Spondyloarthropathies: Theories of Pathogenesis

The role of the human histocompatibility complex
The spondyloarthropathies are variably associated with the HLA class I antigen B27.(3) The histocompatibility or HLA complex is responsible for antigen recognition, allowing the distinction between self and nonself. In humans, the HLA complex is located on chromosome 6 and is made up of genes that code for HLAs. HLA class I genes code for HLA-A, HLA-B, and HLA-C molecules, which are expressed on all nucleated cells. HLA class II genes code for HLA-DR, HLA-DQ, and HLA-DP molecules, found on antigen-presenting cells such as macrophages and dendritic cells.

An important biologic role of the HLA molecules is to present antigenic peptides in a manner that enables appropriate T-cell receptors to engage them while simultaneously discriminating self from nonself, leading to T-cell activation. HLA class I molecules generally present antigen to CD8-positive T cells, whereas HLA class II molecules generally present antigen to CD4-positive T cells.

Only a minority of people with the B27 gene develop spondylitis. While 90% of Caucasian patients with ankylosing spondylitis are B27-positive, far fewer African Americans or Asians with this disease have this antigen.

Molecular mimicry and an environmental stimulus
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 spondyloarthropathy in genetically susceptible hosts by an environmental stimulus, such as bacteria in the gastrointestinal tract.(12) Another possible mechanism is presentation of an arthritogenic peptide from enteric bacteria by specific HLA molecules. Many patients with ankylosing spondylitis have subclinical gastrointestinal tract inflammation and elevated serum immunoglobulin A antibodies directed against Klebsiella. The bacteria may invade the gastrointestinal tract of a genetically susceptible host, leading to chronic inflammation and increased permeability. Over time, bacterial antigens containing arthritogenic peptides enter the blood stream. Bacterial antigens are thought to play a role in the pathogenesis of reactive arthritis.(13) Further studies are needed to establish their exact role in the pathogenesis of reactive arthritis and related arthritides. Experimental work with transgenic mice and rats transfected with human HLA-B27 and beta-2-microglobulin has shown that certain strains develop a multisystemic illness resembling spondyloarthropathy, whereas identical animals raised in a germ-free environment remain healthy.(14,15)

Classification and Diagnosis
The system most commonly used to classify spondyloarthropathies for diagnostic purposes (10) is the European Spondyloarthropathy Study Group (ESSG) criteria,(10) which have a sensitivity of 83.5% and a specificity of 95.2%. Diagnosis is based on the presence of one of two major criteria (inflammatory spinal pain or synovitis) plus one or more of the following:

•Positive family history of ankylosing spondylitis, psoriasis, acute uveitis, reactive arthritis, or inflammatory bowel disease (all linked to the presence of B27 and spondylitis)

•Psoriasis

•Inflammatory bowel disease

•Urethritis, cervicitis, or acute diarrhea less than 1 month before arthritis

•Alternating buttock pain

•Enthesitis

•Sacroiliitis

According to the Amor criteria,(16) which are less commonly used, the diagnosis is based on a total score derived from consideration of 12 weighted criteria, which include history, clinical presentation, radiologic findings, genetic background, and response to treatment. This method is less convenient than the ESSG criteria. Its rates of sensitivity (90.8%) and specificity (96.2%) are statistically comparable to those of the ESSG method.(17)

These general diagnostic criteria are useful for the diagnosis of spondyloarthropathies, including atypical, undifferentiated forms.

Cleveland Clinic Journal of Medicine
Volume 71, Number 3, March 2004

This paper discusses therapies that are experimental or are not approved by the U.S. Food and Drug Administration for use under discussion.