Genome-wide association studies (GWAS) have identified genetic factors shared between AS, psoriasis and IBD, as well as disease-specific susceptibility gene loci. The shared genetic factors appear to be predominantly genes with roles in intracellular antigen processing, the type 17 helper T (T_H17) cell pathway and the nuclear factor kappa B pathway. Thus, the immune response is clearly implicated and therefore immune mediated mechanisms in the common features of disease. Of note is that interleukin (IL) 23 receptor variants confer susceptibility to AS, psoriasis, PsA, CD, and UC [6, 7] leading to particular interest in this pathway for therapeutic purposes. The most significant SpA susceptibility gene identified to date is a series of alleles of the human leukocyte antigen (HLA) region of the major histocompatibility complex (MHC). The HLA-B27 allele is present in over 85 % of patients with AS but only 1–5 % of carriers develop the disease [8]. Nearly all patients with IBD who are HLA-B27⁺ develop AS [1] and HLA-B27⁺ individuals are more likely to develop reactive arthritis. The exact mechanism for how HLA-B27 confers a risk is unknown though several mechanisms are proposed. These include some primary pathway whereby antigen presentation is paramount to a class I restricted cell lineage (e.g., CD8 T cells). However, HLA-B27 molecules have the propensity to misfold and as such have been shown to cause endoreticulum stress—this in turn can promote myeloid lineage cytokine production, particularly of IL-23 leading to theoretical amplification of the type 17 immune response that has been associated with disease. Finally it is proposed that HLA-B27 homodimers can form that in turn can activate innate lineage cells via killer receptor recognition. The identification of the endoplasmic reticulum aminopeptidase 1 (ERAP1) gene as a further susceptibility gene for to AS in HLA-B*27⁺ individuals suggest that they work in the same pathway to affect disease susceptibility [8]. ERAP1 trims peptides in the endoplasmic reticulum in preparation for binding to MHC class 1 molecules. This perhaps offers antigen presentation dependent pathways as more likely than misfolding of HLA-B27 as the dominant mechanism. That said none are mutually exclusive and as this is a polygenic disorder there may be several routes to disease susceptibility and progression. Much further work in which GWAS outcomes, detailed clinical phenotyping, and ex vivo immune analyses are combined will assist in resolution of these issues.

The most often described example of an environmental factor causing SpA is a bacterial infection preceding reactive arthritis. Although most patients with reactive arthritis have a self-limiting illness, up to 20 % develop AS within 10–20 years [9]. However, recently the critical role played by the microbiome in defining risk susceptibility has come to the fore in many autoimmune disorders, with IBD and SpA no exception. Dysbiosis of the intestinal microbiota is a recognized concept in IBD, and has been suggested to play a role in the SpA spectrum as well [9]. Transgenic rats expressing HLA-B27 develop a SpA like illness and colitis and raising the rats in a germ-free environment reduces these phenotypes [9]. In humans, initial studies did not identified any consistent differences between AS and controls [9], but recently a decreased diversity in the gut microbiota with similar microbiota profile to that of IBD, has been identified in PsA [10].

Biomechanical stress is a further factor implicated in the pathogenesis of SpA. Studies have mainly focused on the enthesis, the site of tendon insertion into bones, which are anatomical sites under high biomechanical stress—enthesitis is often one of the first signs of SpA [11, 12]. In animal models, mechanical stress can induce enthesitis with inflammation progressing to adjacent tissues [11]. The same mechanism has not been proposed in human SpA; PsA and PsA nail disease tend to localize to sites of mechanical stress and there are associations between PsA and joint trauma and occupations involving heavy lifting [11].

The clinical features of SpA are the result of a cascade of proinflammatory adaptive immune cells and the cytokines that they produce. The cascade, as illustrated in Fig. 55.3, is initiated by the interaction of an antigen-presenting cell (APC) with a naive CD4⁺ T cell [13]. The APC is typically a dendritic cell but could comprise a B cell or macrophage. In the presence of IL-12, naive CD4⁺ T cells differentiate to T_H1 cells which produce interferon-ɣ. This can activate macrophages that in turn release additional cytokines, including tumor necrosis factor-α (TNF-α) and IL-1 [13]. If instead IL-6 and TGF-β are expressed, together with IL-1, the antigen-activated precursor T cell develops down the T_H17 pathway by inducing the expression of IL-21 [14]. IL-21 drives the expression of the T_H17-specific transcription factor retinoic acid receptor (RAR)-related orphan receptor (ROR)-γ that in turn induces the expression of the receptor for IL-23, a cytokine that further amplifies T_H17-cell differentiation [14]. T_H17 produce cytokines such as TNF-α, IL-22, and IL-17A and F. The roles of IL-23 and IL-17-secreting T_H17 cells are described below.

