Signs and symptoms

AS is the most common and most typical form of SpA, with a prevalence of 0.2–1.2% in the Caucasian population , depending on regional genetic and environmental factors. This prevalence tends to be higher in populations with a higher prevalence of HLA-B27 positivity. Historically, AS was considered to affect men up to 10 times more commonly than women ; however, recent epidemiological studies demonstrated a lower male to female ratio, approximated at 2–3:1 . The initial symptoms, typically in the early adulthood, are usually of dull pain over the buttock and lower lumbar area, accompanied by morning stiffness, relived with exercise and worsened with inactivity. This inflammatory back pain, which usually responds well to nonsteroidal anti-inflammatory drugs (NSAIDs), may be unilateral or bilateral and may alternate from side to side. Since low back pain is very common in the general population, the diagnosis of AS is usually delayed by years. The mean delay from onset of symptoms to the diagnosis of AS can be as long as 8 years, with longer delays in females . Hopefully, the newly Assessment in SpondyloArthritis international Society (ASAS) diagnostic criteria, described below, will enable shortening this diagnostic delay. Other initial features include localised pain as a sign of enthesitis, inflammation at bone insertion sites of ligaments and tendons. The pain expressed due to the enthesopathy depends on the affected location (heels, ischilal tuberosities, costosternal junctions, greater trochanters and other locations). Frank arthritis may occur in 25–35% of the patients, usually involving large joints in an asymmetrical fashion (shoulder, knee, ankle and hip). Involvement of the cervical spine with neck pain leading to a reduced range of motion is generally a later manifestation in the course of the disease. Dactylitis, inflammation of an entire digit, commonly termed ‘sausage digit’, is another typical feature of the SpA, mainly in PsA and ReA. It is thought to arise from joint and tenosynovial inflammation. Other clinical features include recurrent acute anterior uveitis which occurs in about 30% of the patients and can antedate the spondylitis, cardiovascular manifestations (aortic insufficiency, congestive heart failure, aortitis, angina, pericarditis and cardiac conduction abnormalities). Dyspnoea, cough or haemoptysis can result from upper lobe pulmonary fibrosis.

PsA develops in 5–40% of psoriasis patients . Its prevalence ranges from 0.02% to 0.2% and the incidence in the normal population is 7.2 per 100,000 per year. In patients who are already suffering from psoriasis, the prevalence of PsA is much higher and rises to 7–40%. The arthritis is often asymmetric, involving small and large joints. A number of patterns of joint involvement have been described: arthritis mutilans, peripheral oligoarthritis or polyarthritis, spondylitis and distal interphalangeal joint arthritis (fingers and toes) which are commonly affected (>50%). Cervical spine disease is common (>50%) and usually progresses in severity in parallel with the peripheral joint disease. Psoriasis of the nails (in 83%) or skin may precede or follow joint involvement. The typical psoriatic lesions may be hidden in the scalp, behind the ears, gluteal folds or umbilicus, occasionally even un-noticed by the patient. Extra-articular features include constitutional symptoms, fatigue and iritis or uveitis. Similarly to other SpAs, various biomarkers have been suggested for assessing PsA. Of these biomarkers, which are still being studied, C-reactive protein (CRP), matrix metalloproteinase-3 and circulating osteoclast precursors seem to be promising . PsA, like other SpAs, is associated with HLA-B27, predominantly in those patients who suffer from axial involvement such as sacroiliitis or spondylitis.

ReA usually manifests itself as arthritis, 2–4 weeks following a urogenital or enteric infection, often in patients bearing the HLA-B27 antigen. The risk of developing ReA has been shown to occur up to 50 times higher in an HLA-B27-positive individual, as opposed to a B27-negative patient, following exposure to a preceeding infection . Furthermore, HLA-B27 positivity is involved with a more severe disease and tends to progress into a more chronic form of the disease . Enthesitis, the typical feature of ReA, occurs in 70% of the patients, usually manifesting itself as a calcaneal spur with heel pain or Achilles tendinitis. The knees may be involved with large effusions. Sacroiliitis and inflammatory back pain with spondylitis may occur in almost 50% of the patients. Dactylitis of the fingers or toes is also typical for ReA. A wide range of extra-articular features of ReA includes urethritis, cervicitis, vulvovaginitis, salpingitis and prostatitis. There are also typical dermatological manifestations, oral ulcers, erythema nodosum, conjunctivitis as well as cardiac involvement.

