The current concept of spondyloarthritis with special emphasis on undifferentiated spondyloarthritis

In a recent international workshop for ankylosing spondylitis (AS), a consensus was reached that the term ‘spondyloarthritis’ is preferable to ‘spondyloarthropathy’, to emphasize the inflammatory nature of these diseases [1]. The term is often quoted in the plural form, ‘the spondyloarthritides’, accentuating that this is a group of similar diseases with distinct clinical features and a common genetic predisposition, rather than one disease with different clinical presentations. The main association recognized is with HLA B27 but it is clear that there are other genes involved, including the interleukin-1 family gene cluster [2, 3]. Irrespective of the subtype of spondyloarthritis (SpA), the main clinical manifestations of this group are inflammatory back pain (IBP), peripheral arthritis, enthesitis and anterior uveitis, while other organ manifestations are rare. Psoriasis and inflammatory bowel disease (IBD)-associated colitis should be considered as basic subtype-defining entities with their own genetic background, rather than as disease manifestations. Five major subtypes of SpA are recognized on the basis of recently proposed classification criteria (European Spondyloarthropathy Study Group [ESSG]). In recent years we and others have defined the subgroups as AS, psoriatic arthritis (PsA), reactive arthritis (ReA), arthritis associated with inflammatory bowel disease (AIBD) and ‘undifferentiated’ SpA (uSpA). This terminology suggests that it is intended to, for example, include the whole group of patients with psoriasis-associated arthritis. Even on the basis of the ESSG criteria, this is certainly not correct and it is well recognized that there are different subtypes of PsA, including patient groups that rather resemble rheumatoid arthritis or osteoarthritis. Therefore, it is much clearer to choose another terminology, which is hereby introduced. The subtypes are ankylosing spondylitis, psoriatic SpA (PsSpA), reactive SpA (ReSpA), SpA associated with inflammatory bowel disease (SpAIBD) and uSpA. Alongside AS, uSpA is the most common subtype of the spondyloarthritides [4, 5] with a prevalence between 0.7% and 2.0% [5–7], and yet we know less about it than the other subtypes. This is often the case when new disease classifications emerge, and it can be difficult to retrospectively assess disease prevalence and associations from studies designed to address different disease classifications. This review aims to outline the current concept of SpA and uSpA, the latter in more detail, looking at its clinical features and natural history and the current evidence for therapy. The clear definition of uSpA as a clinical entity separate from other spondyloarthritides is a part of the current disease classification schema. Historically, there have been numerous changes in the classification of what we now recognize as SpA, as we have learned more about disease mechanisms and the effects of therapy. In 1957 the International League against Rheumatism (ILAR) first described a group of ‘atypical rheumatoid arthritis’ [8] including AS, arthritis associated with psoriasis (PsA) and ReA, grouped together as a pot pourri of inflammatory arthritides that did not conform to the symmetrical polyarthritis phenotype of rheumatoid disease, rather than as a group with common features. Over the years it was realized that this classification did not address the clinical similarities of the atypical group, including a predilection for spondylitis and sacroiliitis, enthesitis and extra-articular manifestations such as acute uveitis and inflammatory bowel lesions. Moll et al. [9] first described the ‘seronegative spondyloarthropathies’, being rheumatoid factor-negative but sharing common clinical, radiological and genetic features. The changing scope of SpA terminologies has made it difficult to compare studies. It is very likely that the incomplete Reiter's syndrome described by Arnett et al. in the 1970s [10] would today be reclassified as uSpA; in the absence of evidence of preceding infection, it is unknown if such patients were really ReA with an undefined trigger, or what we now recognize as uSpA. The need for a standardized, evidence-based approach to classification led to the development of the ESSG preliminary classification criteria for spondyloarthropathy [11]. This introduces the unifying concept of SpA as a group of related diseases with common features (Table 1). In the last 10 yr the work of this historical group has been taken over by the Assessments in AS (ASAS) working group, which is currently working on a novel set of criteria on the basis of recent statistical calculations and a probability model [12]. One aim of this enterprise is to include magnetic resonance imaging (MRI) in the criteria set. European Spondyloarthropathy Study Group (ESSG) classification criteria for spondyloarthritis European Spondyloarthropathy Study Group (ESSG) classification criteria for spondyloarthritis The ESSG classification criteria for SpA have been well studied and validated in population studies [13–16] and have a good sensitivity of 75% and a specificity of 87%. An alternative classification scheme was put forward by Amor et al. [17] (Table 2), which is more complicated but gives improved sensitivity (85%) and specificity (90%), due to the incorporation of common extra-articular manifestations of disease, including enthesopathy, dactylitis, eye disease and HLA-B27 positivity. The basic concepts underlying each classification set are nevertheless similar. Amor classification criteria for spondyloarthropathy Amor classification criteria for spondyloarthropathy It is important to remember that these were developed as classification criteria, not diagnostic criteria. Although they are useful for epidemiological studies they are not necessarily ideal for daily clinical practice, where the spectrum of disease is wider and where it is especially important to include patients in very early disease stages. Therefore, it is important to stress that the ESSG criteria have been shown to lose both sensitivity and specificity when disease has been present for less than 12 months. Nevertheless, it has been suggested and it seems clear by the way rheumatologists refer to it that the classification might be a useful guide in a clinical setting [18, 19], depending on the underlying prevalence of disease. Thus, for practical and pragmatic reasons the criteria are often used in clinical practice and it can be expected that the new criteria set will also be used in clinical practice, provided it is easier to use than the previous set. A patient is considered as suffering from uSpA if he/she fulfils the criteria for SpA as defined by either the ESSG or the Amor criteria, without evidence suggesting a more specific disorder, such as AS (as classified by the modified New York criteria; Table 3 [20]), psoriasis, IBD or evidence of a preceding bacterial infection trigger. More simply, a patient with either IBP or peripheral arthritis who also has evidence of current or previous enthesopathy or alternating buttock pain would be classified as uSpA. There are no pathognomic clinical features for uSpA, and the absence of diagnostic tests for any of the spondyloarthritides requires diagnosis to be made on a combination of history, clinical examination and supportive laboratory tests. The absence of rheumatoid factor is not diagnostic and therefore rarely mentioned, and the term ‘seronegative’ is being increasingly abandoned. Modified New York Criteria for AS (1984) Modified New York Criteria for AS (1984) IBP, peripheral arthritis and, less frequently, enthesitis are the main clinical features of uSpA [5]. In the original definition by Calin [21], IBP occurs in patients less than 40 yr of age, lasts more than 3 months, has an insidious onset, is associated with morning stiffness and is reduced by physical activity. Other authors have since reported that alternating buttock pain and nocturnal spinal pain are also important [22]. Since uSpA as it stands now is mainly a clinical diagnosis with IBP as the prominent clinical feature, there is a need to re-evaluate the proposal originally published in 1977 [21]. A study recently performed in Berlin included 214 AS patients with a disease duration of 12 yr and controls with mechanical back pain of more than 3 months. Morning stiffness for longer than 30 min, improvement by exercise but not by rest, nocturnal pain and alternating buttock pain were the best discriminating features (Rudwaleit M, unpublished data). If two of the four criteria are fulfilled, the set had sensitivity of 70% and a specificity of 80%. These criteria need to be tested in uSpA and early AS patients. In patients with uSpA, overt radiological spinal disease is usually not present [23], since most SpA patients with involvement of the spine will have sacroiliac changes indicating AS. Inflammatory involvement of the spine ([24]; Braun J and van der Heijde D, unpublished data) and occasionally single syndesmophytes may occur. However, if there is a larger number of syndesmophytes or other evidence of definite clinically relevant spinal disease with a clear impact on the patient, a diagnosis of AS should be made by the expert. Very much along this line, it is well established that a small percentage of AS patients does not have clearcut sacroiliac changes. In uSpA, sacroiliitis is milder than in definite AS cases, often due to an earlier stage of disease [by definition, if sacroiliitis of radiological grade 2 or more bilaterally is present, the patient has AS (Table 4) [25]]. Sacroiliitis may not be present at all [22]. Peripheral arthritis is typically asymmetrical, often involving only one to three joints and preferentially involves larger joints in the lower limbs. Enthesitis, defined as an inflammation of tendinous or ligamentous attachments to bone, is common and can occur at any