatory stress response and con-tribute to disease.

Clinical Features

Back pain is the most common symptom and the first manifestation in approxi-mately 75 percent of patients with AS. The inflammatory back pain of AS has particular features that differentiate it from mechanical back pain. These include insidious onset of the pain occurring over months or years, generally with at least three months of symptoms before presenta-tion. Symptoms include morning stiffness lasting at least thirty minutes, improve-ment of symptoms with moderate physical activity, and diffuse nonspecific radiation of pain into both buttocks. Patients often experience stiffness and pain that awakens them in the early morning hours, a dis-tinctive symptom not generally found in patients with mechanical back pain. Ten-derness at tendon insertion points due to enthesitis, an inflammatory reaction, is a common complaint. Typical tender sites include the costosternal junctions, spinous processes, iliac crests, greater trochan-ters, ischial tuberosities, tibial tubercles, or heels (Achilles tendinitis or plantar fasciitis). AS is also characterized by a number of extra-articular manifestations

including uveitis, occurring in 25–35 per-cent of patients during the course of the disease. Manifestations of cardiac involve-ment include ascending aortitis, aortic valve incompetence, conduction abnor-malities, cardiomegaly, and pericarditis. In rare situations, aortitis may precede other features of AS. Aortic incompetence was noted in 3.5 percent of patients who had the disease for fifteen years and in 10 percent after thirty years. Cardiac conduc-tion disturbances are seen with increasing frequency with the passage of time, occur-ring in 2.7 percent of those with disease of fifteen years’ duration and in 8.5 percent after thirty years.

Treatment of Ankylosing Spondylitis

AS is a relatively mild disease for most patients with a good functional prognosis. The majority of patients do not experience significant extraskeletal manifestations, except for acute anterior uveitis. Usu-ally, the eye disease can be well managed with eye drops containing corticosteroids to reduce inflammation and with pupil-dilating, atropine-like agents to prevent or diminish synechiae. The objectives for treatment of AS are to relieve pain, stiff-ness, and fatigue and to maintain good pos-ture and good physical and psychosocial functioning. Physiotherapy provided as exercises is effective in improving thoraco-lumbar mobility and fitness, at least in the short term (up to one year). Until recently, no drug had been shown to significantly influence the course of spinal disease and retard the process of ossification in AS. Similarly, there was no evidence to suggest that any of the conventional DMARDs, including sulfasalazine and methotrexate, altered or inhibited the inflammation seen in the spine and entheses in AS. Recently,

the introduction of anti-TNF agents in the treatment of AS can be regarded as a defi-nite advantage in the therapy of this dis-ease. Both infliximab and etancercept have been shown to improve signs and symp-toms of disease. Continuous treatment is necessary in most patients. More than two-thirds of the patients stay on therapy after one year. Guidelines for the use of anti-TNF therapies have recently been devel-oped. The new therapeutic modalities identify important clinical questions to be answered by further research. Clearly, inf-liximab and etanercept have disease-modi-fying properties, but their long-term safety and disease-controlling effects in terms of improvement or maintenance of func-tion, as well as the prevention of structural damage, still have to be demonstrated.

Animal Models of Seronegative Spondyloarthropathy

HLA-B27 transgenic rats and strains of HLA-B27 transgenic Î²2-microglobulin-deficient mice develop a multisystem inflammatory disease affecting the joints, skin, and bowel with strong similarity to human spondyloarthritis. This model supports a direct mechanistic role for that MHC product in the disease, although the details of that mechanism have not been elucidated.

As is the case for other autoimmune rheumatic diseases, antigen-induced murine models are proving useful in study of AS. Aggrecan and versican are large pro-teoglycan molecules that are present in the intervertebral disc and hyaline cartilages of the sacroiliac joint, as well as in entheses. Versican is generally absent from cartilage tissue except in the sacroiliac joint but is concentrated in ligaments and the annulus of the intervertebral disc. Immunization of BALB/c mice with versican results in an AS-like pathology, including sacroi-liitis, enthesitis, and discitis. Those mice develop an ankylosis of the spine similar to that seen in AS. It has also been noted that immunity to versican can induce uveitis, a clinical feature of the human disease.