Pathogenesis of spondyloarthritis

INTRODUCTION — The term spondyloarthritis (SpA, formerly spondyloarthropathy) refers to a group of disorders that includes ankylosing spondylitis (AS), nonradiographic axial SpA (nr-axSpA), undifferentiated spondyloarthritis (USpA), reactive arthritis, and the arthritis and spondylitis that may accompany psoriasis and inflammatory bowel diseases (IBD). SpA can also be differentiated into axial and peripheral SpA, depending upon the predominant regions of involvement. Axial SpA includes both AS and nr-axSpA, based upon the presence or absence, respectively, of abnormalities of the sacroiliac joints on plain radiography.

This topic review will focus primarily on the pathogenesis of AS, regarding which the most is known. The pathogenesis of each of the other members of the SpA family, especially nr-axSpA, is probably closely related to that of AS [1]. The clinical manifestations, diagnosis, and treatment of AS are presented separately. (See "Clinical manifestations of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults" and "Diagnosis and differential diagnosis of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults" and "Treatment of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults".)

The clinical aspects of the other types of SpA are also presented in detail elsewhere, as is SpA in children. (See "Clinical manifestations of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults" and "Clinical manifestations and diagnosis of peripheral spondyloarthritis in adults" and "Reactive arthritis" and "Clinical manifestations and diagnosis of psoriatic arthritis" and "Clinical manifestations and diagnosis of arthritis associated with inflammatory bowel disease and other gastrointestinal diseases" and "Spondyloarthritis in children".)

OVERVIEW OF PATHOGENESIS — Several elements are important in the pathogenesis of spondyloarthritis (SpA), a group of diseases with diverse clinical manifestations, which involve several different structures (figure 1). These elements include interactions in the context of a particular genetic background between the gut microbiome, innate-like lymphoid cells, and mechanical stress at the anatomic structures that are disease targets. Those structures include, for axial SpA, the entheses along the axial skeleton and for peripheral SpA, the peripheral entheses and the peripheral joints. At the sites of pathology, the major mediators are tumor necrosis factor (TNF) alpha and interleukin (IL) 17. (See 'Proinflammatory mediators validated by clinical observations' below and 'The gut mucosa, gut microbiome, and IL-17A' below.)

The largest single genetic contribution is from the gene for human leukocyte antigen (HLA) B27, but the presence of HLA-B27 is not absolutely essential. Moreover, non-HLA genes and others are also involved. (See 'Genetic factors' below.)

A major challenge for investigators is that at the entheses, where ligaments are attached to the cartilage in the vertebrae, two different processes both occur that may seem paradoxical. One is inflammation, sometimes with destruction of bone (an osteoclastic process), while the other process is new bone formation leading to syndesmophytes (an osteoblastic process). At its worst, the new bone formation can convert the entire vertebral column into a rigid bamboo spine, the hallmark of severe ankylosing spondylitis (AS). A comprehensive hypothesis of SpA pathogenesis needs to address both the inflammatory osteoclastic and the osteoblastic processes. (See 'Coexisting bone erosion and new bone formation' below.)

PROINFLAMMATORY MEDIATORS VALIDATED BY CLINICAL OBSERVATIONS — Among the variety of targeted therapies tested in spondyloarthritis (SpA) clinical trials, the only ones considered effective are aimed at one of three targets: Cyclooxygenase (COX), tumor necrosis factor (TNF) alpha, and interleukin (IL) 17A [2-8]:

●Cyclooxygenase – Inhibition of COX by nonsteroidal antiinflammatory drugs (NSAIDs) is very effective in controlling disease activity in some patients with SpA. This is probably because the COX enzymes are required for the generation of the proinflammatory compounds, the prostaglandins [9]. (See "NSAIDs (including aspirin): Pharmacology and mechanism of action", section on 'Mechanisms of analgesia and antiinflammatory effects'.)

●TNF-alpha and IL-17 – TNF itself is a pleiotropic cytokine released among other cells by macrophages, neutrophils, and lymphocytes. It is a strong inducer of a host of inflammatory mediators [10]. The targets of therapeutic TNF blockers are the innate immune response system, the prostaglandin system, the macrophages, and the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) pathway, as well as pathways downstream of NF-kB [11]. TNF blockers do not directly activate the T helper 1/T helper 17 (Th1/Th17) pathways.