IBD (enteropathic)-associated arthritis is usually a peripheral large joint, lower limb asymmetric oligoarthritis. It accompanies IBD in about 10% of patients and occasionally antedates it. Occasionally, symmetrical small-joint polyarthritis may also occur in this group of patients. As with the other SpA, extra-articular and extra-intestinal features such as uveitis, erythema nodosum, pyoderma gangrenosum and others are more common in Crohn’s disease than in ulcerative colitis, and occur more often in patients with arthritis. The synovitis usually runs in parallel with the bowel disease, and may resolve completely following colectomy. The spondyloarthritis and sacroiliitis run however an independent course compared to the bowel disease, and usually run a milder course compared to AS. HLA-B27 association in IBD-associated arthritis is weaker than in AS, and only nearly 25–60% of the patients are found to be positive for B27 .

Undifferentiated spondyloarthropathy or spondyloarthritis (uSpA) is used to describe manifestations of SpA in patients who do not meet criteria for any of the well-defined SpA . There is a female predominance of 1:3 and the clinical manifestations of this type of SpA are basically similar to all other SpAs with fewer extra-articular manifestations. Similar to AS, uSpA is also linked to HLA-B27 and other human leukocyte antigen (HLA) alleles, suggesting that this subgroup of SpAs is also genetically determined . Long-term follow-up of these patients shows that even after years of active disease, sacroiliitis and spondylitis are either absent or appear very mildly on routine radiographs. Prognosis is generally good.

Juvenile-onset spondyloarthropathy is an asymmetric, mostly lower extremity peripheral arthritis, similar to adult AS, that begins most commonly in boys aged 7–16 years. Enthesitis and dactylitis are prominent features of the disease in children. Systemic manifestations are more frequent in the juvenile SpA than in the adult form.

Laboratory findings and serological markers

There are no specific laboratory tests for the SPAs. The diagnosis is therefore made by combining clinical criteria with radiological findings. Inflammatory disease markers, such as CRP, serum amyloid A (SAA) and erythrocyte sedimentation rate (ESR), are generally elevated, though not in all patients, and are therefore less useful for monitoring disease activity of AS. However, CRP, SAA and interleukin-6 (IL-6) are currently still considered the best predictors of treatment response, and an elevated level of CRP was found to be a strong positive predictor of sacroiliitis progression . Recent studies have suggested a rather new candidate biomarker representing disease activity in SpA, the soluble cytotoxic T-lymphocyte-associated molecule-4, suggesting that regulation of T-cell costimulation may reflect disease activity . This biomarker still requires however further studies. The ASAS international working group has adopted and validated the ASDAS, an instrument for assessing disease activity in AS. ASDAS components include back pain, duration of morning stiffness, patient global assessment, peripheral joint complaints, and CRP or ESR, preferably CRP . Disease activity scores are essential to measure treatment responses, as well as to decide whether patients might be candidates for treatment with the modern biologic drugs. A mild normocytic anaemia and thrombocytosis may be present in the more severe cases. Rheumatoid factor and antinuclear antibodies are generally absent in the SpAs. Radiographic changes of the sacroiliac joints are usually symmetric and consist of blurring of the subchondral bone plate, followed by erosions and sclerosis of the adjacent bone. Conventional plain radiographs of the pelvis serve as a good screening tool for evaluation of the sacroiliac joints in patients with inflammatory back pain. Nuclear scanning, computed tomography (CT) or magnetic resonance imaging (MRI) may be employed if the plain X-rays of the pelvis are negative or equivocal. It should be noted that based on recent data from the ASAS group, MRI changes have been included for the first time in the new classification criteria of early axial SpA and are now considered a major tool in the diagnosis, allowing the diagnosis of early forms of the disease long before structural damage becomes visible on X-rays . The presence of subchondral bone marrow oedema on the short tau inversion recovery (STIR) sequence or signs of osteitis on the T1-weighted gadolinium augmented sequence are positive MRI signs, indicating the presence of sacroiliitis. MRI also allows visualisation of synovial fluid and synovitis within the sacroiliac joint.

