The spondyloarthritides are a group of overlapping disorders that share certain clinical features and genetic associations. These disorders include ankylosing spondylitis, reactive arthritis, psoriatic arthritis and spondylitis, enteropathic arthritis and spondylitis, juvenile-onset spondyloarthritis (SpA), and undifferentiated SpA. The similarities in clinical manifestations and genetic predisposition suggest that these disorders share pathogenic mechanisms.
Ankylosing spondylitis (AS) is an inflammatory disorder of unknown cause that primarily affects the axial skeleton; peripheral joints and extraarticular structures are also frequently involved. The disease usually begins in the second or third decade; male to female prevalence is between 2:1 and 3:1. The term axial spondyloarthritis, coming into common use, includes early or mild forms that do not meet classical criteria for AS.
AS shows a striking correlation with the histocompatibility antigen HLA-B27 and occurs worldwide roughly in proportion to the prevalence of B27 (Chap. 315). In North American whites, the prevalence of B27 is 7%, whereas it is 90% in patients with AS, independent of disease severity.
In population surveys, AS is present in 1–6% of adults inheriting B27, whereas the prevalence is 10–30% among B27+ adult first-degree relatives of AS probands. Concordance rate in identical twins is about 65%. Susceptibility to AS is determined largely by genetic factors, with B27 comprising up to one-half of the genetic component. Other HLA-linked genes may also contribute to susceptibility to AS. Genome-wide single-nucleotide polymorphism (SNP) analysis has identified additional susceptibility alleles in the genes encoding ERAP1 (chromosome 5q15) and IL-23R (chromosome 1p31.3). The genes encoding TNFSF15, TNFSF1A, STAT3, ANTXR2, and IL1R2, and at least six other chromosomal regions have also been implicated.
The sites of axial inflammation in AS are inaccessible to routine biopsy and are rarely approached surgically. Knowledge of the axial histopathology is therefore based mostly on advanced cases. Sacroiliitis is often the earliest manifestations of AS. Synovitis, pannus, myxoid marrow, subchondral granulation tissue and marrow edema, enthesitis, and chondroid differentiation are found. Macrophages, T cells, and osteoclasts are prevalent. Eventually the eroded joint margins are gradually replaced by fibrocartilage regeneration and then by ossification. The joint may become totally obliterated.
In the spine, there is inflammatory granulation tissue at the junction of annulus fibrosis and vertebral bone. The outer annular fibers are eroded and eventually replaced by bone, forming the beginning of a syndesmophyte, which then grows by continued endochondral ossification, ultimately bridging the adjacent vertebral bodies. Ascending progression of this process leads to the “bamboo spine.” Other lesions in the spine include diffuse osteoporosis, erosion of vertebral bodies at the disk margin, “squaring” or “barreling” of vertebrae, and inflammation and destruction of the disk-bone border. Inflammatory arthritis of the apophyseal joints is common, with erosion of cartilage by pannus, often followed by bony ankylosis. Bone mineral density is diminished in the spine and proximal femur early in the course of the disease.
Peripheral synovitis in AS shows marked vascularity, lining layer hyperplasia, lymphoid infiltration, and pannus formation. Central cartilaginous erosions caused by proliferation of subchondral granulation tissue are common.
Inflammation in the fibrocartilaginous enthesis, the region where a tendon, ligament, or joint capsule attaches to bone, is a characteristic lesion in AS and other SpA, both at axial and peripheral sites. Enthesitis is associated with prominent edema of the adjacent bone marrow and is often characterized by erosive lesions that eventually undergo ossification.
The pathogenesis of AS is thought to be immune-mediated, but there is no direct evidence for autoimmunity. There is uncertainty regarding the primary site of disease initiation. A unifying concept is that the AS disease process begins at sites where articular cartilage, ligaments, and other structures attach to bone. The dramatic response of the disease to therapeutic blockade of tumor necrosis factor α (TNF-α) indicates that this cytokine plays a central role in the immunopathogenesis of AS. There is recent evidence that TH17 T cells and their cytokines may also play an important role.
The inflamed sacroiliac joint is infiltrated with CD4+ and CD8+ T cells and macrophages and shows high levels of
TNF-α, particularly early in the disease. Abundant transforming
growth factor β (TGF-β) has been found in more advanced lesions. Peripheral
synovitis in AS and the other spondyloarthritides is characterized by
neutrophils, macrophages expressing CD68 and CD163, CD4+ and CD8+ T cells, and B cells. There is prominent staining for intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), matrix metalloproteinase 3 (MMP-3), and myeloid-related proteins 8 and 14 (MRP-8 and MRP-14). Unlike
rheumatoid arthritis (RA)
synovium, citrullinated proteins and cartilage gp39 peptide–major histocompatibility complexes (MHCs) are absent. No specific event or exogenous agent that triggers the onset of disease has been identified, although overlapping features with reactive arthritis and inflammatory bowel disease (IBD) suggest that enteric bacteria may play a role. Triggering of innate
immunity by microdamage at entheseal sites has recently been emphasized. Strong evidence that B27 plays a direct role is provided by
genetic epidemiology studies and by the finding that rats transgenic for B27 spontaneously develop dramatic arthritis and spondylitis. However, the role of B27 remains unresolved. Since B27 rats lacking CD8+ T cells still develop arthritis and spondylitis, classical peptide antigen presentation to CD8+ T cells is probably not the primary disease mechanism. However, the association of AS with ERAP1, which strongly influences the
MHC class I peptide repertoire, is only found in B27+ patients and suggests that peptide binding to B27 is nonetheless important. The B27 heavy chain has an unusual tendency to misfold, a process that may be proinflammatory. Genetic and functional studies in humans have suggested a role for natural killer (NK) cells in AS, possibly through interaction with B27. Defective dendritic cell function is a consistent feature of SpA-prone B27 rats not yet well investigated in patients.