Blocking of IL-17 requires IL-17-specific blockers. There are six members in the IL-17 family, named IL-17A through IL-17F. Because IL-17A is the best characterized, the term IL-17, in general, refers to IL-17A. The engagement of IL-17A with its receptors leads to a cascade of pathways, which leads to activation of the transcription factors NFkB, AP-1, and C/EBP. These induce activation of genes encoding multiple inflammatory cytokines, chemokines, and metalloproteinases. Hence, IL-17A, like TNF-alpha, is also an orchestrator for a family of mediators [12,13]. IL-17A also acts in a positive feedback loop to enhance the production and effects of IL-17A. As a result of these interactions, IL-17A has a clinical effect that is as potent as that of TNF-alpha [14-16]. (See 'Overview of pathogenesis' above.)

Given that an ultimate goal of studying pathogenesis is to provide better therapy, the observations from clinical trials that these three classes of target-specific therapeutic agents are effective in at least some patients with SpA have been important contributions to the identification of critical elements in disease pathogenesis.

MAJOR ELEMENTS IN THE PATHOGENESIS OF SPONDYLOARTHRITIS — The events that contribute to the pathogenesis of spondyloarthritis (SpA) are not a linearly linked series of cascades. It is a complex network of interactions involving the following:

●The axial skeleton and its entheses

●The peripheral entheses and joints

●Genetic influences

●The innate and perhaps also the adaptive immune systems

●The bowel

There are substantial variations among these elements, accounting for the enormous diversity of clinical presentations in SpA patients. As an example, these processes are thought to begin in the bowel, at least in patients with compromised bowel integrity. (See 'The gut mucosa, gut microbiome, and IL-17A' below.)

THE GUT MUCOSA, GUT MICROBIOME, AND IL-17A

Presence of mucosal lesions — The gut microbiome has been incriminated as having a role in the pathogenesis of several types of inflammatory arthritis, including spondyloarthritis (SpA), in which defects in the gut mucosal barriers have been implicated in this process. Normally, the microbiome is separated from the host by a gut epithelial barrier and a gut vascular barrier [17]. However, when the integrity of the barriers is compromised, the microbes become capable of initiating a systemic immune response [18]. Lesions in the gut mucosa in patients with SpA were first demonstrated in the 1980s [19]. Additional evidence supporting a role for these issues in pathogenesis includes [20,21]:

●The demonstration by ileocolonoscopy of the presence of subclinical acute or chronic intestinal inflammation in about two-thirds of patients with SpA, with functional breaches in the gut epithelium in SpA

●The correlation between chronic gut inflammation and magnetic resonance imaging (MRI)-demonstrable SpA disease activity

●The sharing of genes between ankylosing spondylitis (AS) and Crohn disease

●The presence of AS in 4 to 10 percent of patients with ulcerative colitis and Crohn disease

●Findings of sacroiliitis on plain radiographs in a significant proportion of patients with Crohn disease, many of whom do not have symptoms of inflammatory back pain

SpA-specific gut microbiome and damage of intestinal mucosal barriers — The composition of the gut microbiome, which is influenced by genetic and other factors, differs in patients with SpA from healthy individuals. Evidence in both humans and more so in animal models supports the view that the gut microbiome plays a vanguard role in the cascade of events leading to inflammation in many patients with SpA.

The strongest evidence that the gut microbiome is necessary for development of SpA comes from animal models [22]. In these models, rats and mice develop SpA-like clinical and pathologic features when housed in their usual laboratory environment; however, they fail to develop such features when raised in a germ-free environment, although the SpA-like features do appear when the animals are brought out of the germ-free environment.

Data in humans also argue for a role of the gut microbiome in disease pathogenesis. The enormous diversity in the trillions of commensal microbial cells in the human gut is affected by multiple factors, including geography, ethnicity, major histocompatability complex (MHC) genes, therapy, age, sex, and diet. A description, or "census," of the microbiota in each individual can allow for the characterization of that individual's microbiome by sequencing and analytic techniques [23,24]. Using this approach, a core microbiome set can be demonstrated, which is unique for each person at a given point in time and has the capacity to distinguish between different individuals [25].

A large number of studies have been reported comparing the gut microbiome between SpA and healthy subjects, consistently demonstrating differences in the microbiome between SpA and healthy subjects. However, findings concerning the particular SpA-specific microbial species vary between studies. What appears to be more consistent is that the SpA microbiome is more enriched in species that are mucolytic and potentially able to degrade the gut barrier. Breakdowns were demonstrated by immunohistologic findings of the downregulation of junctional proteins and evidence of increased serum levels of bacterial lipopolysaccharides [26-31].