site, including the spine, commonly (but certainly not exclusively) at the Achilles tendon insertion, plantar fascial insertion on the calcaneus and the tibial tuberosity. Dactylitis, a soft-tissue swelling of one or more digits, can also occur, although not as frequently as might be seen in PsSpA or ReSpA. Extra-articular features of SpA are less frequent [26], including acute anterior uveitis or conjunctivitis (33%), mucocutaneous involvement (16%) and cardiac manifestations (8%), and may have preceded the more characteristic spinal or joint symptoms by years. Grading of radiographic sacroiliitis (1966) Adapted from reference 25. Grading of radiographic sacroiliitis (1966) Adapted from reference 25. As already pointed out, on a cautionary note, the classification of uSpA relies heavily on the presence of IBP or peripheral oligoarthritis. It does not include, for example, a patient with only enthesitis, dactylitis or anterior uveitis as major clinical symptoms; there still remain a number of clinical that are not by current schema. of these SpA manifestations can be considered as early disease, as there are patients with IBP who did not have or features of SpA, but have sacroiliitis by without definite sacroiliitis on were classified as of were HLA [5]. As with any classification criteria, there will be patients who not this of all symptoms and are important in a diagnosis in patients (Table imaging and laboratory in SpA imaging and laboratory in SpA As with all ‘seronegative’ there is a of HLA B27 in uSpA. studies the prevalence of HLA B27 in uSpA to be between and between studies as a of underlying population HLA B27 In with IBP, HLA B27 a of SpA and a of radiological sacroiliitis than in when B27 is other genes have been to to uSpA. A number of patients with SpA not have inflammatory it is by IBP and peripheral inflammatory arthritis. An or has therefore no diagnostic and should be used to disease in patients rather than to a in SpA can in diagnosis if syndesmophytes are present, but not the disease. changes of the sacroiliac joints are by definition and may often be The radiological between uSpA and AS is the presence of two or more sacroiliac joint and more than one or imaging is more than in and inflammatory sacroiliac and may early sacroiliac disease. A recent study of in uSpA patients a prevalence of sacroiliitis patients did also have evidence of spondylitis Thus, is in early diagnosis of SpA but the of such imaging use for diagnosis or of of peripheral joints are often or evidence of swelling in the acute are not prominent in AS or uSpA, the in changes seen in can often be seen at of enthesitis example, the and at the tibial or is an imaging to the changes of enthesitis, and which are frequently associated with Since IBP is the most clinical in uSpA and since these patients are most likely to AS this has been the use of in early disease has led to the proposal of SpA as a separate clinical Since peripheral arthritis and enthesitis are to occur and in to IBP we the term which in the there are at two of uSpA one AS and one uSpA. The patients who AS may rather or it may years definite spinal changes have there are that the between symptoms and the of definite changes. Since patients with inflammatory spinal changes both clinically and by at early disease are most likely to AS, the concept of uSpA or early SpA with involvement is important may have the to these patients but also to AS. A study this is but also difficult to since the early of these patients has been in recent One major for this is the prevalence of back pain in the population If the disease is and there may be to or a patient as uSpA. However, since it is that the duration of symptoms diagnosis in AS the concept of SpA and uSpA should have in this patient As already we need to the criteria for early SpA to in early Thus, the most important of uSpA is the of to AS or other of et al. have reported on SpA patients with sacroiliitis with no changes at 3 of the patients had developed radiological AS. In an earlier clinical of uSpA patients were reported to have to AS over 10 yr with associated and A more recent study of the natural history of uSpA patients an of the patients to AS This group had established disease at a at disease uSpA being defined by the ESSG criteria. was seen in four one had developed psoriatic disease and four patients The was with rather in most patients at but the had evidence of sacroiliac changes 2 or There were patients with syndesmophytes and had developed a spine in the et al. that only of a of patients with uSpA disease duration had to AS 2 yr of one patient PsSpA in this and 75% of patients As already this is to over These may well the of changes to AS in uSpA patients. there is only one study patients for more than yr which would that yr is well but were small and studies are to a of Other studies of SpA that may retrospectively be considered to the uSpA definition have reported of to AS from to from uSpA to AS is not the