Laboratory findings and serological markers

There are no specific laboratory tests for the SPAs. The diagnosis is therefore made by combining clinical criteria with radiological findings. Inflammatory disease markers, such as CRP, serum amyloid A (SAA) and erythrocyte sedimentation rate (ESR), are generally elevated, though not in all patients, and are therefore less useful for monitoring disease activity of AS. However, CRP, SAA and interleukin-6 (IL-6) are currently still considered the best predictors of treatment response, and an elevated level of CRP was found to be a strong positive predictor of sacroiliitis progression . Recent studies have suggested a rather new candidate biomarker representing disease activity in SpA, the soluble cytotoxic T-lymphocyte-associated molecule-4, suggesting that regulation of T-cell costimulation may reflect disease activity . This biomarker still requires however further studies. The ASAS international working group has adopted and validated the ASDAS, an instrument for assessing disease activity in AS. ASDAS components include back pain, duration of morning stiffness, patient global assessment, peripheral joint complaints, and CRP or ESR, preferably CRP . Disease activity scores are essential to measure treatment responses, as well as to decide whether patients might be candidates for treatment with the modern biologic drugs. A mild normocytic anaemia and thrombocytosis may be present in the more severe cases. Rheumatoid factor and antinuclear antibodies are generally absent in the SpAs. Radiographic changes of the sacroiliac joints are usually symmetric and consist of blurring of the subchondral bone plate, followed by erosions and sclerosis of the adjacent bone. Conventional plain radiographs of the pelvis serve as a good screening tool for evaluation of the sacroiliac joints in patients with inflammatory back pain. Nuclear scanning, computed tomography (CT) or magnetic resonance imaging (MRI) may be employed if the plain X-rays of the pelvis are negative or equivocal. It should be noted that based on recent data from the ASAS group, MRI changes have been included for the first time in the new classification criteria of early axial SpA and are now considered a major tool in the diagnosis, allowing the diagnosis of early forms of the disease long before structural damage becomes visible on X-rays . The presence of subchondral bone marrow oedema on the short tau inversion recovery (STIR) sequence or signs of osteitis on the T1-weighted gadolinium augmented sequence are positive MRI signs, indicating the presence of sacroiliitis. MRI also allows visualisation of synovial fluid and synovitis within the sacroiliac joint.

Pathogenesis and environmental aspects

The exact etiology and pathogenesis of the SpAs still remains unclear, though strong evidence supports the genetic background to play a major role in the susceptibility of this group of diseases, together with environmental factors, which seem to trigger the genetically predisposed, leading to the release of pro-inflammatory cytokines such as tumour necrosis factor (TNF)-alfa .

The first and most frequently documented genetic factor identified was the tissue antigen HLA-B27. This gene consists of multiple different alleles that encode at least 70 different subtypes, many of which have yet to be studied for their disease association. However, some of these subtypes are sufficiently prevalent, so that the relative strength of their association with AS can be compared. A decreasing north–south gradient in the frequency of HLA-B27 has been noted. Twin studies, family studies and genome-wide scans, were and are amongst the techniques used in identifying the genetic factors involved. In most ethnic groups, HLA-B27 is present in approximately 90–95% of patients with AS . In the general population AS is likely to develop in up to 6% of HLA-B27-positive adults. Approximately 4–8% of the healthy population is positive for HLA-B27. Family studies have shown that first, second and third degree relatives of patients with AS have a significantly increased risk of developing AS (relative risks of 94, 25 and 3.5, respectively). Sixty percent of psoriatic patients with spondylitis and IBD-associated spondylitis are positive for B27, whereas 60–80% of ReA patients and 20–25% of patients with uSpA are positive for B27. HLA typing for B27 should however not be used as a routine diagnostic test, and should be only reserved for rare clinical situations in which the presentation is atypical or complex.

Further genetic epidemiological studies as well as modern genomics-based approaches have suggested the existence of at least six other predisposing genes to this group of diseases. Among these are HLA-B60, and HLA-DRB1 for AS, and HLA-Cw∗0602, HLA-B38 and HLA-B39 for PsA.

Association of AS with the major histocompatibility complex (MHC) explains less than half of the familiarity of AS. Major advances have occurred in recent years in demonstrating non-MHC genes involved. These include genes involved in peptide editing for loading onto class I MHC molecules (ERAP1 gene, formerly known as the ARTS-1 gene) , as well as cytokine genes such as IL-1A and those involved in the Th17 network (IL23R gene), previously known to be associated with IBD and psoriasis. Association of AS with this gene has been shown to occur in multiple different populations and was the first suggestion that the TH17 lymphocyte pathway may be involved in the disease. These findings might have an obvious therapeutic implication via an antibody which inhibits TH17 activity .