IL-17 and gut microbial invasion — The loss of architectural and functional integrity in the intestinal epithelium allows for passage of microbiota or their metabolites into the submucosa and the systemic circulation (see 'SpA-specific gut microbiome and damage of intestinal mucosal barriers' above). The first line of cytokine defense is IL-17. Acting in synergy with IL-22, it guards the integrity of the gut epithelium against microbes by inducing the generation of anti-microbial peptides. These effects are probably why there is a higher incidence of inflammatory bowel disease (IBD) flares in the anti-IL-17-treated patients in clinical trials of anti-IL-17 in psoriasis and AS, compared with placebo-treated patients [32]. There are multiple factors that can drive a variety of cell types to generate IL-17 [12,33].

Although the IL-17 cells activating IL-23 were at one time considered the most likely orchestrating disease-causing candidate in SpA, multiple randomized trials have failed to demonstrate a significant clinical benefit of two different anti-IL-23 antibodies in AS. This is despite the efficacy of both antibodies for psoriasis [34,35]. Hence, the IL-17-producing cells in AS are probably predominantly IL-23-independent [36].

Potential roles of several types of IL-17-positive cells — Besides the granulocytes and macrophages, several other types of cells in the intestine are capable of producing IL-17. These include the type 3 innate-like lymphoid cells (ILC3), mucosal-associated T cells (MAIT), gamma-delta T cells, innate-like invariant natural killer T cells (iNKT), and mast cells [16,37]. The ILC and the innate-like T cells recognize microbial products without requiring extensive rearrangement of their T-cell receptors [29,38]. Because of this, they can rapidly produce a large quantity of cytokines [36,39].

ILC3 is an example of how the innate immune cells can travel from the gut to the entheses and joints (figure 1) [40-42]. Upon becoming activated in the gut, these ILC3 express the alpha-4/beta-7 integrin, which can function as a homing receptor. The ligand for this integrin is mucosal vascular addressin cell adhesion molecule 1 (MADCAM1), which, in patients with AS, is strongly expressed in the high endothelial venules (HEV) of the gut and bone marrow [41]. Although not directly demonstrated, these gut-derived ILC3 in patients with AS are postulated to migrate into the systemic circulation and to home via this integrin-ligand interaction towards the bone marrow, the peripheral joints, and the entheses [2,43,44].

Alternately, such IL-17-positive cells might originate in areas other than the gut such as the entheses and the bone marrow.

Entheses and the role of mechanical stress — The major targets of the disease process in patients with SpA are the entheses, where tendons and ligaments are attached to bone [45]. Because of the mechanical load, entheses are highly susceptible to micro-injury. The attachment of the Achilles tendon to the calcaneus, for example, is subjected to mechanical stress of 3 to 10 times the body weight during activities. Such micro-injuries can activate resident immune cells that include the ILC, gamma delta T cells, natural killer cells, and conventional T cells. Together with the neutrophils, they also release chemoattractants for circulatory proinflammatory cells. All these cells orchestrate a TNF- and IL-17-dependent inflammatory reaction even in subjects with no arthritis. It is postulated that SpA is caused by a faulty fine-tuning of this local reactivity [46-48]. The proportion of peripheral blood T cells carrying surface markers of regulatory T cells (Treg) is lower in AS patients [49]. One possible contributory factor is that their proliferation is inhibited by microribonucleic acids (microRNAs) carried in exosomes [50].

GENETIC FACTORS — Genetic factors have overwhelming importance in susceptibility to ankylosing spondylitis (AS). First-, second-, and third-degree relatives of patients with AS have markedly increased risks of developing the disease (relative risks of 94, 25, and 4, respectively) [4]. The mode of inheritance is polygenic with multiplicative interaction among loci [5,6]. The association with the human leukocyte antigen (HLA) B27 gene was recognized in 1973 and has the strongest association with the disease (table 1) [7,51]. The overall contribution to AS heritability by HLA-B27 is estimated at approximately 20 to 30 percent [52]. The contribution of the major histocompatability complex (MHC) region is 40 to 50 percent [36]. (See 'Role of HLA-B27' below.)