Ankylosis , new bone formation extending from, and beyond, the normal border of bone [25], is a feature of SpA. This occurs as progenitor cells in the extracellular matrix are committed to developing into osteoblasts and chondrocytes via disruption of bone homeostatic signaling pathways [25]. Two bone protein regulatory families deserve particular attention, namely BMPs and Wnts. These pathways are critical in regulating the extracellular matrix via effects upon cell signaling and transcription promoting chondrogenic differentiation and hypertrophy, and new bone formation via osteoblasts respectively. Critically they appear to operate as a downstream effect of IL-23 [25]. It is not yet understood whether inflammation, and its resolution, results in new bone formation or whether inflammation and bone formation are two separate processes in the same disease [25]. On MRI, sites of ankyloses correlate to previous sites of inflammation, but sites of syndesmophytes do not [25]. TNF-inhibitors appear to have no influence on development of new bone formation; however, it appears NSAIDs do [25]. Control of inflammation does resolve the trabecular bone loss contributing to the osteoporosis seen [25]. In SpA, the contradictory presence of osteoporosis next to new bone formation in ankyloses is seen [25]—trying to understand and target bone metabolism at the molecular biomarker and therapeutic levels is therefore challenging.

The cardinal features of inflammation with pain, erythema, heat, swelling, and stiffness with subsequent loss of function of peripheral joints are seen in peripheral SpA. Classically, patients describe progressive onset of symptoms with significant morning stiffness in affected joints. Symptoms typically improve with activity. The number and distribution of joints involved can vary. Peripheral SpA associated with IBD can be further divided into types 1 and 2 (see Table 55.1). Dactylitis, inflammation of a digit (which does not obviously localize to an articular structure, but rather to the entire digit), can also be present. Type 1 peripheral arthritis is associated with larger and fewer joints, appears to be related to the course of the inflammatory bowel disease, and causes a self-limiting disease that does not cause erosions [5]. Type 2 peripheral arthritis is a symmetrical polyarticular disease that can last for decades and is associated with destructive (erosive) changes in the joints. It does not appear to be related to the course of the underlying bowel disease [5].

AS is the model disease of axial SpA . Patients complain of inflammatory back pain (see Table 55.2; Fig. 55.4) with early morning stiffness improving with exercise. Sacroiliitis can cause pain in the buttocks that may radiate to the thighs. Chronicity can result in ankyloses of the spine with irreversibly reduced range of movement. It is now rare however to see the classical deformities of the AS spectrum.

If a patient has only symptoms of peripheral disease , the following criteria are applied.

Perhaps given reliance on clinical features , sensitivity is 78 % and specificity 82 % [25].

If a patient has axial disease or peripheral and axial disease the following pathway should be applied [30].

Imaging is an important component of assessment and when positive comprises an important diagnostic clue—with an associated SpA feature it can carry a specificity of 97 %. However, negative imaging does not exclude the diagnosis and in particular may miss early disease—thus the sensitivity of this arm is 66 %, and hence a “clinical arm” has been included which has a lower specificity of 85 % but a higher sensitivity of 83 % [30]. Due to its lower specificity, two rather than one additional features are required. Of note, patients were only used in the criterion if they had had back pain for 3 months and were under 45. It can be expected that, at least, the specificity of the criteria will be reduced when applied in older age groups as other causes of back pain become more prevalent.

Disease scores. There are several scoring systems that can be used to assess disease activity and the functional impact of the disease. They can be used to justify treatment with biologics and serial measurement is a means to formally assess response to treatment. The choice of scoring system depends on the clinical manifestation. In axial SpA, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Assessment of Spondyloarthritis international Society Health Index (ASAS HI) are used—the latter is preferred by ASAS (http://​www.​asas-group.​org/​clinical-instruments.​php?​id=​01). They are both self-rated scoring systems. For the BASDAI, patients score the severity of their symptoms between 0 and 10. The ASAS HI is a questionnaire of 17 binary responses to statements about ability to perform in everyday situations based on the WHO International Classification of Functioning Disability and Health (ICF) [31]. In peripheral SpA, scoring systems like the Disease Activity Score (DAS) comprising a composite measure of joint examination by a trained assessor, patient assessment of global health and markers of inflammation have been adapted from their use in RA. There are also scoring systems for enthesitis and dactylitis (described in detail by Mease [32, 33]).

C-reactive protein (CRP) and the erythrocyte sedimentation rate have low specificity but can reflect disease activity, and CRP can aid diagnoses. High sensitivity CRP does not provide any further usual information [34]. Other biomarkers are not yet reliable, sensitive, or specific enough to be used out with clinical trials [35]. HLA-B27 should be measured and has an appreciable sensitivity (66–78 %) and specificity (73–94 %) [34]. The acute phase response does not distinguish gut from articular inflammation and cannot replace detailed clinical assessment.

XR can detect destructive changes and bone proliferation [35], both in peripheral and axial SpA. Sacroilitis on XR and with an associated feature carries a specificity of 97 % for AS [30]. Plain anteroposterior X-ray of the pelvis is the recommended view when investigating for axial SpA [34], allowing assessment of both sacroiliac joints and hip joints. XRs are however not sensitive to detect early disease [34] and MRI is then the imaging of choice.