The exact molecular mechanisms involved in the association of HLA-B27 and SpA still remain unclear, though progress has been made in unfolding some of the genetic, structural, biochemical and immunological processes involved. Several suggested theories attempt to explain the possible role of HLA-B27 in the pathogenesis of SpAs . CD4+ as well as CD8+ B-27 reactive T-cells have been both found to be related to the pathology of SpA, and it has thus suggested that SpA associated with certain HLA-B27 subtypes may be the result of the presentation of ‘arthritogenic’ peptides to these CD4+ and CD8+ T-cells . Except for bacteria which clearly trigger ReA, this clear association has not been substantiated in any of the other SpA though it has been shown already over a decade ago that some forms of SpA may be triggered by enterobacterial infections, and certain subtypes share sequence homologies with these bacterial antigens such as Klebsiella pneumoniae nitrogenase . The true significance of this molecular mimicry theory remains unclear and debateable. However, the importance of intestinal pathogens was further illustrated by the HLA-B27 transgenic rat model, in which arthritis and colitis did not develop in germ-free conditions . Subclinical gut inflammation has been shown to occur in patients with AS as well as with other SpAs, although there is no obvious link to explain this association between the joint and the gut inflammation . In the case of ReA there is a clear association with a previous infection, either intestinal or genito-urinary, triggering HLA-B27-associated ReA. These patients develop a chronic SpA following infections with Yersinia enterocolitica , Salmonella typhimuriuim and enteritides , Shigella flexneri , Chlamydia trachomatis , Ureaplasma urealyticum and Campylobacter jejuni . Other pathogenic organisms have been implicated in ReA, however with less frequent associations.

DNA from some of the more frequent organisms has been found by polymerase chain reaction (PCR) in synovial cells and fluid of patients with ReA. This finding of bacterial products in the joints provides a potential link between enteric infection and joint inflammation .

Worldwide incidence and prevalence

Many studies have attempted to assess the estimates of the incidence and prevalence of AS and SpAs in various populations using different methods. Using a 50-year period hospital attendance in Rochester, US, the incidence of AS was found to be approximately 1 per 10,000 males per year and one-third of that in females . Similar findings were found in a Norwegian as well as in a Finish population over a 10-year period . Thus, these rather almost identical findings indicate the constancy in the epidemiologic characteristics of AS in those countries. However, in countries such as Japan or Greece, the incidence, as well as the prevalence of AS, was found to be much lower, as opposed to a much higher incidence in the arctic regions . AS is rare in Africa, although when it does occur it is still associated with HLA-B27.

There seems to be a clear correlation between the prevalence of HLA-B27 and the prevalence of AS in any given population throughout the world. HLA-B27 positivity varies throughout the world with a wide ethnic and geographical variation. A definite exception to the prevalence rate of 0.2–1.2% of AS in Caucasians is its prevalence amongst Haida and Bella Indians, where the estimated prevalence is much higher, reaching 6.1% . Recent studies from the US, Germany and Lithuania suggest that SpA is among the most frequent rheumatic diseases, and probably at least as common as rheumatoid arthritis .

Prevalence rates for PsA and ReA have not been studied well; however, it seems that the prevalence of the whole group of SpAs is similar, that is, approximately 1.9% . A recent population-based study found an incidence of 13% of possible ReA following a culture confirmed infection with bacterial enteric pathogens .

Diagnostic criteria

The various sets of validated diagnostic criteria which have been proposed over the years for the diagnosis of the SpAs have been recently summarised in a special supplement of the Annals of the Rheumatic Diseases dedicated to this issue . The new ASAS international working group has proposed a new set of diagnostic criteria that would enable identification of SpA before structural changes develop in the spine . These criteria which are for both axial SpA as well as peripheral SpA are shown in Table 1 a and b∗, and they permit the diagnosis of SpA in the absence of imaging, if the patient is positive for HLA-B27 and has two other characteristic features of SpA. On the other hand, they also allow this diagnosis earlier, based on MRI imaging, demonstrating sacroiliitis, rather than waiting for typical radiographic changes, which take much longer to develop. Another advantage of these criteria, compared to the previous existing sets of criteria, is that patients with the so-called uSpA can now be easily classified, according to the leading symptom. The sensitivity of the ASAS criteria is 79.5% and their specificity 83.3% .

Table 1

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