Role of HLA-B27 — Because HLA-B27 is present in approximately 80 to 95 percent of patients with AS in most ethnic groups, compared, for example, with 6 percent of the general population in the United States, it is assumed to play a major role in the pathogenesis of AS. At least 160 subtypes of HLA-B27 have been characterized; differences between these subtypes affect whether they are associated with spondyloarthritis (SpA), including AS [51,53-55]. The most frequent subtypes are HLA-B2705 and HLA-B2704 [53,56,57]. Only two subtypes, HLA-B2706 and HLA-B2709, are considered not to be associated with SpA [4,58,59].

At this point, it is still unclear what role HLA-B27 plays in the pathogenesis of SpA [60]. Besides its role in cell-mediated immunity, studies in healthy HLA-B27 positive individuals have shown that there is an association of the HLA-B27 genotype with the overall gut microbial composition, which is distinct from the composition of the gut microbiome that is observed in subjects without HLA-B27 [61,62]. These findings may relate to the proposed role of the gut microbiome in the pathogenesis of SpA, and will be a focus of further research.

Most research on the role of HLA-B27 in the pathogenesis of SpA has historically focused on how different structures of HLA-B27 mediate inflammatory processes. Although no fully satisfactory explanations have been established, it is clear that the entire set of intracellular processes of formation of the HLA-B27 molecule need to be considered (figure 2).

Classical (canonical) structure of HLA-B27 — Several features distinguish HLA-B27 from most other HLA class I molecules; these features may be relevant to disease susceptibility according to some hypotheses. The classical (canonical) structure is one shared with other HLA class I molecules [63-66]:

●The HLA class I molecule is composed of a 45 kD polymorphic heavy chain, noncovalently complexed with a 12 kD monomorphic unit, beta-2-microglobulin.

●The heavy chain is composed of three domains. The first two domains (alpha-1 and alpha-2) together form two antiparallel helices resting on a platform of an eight-stranded pleated sheet, which itself rests on two barrel-shaped structures derived from the complex of the third domain (alpha-3) and the beta-2-microglobulin (figure 3).

●An antigenic peptide that is usually 8 to 11 amino acids in length rests inside the platform. These peptides are derived from endogenous proteins and from proteins of viruses and bacteria that have invaded the cells (figure 4).

The features that distinguish HLA-B27 from most other HLA class I molecules include:

●Most antigenic peptides associated with HLA-B27 have arginine as the second residue [63-65].

●The presence of an unpaired cysteine at residue 67 (Cys67) – This unique feature allows for the formation of homodimers and oligomers of free heavy chains. (See 'HLA-B27 misfolding and autophagy' below.)

Since the physiologic function of HLA-B alleles is for CD8+ T lymphocyte to present peptides to the corresponding T-cell receptors on target cells, the favorite hypothesis for SpA is the "arthritogenic peptide hypothesis." It postulates that there are certain microbial peptides that are very similar to self-peptides from the point of view of the T-cell receptors of certain HLA-B27-specific CD8+ T lymphocytes (cytotoxic T lymphocytes). The reactivity of these T lymphocytes with these HLA-B27-peptide complexes would then lead to autoreactivity and autoimmune disease [67-69]. There is indeed an enrichment of such bacterial peptides in the stool of patients with AS [70]. Most importantly, this hypothesis is supported by multiple studies of T cell profiling to identify both the responsible T-cell receptors as well as the cross-reactive self and microbial peptides [71,72]. This approach can lead to refinement in diagnosis as well as targeted therapies.

HLA-B27 as free heavy chains — HLA-B27 can also exist as a dimer of two heavy chains without the beta-2-microglobulin [73-75]; these proteins may contribute to the pathogenesis of SpA. These dimers are present in the gut and synovium of SpA patients. When present on antigen-presenting cells, they can stimulate interleukin (IL) 23 receptor positive T cells to produce IL-17 [76].

HLA-B27 misfolding and autophagy — HLA-B27 folds more slowly than other HLA molecules into the canonical class I structure inside the endoplasmic reticulum, where it may accumulate and influence pathways promoting the production of immune mediators important in the development of SpA. The misfolding hypothesis explaining the HLA-B27 association with SpA is based upon a feature of molecular biogenesis peculiar to HLA-B27, by which HLA-B27 could begin to induce SpA before it reaches the surface of the cell due to protein misfolding [77,78]. The HLA-B27 misfolding hypothesis can be summarized as follows (figure 5):

●Mature HLA-B27 has a quaternary structure with three different components. It is assembled and folded from a linear structure in the endoplasmic reticulum, a cellular compartment.

