1. The Seronegative Spondyloarthropathies
The seronegative spondyloarthropathies refer to a group of chronic inflammatory arthritides that share histological features with rheumatoid arthritis and Lyme arthritis yet have some unique clinical features. The four major spondyloarthropathies include ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease related arthritis, and reactive arthritis (sometimes called Reiter’s syndrome). The seronegative spondyloarthropathies are associated with the presence of the class I marker HLA B27, the absence of rheumatoid factor (hence the term seronegative), various extrarticular manifestations (uveitis, rash, oral ulcers, etc.), inflammation of the enthesis (tendon or ligament insertion sites such as the insertion of the Achilles tendon), and inflammation of the sacroiliac joints and spine (which contrasts with rheumatoid arthritis, hence the name spondyloarthropathy). Not all the spondyloarthropathies have all of these features present at all times.
1.1. Learning Objectives
- Identify the four major spondyloarthropathies by pattern and be able to distinguish them from Lyme arthritis and Rheumatoid Arthritis
- Understand the role of the HLA-B27 gene in the pathogenesis of the spondyloarthropathies
- Learn what an enthesis is and its importance in understanding the pathophysiology and clinical manifestations of the spondyloarthropathies
2. Clinical and Laboratory Findings
Ankylosing Spondylitis (AS) is the prototypic spondyloarthropathy. Over 95% of patients with AS test positive for HLA B27. The presence of HLA B27, however, does not make the diagnosis of a spondyloarthropathy. About 8% of the normal Caucasian population tests positive for HLA B27; less than 5% of HLA B27 positive individuals develop AS. However a first degree relative who is HLA-B27 positive has a 20% chance of developing AS and an identical twin has a 63% chance. These data convincingly demonstrate that other genes as well as other unknown factors play a role in determining whether an individual will develop AS. These unknown factors may consist of such events as exposure to an external or internal antigen (such as from an infection), a toxin or a somatic genetic mutation. The significance of a positive HLA-B27 in non-Caucasian ethnic groups has overall been less well studied and varies from group to group. The difference in disease expression between different ethnic groups is at least partially explained by the existence of at least 25 HLA-B27 subtypes that are products of alleles related by nucleotide sequence homology. Certain subtypes clearly predispose to disease more so than others
Clinically, AS typically begins in the third decade of life, and is more common in men. Inflammatory back pain usually heralds the onset of the disease. Patients with inflammatory back pain usually find that movement progressively alleviates their discomfort, while those with mechanical back pain (herniated disc, back strain) find that movement worsens their pain. Individuals with inflammatory back pain typically find mornings worse, and their pain improves as the day continues; the reverse is true for those with mechanical back pain. In AS, the cause of the back pain is due to sacroiliitis, usually in a symmetric fashion, and the inflammatory process ascends to involve the entire spine. Ossification and inflammation of paralumbar ligaments leads to syndesmophyte (calcified ligament) formation along the vertebral bodies, and ultimately squaring of the vertebral bodies develops due to patterns of bone resorption and remodeling seen with entheseal inflammation. A “bamboo” spine, inflexible, rigid and apt to fracture, is the late skeletal manifestation of untreated AS. Peripheral synovitis is commonly seen, with inflammatory joint fluid and erosive radiographic changes. Enthesitis results in features such as severe heel pain and sternal pain.
Extrarticular disease is commonly seen in AS. Acute anterior uveitis is seen in about a third of patients. Aortic valvular disease that may progress to serious valve failure can also be seen, though is not common. Oral ulcers (canker sores) can also be seen.
Psoriatic arthritis (PsA) mimics RA in many respects, and is also often progressive. Reactive arthritis, however, frequently can remit, and its course may not be as relentless as that of AS and PsA. The arthritis of inflammatory bowel disease is generally divided into two groups: the spondylitic form, associated with the presence of HLA B27, and the peripheral form, usually associated with activity level of the bowel inflammation and not associated with HLA-B27.
3. Pathogenesis/Molecular Mimicry
Abnormal presentation of microbial antigens in individuals who test positive of HLA B27 is thought to play a role in the pathogenesis of the disease, though the specific organism has not been elucidated. Klebsiella aeruginosa has been implicated on the basis of observed molecular mimicry between it and HLA B27. Other organisms have also been implicated. In reactive arthritis, specific infections are known to trigger the inflammatory arthritis. For example, Chlamydia trachomatis, a cause of urogenital infection, precipitates reactive arthritis and in some case the full-blown Reiter’s syndrome (arthritis, conjuctivitis, urethritis), and other causes of gastrointestinal infection (Salmonella, Yersinia, Campylobacter, Shigella) have also been shown to trigger reactive arthritis. It is important to note the difference between septic arthritis and reactive arthritis. In septic arthritis, the causative bacteria is easily cultured from the joint fluid and the arthritis is directly due to the destructive process cause by rapidly multiplying bacteria and the aggressive inflammatory response it incites; in reactive arthritis, the joint fluid remains sterile by routine culture methods and the infection is antecedent to the inflammatory arthritis and distant from the site of arthritis. However both bacterial antigens and small numbers of viable bacteria have been found in the synovium of patients with reactive arthritis and a debate continues over whether it is a low grade infection or the host response to the infection that is responsible for the pathologic process in reactive arthritis.
AS is a chronic rheumatic disease that has been characterized by relentless progression toward spinal fusion. Nonsteroidal antinflammatory drugs (NSAIDS) remain a cornerstone of the treatment of AS and the other spondyloarthropathies as they provide significant symptomatic relief. Often, NSAIDS alone cannot control the inflammatory process in AS, and other remitting agents (sulfasalazine, methotrexate) are used to attempt to halt disease progression. Recently, as in RA, biological agents like the TNF-α blockers have been shown to markedly ameliorate the inflammatory process and associated symptoms of pain and stiffness; there is great hope that disease progression may be preventable for the first time.