The spondyloarthropathies (SpAs) are a family of related disorders that includes ankylosing spondylitis (AS), reactive arthritis (ReA; also known as Reiter syndrome [RS]), psoriatic arthritis (PsA), spondyloarthropathy associated with inflammatory bowel disease (IBD), undifferentiated spondyloarthropathy (USpA), and, possibly, Whipple disease and Behçet disease. Ankylosing spondylitis, which literally means “inflamed spine growing together,” is the prototypical spondyloarthropathy.
Ankylosing spondylitis has been designated by various names, including rheumatoid spondylitis in the American literature, spondyloarthrite rhizomegalique in the French literature, and the eponyms Marie-Strümpell disease and von Bechterew disease.
The spondyloarthropathies are linked by common genetics (human leukocyte antigen [HLA] class-I gene, HLA-B27) and a common pathology (enthesitis). Ankylosing spondylitis was the first disease to be linked with an HLA gene (1973).[1, 2, 3] The first documented ankylosing spondylitis case was reported in 1691, although it may have been present in ancient Egyptians.
The family of spondyloarthropathies is included in the image below.
The spondyloarthropathies are chronic inflammatory diseases that involve the sacroiliac joints, axial skeleton, and, to a lesser degree, peripheral joints and certain extra-articular organs, including the eyes, skin, and cardiovascular system. The etiology is unknown but involves the interaction of genetic and environmental factors.
The spondyloarthropathies are associated strongly with HLA-B27, an HLA class-I gene. Several genotypic subtypes of HLA-B27 are associated with the spondyloarthropathies, with HLA-B*2705 having the strongest association. HLA-B*2702, *2703, *2704, and *2707 are also associated with ankylosing spondylitis.HLA-B27 –restricted CD8+ (cytotoxic) T cells may play an important role in bacterial-related spondyloarthropathies such as reactive arthritis.
Table 1. Association of Spondyloarthropathies With HLA-B27 (Open Table in a new window)
|Population or Disease Entity||HLA-B27 –Positive|
|Healthy African Americans||4%|
|Ankylosing spondylitis (whites)||92%|
|Ankylosing spondylitis (African Americans)||50%|
|Psoriasis associated with spondylitis||60%|
|IBD associated with spondylitis||60%|
|Isolated acute anterior uveitis||50%|
The shared amino acid sequence between the antigen-binding region of HLA-B*2705 and nitrogenase from Klebsiella pneumoniae supports molecular mimicry as a possible mechanism for the induction of spondyloarthropathies in genetically susceptible hosts via an environmental stimulus, including bacteria in the gastrointestinal tract.
The primary pathology of the spondyloarthropathies is enthesitis with chronic inflammation, including CD4+ and CD8+ T lymphocytes and macrophages. Cytokines, particularly tumor necrosis factor-α (TNF-α) and transforming growth factor-β (TGF-β), are also important in the inflammatory process by leading to fibrosis and ossification at sites of enthesitis.
Animal models of spondyloarthropathy have been developed using transgenic technology. Transgenic rats expressing human HLA-B27 and β2 -microglobulin develop an illness similar to a spondyloarthropathy, with manifestations that include sacroiliitis, enthesitis, arthritis, skin and nail lesions, ocular inflammation, cardiac inflammation, and inflammation of the gastrointestinal and male genitourinary tracts. The severity of the clinical disease correlates with the number of copies of HLA-B27 expressed in the transgenic animal. HLA-B27 –positive transgenic rats that are raised in a germ-free environment do not develop clinical disease. Once introduced into a regular environment (ie, non–germ-free) and exposed to bacteria, the rats develop clinical manifestations of spondyloarthropathy, suggesting an important interaction between genetic and environmental factors.[10, 11]
The prevalence of ankylosing spondylitis is 0.1-0.2% overall but is higher in certain Native American populations and lower in African Americans.
Ankylosing spondylitis is the most prevalent of the classic spondyloarthropathies. Prevalence varies with the prevalence of the HLA-B27 gene, which increases with distance from the equator. Ankylosing spondylitis is more common in whites than in nonwhites. Prevalence is 0.1-1% of the general population,[12, 13, 14] with the highest prevalence in northern European countries and the lowest in sub-Saharan Africa.[5, 15] Approximately 1-2% of all people who are positive for HLA-B27 develop ankylosing spondylitis. This increases to 15-20% if they have a first-degree relative with ankylosing spondylitis.[16, 4] Prevalence data for undifferentiated spondyloarthropathy are scarce, although this disorder appears to be at least as common as ankylosing spondylitis, if not more so. Its actual prevalence may be as high as 1-2% of the general population.
The outcome in patients with spondyloarthropathies, including ankylosing spondylitis, is generally good compared with a disease such as rheumatoid arthritis. Some patients have few, if any, symptoms. A significant portion of patients develop chronic progressive disease and develop disability due to spinal inflammation leading to fusion, often with thoracic kyphosis or erosive disease involving peripheral joints, especially the hips and shoulders. Patients with spinal fusion are prone to spinal fractures that may result in neurologic deficits. Most functional loss in ankylosing spondylitis occurs during the first 10 years of illness.
In rare cases, patients with severe long-standing ankylosing spondylitis develop significant extra-articular manifestations such as cardiovascular disease, including cardiac conduction defects and aortic regurgitation; pulmonary fibrosis; neurologic sequelae (eg, cauda equina syndrome); or amyloidosis. Patients with severe long-standing ankylosing spondylitis have a greater risk of mortality than the general population.
Undifferentiated spondyloarthropathy appears to carry a good-to-excellent prognosis, although some patients have chronic symptoms associated with functional disability. Erosive arthritis is very uncommon. Uveitis occasionally occurs and may be recurrent or chronic. Patients who develop sacroiliitis and spondylitis, by definition, have ankylosing spondylitis.[18, 19]
The prevalence of ankylosing spondylitis parallels the prevalence of HLA-B27 in the general population. The prevalence of HLA-B27 and ankylosing spondylitis is higher in whites and certain Native Americans than in African Americans, Asians, and other nonwhite ethnic groups.[5, 20]
Undifferentiated spondyloarthropathy is not associated as strongly with HLA-B27, although it is more prevalent in whites than in nonwhite ethnic groups.
Ankylosing spondylitis, in general, is diagnosed more frequently in males. However, females may have milder or subclinical disease.
The male-to-female ratio of ankylosing spondylitis is 3:1.[16, 21]
The male-to-female ratio of undifferentiated spondyloarthropathy is 1:3.
The age of onset of ankylosing spondylitis is usually from the late teens to age 40 years. Approximately 10%-20% of all patients have onset of symptoms before age 16 years. Onset in persons older than 50 years is unusual, although diagnosis of mild or asymptomatic disease may be made at a later age.
There is often a significant delay in diagnosis, usually occurring several years after the onset of inflammatory rheumatic symptoms. In a study of German and Austrian patients with ankylosing spondylitis, the age of onset of disease symptoms was 25 years in HLA-B27 –positive and 28 years in HLA-B27 –negative patients, with a delay in diagnosis of 8.5 years in HLA-B27 –positive and 11.4 years in HLA-B27 –negative patients. In a study of Turkish patients with ankylosing spondylitis, the age of onset of disease symptoms was 23 years, with a delay in diagnosis of 5.3 years in HLA-B27 –positive patients and 9.2 years in HLA-B27 –negative patients. Patients with inflammatory back pain or a positive family history of ankylosing spondylitis had a shorter diagnostic delay.
Undifferentiated spondyloarthropathy is generally found in young to middle-aged adults but can develop from late childhood into the fifth decade of life.