●For several reasons, including the cysteine residue at position 67, the folding process of HLA-B27 is slower than that for other HLA alleles.

●Improperly folded HLA-B27 proteins (ie, those not yet in the canonical mature class I conformation) accumulate in the endoplasmic reticulum.

●This can lead to a misfolding process, which activates autophagy and activation of the IL-23/IL-17 pathway. Alternately, misfolding can lead to another process termed the endoplasmic reticulum unfolded protein response (ERUPR), which can also activate the IL-23/IL-17 pathway (figure 6). (See 'Coexisting bone erosion and new bone formation' below.)

The likelihood is that misfolding of HLA-B27 leads only to autophagy, and it is this autophagy which activates the IL-23/IL-17 pathway [36]. One type of cells that undergo autophagy in AS are the Paneth cells in the intestinal epithelial lining [43,79].

Non-HLA genes — The search for non-HLA-B27 genes that may be important in SpA pathogenesis has focused almost exclusively on patients with AS and has suggested that non-MHC genes are also important in disease susceptibility. Since 2010, several large genome-wide association studies (GWAS) have been carried out in several populations of European [80-82] and Han Chinese descent [83]. These studies have identified a total of at least 114 genetic variants. The MHC, especially HLA-B27, is a major contributory factor. Approximately 7 percent of the heritable risk is from non-MHC variants (table 1) [52,84-89]. The apparent need for an HLA-B27-positive individual to also carry some of these non-MHC genes in order to develop AS may explain, at least in part, why only 1 to 5 percent of HLA-B27-positive individuals develop AS.

Even though the total contribution of all these non-MHC genes to AS heritability is relatively small, these associations provide clues about the pathogenesis of AS. In addition, their significance can be amplified by gene-gene interaction [90]. These non-MHC AS-causing genes can be grouped into several functional categories:

●ERAP1 and ERAP2 – The two endoplasmic reticulum aminopeptidases that encode genes related to AS are termed ERAP1 and ERAP2; each of the genes has variants that may increase the risk of AS and variants that are protective. These two enzymes are responsible for the generation as well as trimming and destruction of peptides in the endoplasmic reticulum to achieve the correct length for loading into HLA class I molecules, such as HLA-B27, for antigen presentation [91]. The actual significance of ERAP1 and ERAP2 in SpA is still not entirely clear [76,92].

●Tumor necrosis factor receptor gene family – The presence of an additional group of genes, including those for the lymphotoxin beta receptor (LTBR) and tumor necrosis factor receptor 1 (TNFRSF1A), provides additional support for the role of tumor necrosis factor (TNF) alpha in disease activity [52]. (See 'Proinflammatory mediators validated by clinical observations' above.)

●IL-23/IL-17 axis – GWAS have identified a number of genes that are associated with the IL-23/IL-17 axis [84].

●T lymphocyte activation and differentiation – The association of AS with genes modulating activation and differentiation of either CD4+ or CD8+ T lymphocytes is consistent with potential involvement of these cells with disease pathways.

●Genes shared with inflammatory and immune-mediated bowel disease – The sharing of 65 genes with Crohn disease, ulcerative colitis, and celiac disease may explain the overlap of AS with inflammatory bowel diseases (IBD) and perhaps the presence of subclinical bowel disease in AS itself [84].

●A gene associated with radiographic progress in AS – The genes listed above are associated with susceptibility of disease. In AS, spinal damage is the most disabling factor. Using GWAS in 444 AS patients, 1 study identified a gene known as ryanodine receptor 3 (RYR3), which was associated with severity of radiographic spinal damages [93]. RYR3 encodes a channel release protein that regulates intracellular calcium homeostasis. It is expressed in musculoskeletal tissues.

How these various genes are activated to express their respective proteins and how their expression is modulated in flares and relapses of AS remain to be clarified.

More advanced nucleotide-based technologies might be able to answer these questions. These include whole genome sequencing, studies of microribonucleic acid (microRNA), methylation, and histone acetylation [94].

COEXISTING BONE EROSION AND NEW BONE FORMATION — The mechanisms by which bone inflammation and erosions can occur in patients with spondyloarthritis (SpA) along with new bone formation have not been fully elucidated. These findings may appear paradoxical and there is controversy regarding the interpretation of the available data. The findings in SpA are in contrast with those in rheumatoid arthritis (RA), where only bone erosion is observed.

One clue is provided by longitudinal studies of the spine in the same patients using MRI and radiography. Using two different sequences, MRI can visualize both inflammation and repair processes, identified respectively as bone marrow edema and fat metaplasia. New bone formation (for example, syndesmophytes) is best visualized by plain radiography. These studies suggest that the initial change is inflammation in which cytokines such as tumor necrosis factor (TNF) and IL-17 directly or indirectly activate osteoclast precursor cells. This is then followed to a certain extent by a reparative process at the vertebral corners and other sites of the axial skeleton, and finally by new bone formation (such as syndesmophytes) (figure 7) [95]. Cross-sectional studies of the histology indicate that new bone formation is more likely to take place in areas where there has been fat metaplasia and that new bone formation appears after the inflammation has subsided [96]. Osteoblast differentiation involves use of the bone morphogenic proteins and the Wnt pathway [45]. Several biomarkers have been identified that seem to mediate or inhibit the process of new bone formation [97].

New bone formation does not occur in the vertebral body, where the inflammation has destroyed the microarchitecture; rather, syndesmophyte are formed at the periosteum-cartilage junction. The most important players are the stromal cells: the bone marrow mesenchymal cells (BM-MSC) and the fibroblast-like synovial cells (FLS). Normally, the BM-MSC reside in the bone marrow, but they are capable of migrating through pores into the entheses. There, mesenchymal cells are driven into osteogenesis by interleukin (IL) 22, IL-17, and TNF. These mesenchymal cells also secrete a chemokine to augment the reactivity [16,48,98]. The FLS on the other hand can develop into osteoblasts even independent of an inflammatory environment [37].

Another set of observations found that in the mesenchymal cells of the spinal entheses of ankylosing spondylitis (AS) patients, human leukocyte antigen (HLA) B27 unfolding response activates a pathway leading to generation of tissue-nonspecific alkaline phosphatase (TNAP). Clinical significance is suggested by the finding that serum levels of bone-specific TNAP correlate with scoring vertebral changes in AS patients [99]. Yet another clue is that serum migratory inhibitory factor (MIF) is raised in patients with AS and can predict radiographic progression [100,101].

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Axial spondyloarthritis, including ankylosing spondylitis (Beyond the Basics)")

SUMMARY

●The major areas of involvement in ankylosing spondylitis (AS) and the other forms of spondyloarthritis (SpA) are at the articulations of the axial skeleton, at the interface between ligaments/tendons/bone/cartilage (entheses). (See 'Overview of pathogenesis' above.)

●Mediators that are current targets of therapy are the cyclooxygenases (COX), tumor necrosis factor (TNF) alpha, and interleukin (IL) 17, emphasizing the significance of these enzymes and cytokines to processes important in the pathogenesis of SpA. (See 'Proinflammatory mediators validated by clinical observations' above.)

●For patients with microscopic bowel lesions, the disease processes probably start in the gut, where several types of rapidly responding cells such as the innate lymphoid cells (ILCs) that produce IL-17 (a proinflammatory cytokine) and IL-22 are activated by SpA-specific gut microbiota (figure 1). (See 'The gut mucosa, gut microbiome, and IL-17A' above.)

●Innate-like immune cells activated in the gut migrate to the entheses and the joints, causing an inflammatory process in which TNF-alpha also participates. IL-17 causes a bone-erosive process. (See 'IL-17 and gut microbial invasion' above and 'Coexisting bone erosion and new bone formation' above.)

●The entheses themselves also contain several types of these cells, which can be activated via mechanical stress to generate IL-17. (See 'Entheses and the role of mechanical stress' above.)

●The pathogenic events in SpA take place in a complex genetic background. The major gene is human leukocyte antigen (HLA) B27, which probably participates in several of the key pathogenic processes. Additionally, a large number of non-HLA genes have also been identified as having associations with AS. They interact and reinforce several of the disease-causing pathways. (See 'Genetic factors' above.)

●Initial changes in bone result from inflammation, followed by a reparative process via the mesenchymal cells of the entheses via the effect of IL-22 and IL-17 on mesenchymal cells. The ultimate consequence is new bone formation, such as the formation of syndesmophytes (figure 7). (See 'Coexisting bone erosion and new bone formation' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David Yu, MD, who contributed to earlier versions of this topic review.