only between SpA subtypes. It is also that patients classified as uSpA will psoriasis, to the diagnosis of There may be new of colitis or an of IBD in or new of an Nevertheless, these to be less common than the development of AS or the patient in the uSpA it is more in the radiographic of spinal changes that a definite of the SpA patient should be to the prominent clinical of spinal involvement rather than on the presence of or disease. Thus, a patient with AS and psoriasis has AS and psoriasis he/she fulfils the AS criteria. or can be classified and as psoriatic There are on the of SpA, uSpA and AS. One study suggests that in SpA there are clinical features that disease including the presence of arthritis, acute a to of of at the spine, dactylitis, and early onset, all to more disease In ReA, of patients with acute arthritis will have disease, will with the and only of patients will arthritis or AS is seen in patients with disease, HLA B27 extra-articular manifestations In with it to be that the between uSpA, ReA and may of the with are to be and are but not very Thus, the clinical symptoms and the of by or remain the best In to these it is not clear which features of uSpA may be of pain has been shown to be associated with to definite SpA 2 yr with a a of HLA but studies are the of increasingly for SpA in the last it is important that we are to patients at of to disease who might from early has been shown to be useful for early sacroiliitis, and can the development of radiographic changes of sacroiliitis at 3 yr with a of It well with changes seen on and is to in patients with IBP and clinical symptoms and changes it a in the of patients with early disease, including with uSpA. is useful to enthesitis and not only in the but also in peripheral joints and The latter are also well by The of such imaging has not yet been in this Nevertheless, is likely to be included in classification criteria for early recently there has not been a of evidence to any one for uSpA, the spondyloarthritides as a group have and the definition of uSpA is It is not necessarily to for AS or when we that not all uSpA patients will and it is not yet to at of disease. used for the different clinical manifestations of the may be in uSpA, such as for The currently evidence for the use of is There are no of in uSpA; have been the of of involvement in AS. have been shown to be for IBP in study of patients with improvement in pain and with of patients with mechanical back pain of pain with about of patients with early AS to have disease There is no good evidence to the use of in any of the has been shown in small to be for pain in AS and are useful in the of sacroiliitis in AS patients are useful for enthesitis in other A recent of in uSpA and early AS suggests may have a in the of disease and patients were from 12 the criteria being a 3 disease and In patients a and for to months. of the group was and were HLA had enthesitis at peripheral arthritis and patients with IBP but no peripheral arthritis were seen to have a larger improvement in with than the group, but other patient subgroups were not different from groups also on to their symptoms than did the group, which might have the lower of pain seen in the It is difficult to as it may be the in the group that has any to the this is the only study of in uSpA, and studies are In to uSpA, studies of in AS have been et al. have that was no than for disease in patients with AS, but it may be more than for peripheral joint involvement The currently evidence for peripheral arthritis in uSpA is not has been shown to uveitis in AS patients There have been no studies of in uSpA. One case has reported a of 10 with in a with acute of one previous Achilles with plantar sacroiliitis on and a all and manifestations over months. case are is commonly used as a in rheumatoid arthritis with good symptoms and the of radiological disease. It has not such in AS the different mechanisms of the two another commonly used in rheumatoid arthritis has not been studied in There are no studies in uSpA; a study in AS patients recently suggested that it is not for the manifestations of AS and a larger in AS to any disease to as by the There are no studies on the of peripheral arthritis or extra-articular manifestations to in the There are to no of in uSpA. There is a small but of evidence for the use of a used in disease, in AS. studies have shown in spinal pain with but effects on The only recent 10 of over to at the spinal pain and were improved in the group with the There are no to the in a for a with characteristic The of factor in sacroiliac joints in AS patients led to the of as a for has since to be the most important in SpA to is a of the from case studies early evidence for an of in uSpA can be in studies a of different SpA subtypes studies included only small of uSpA and although the different subtypes were not study were A study of on and good in SpA of two had uSpA. was seen in all of the joint pain in the group for each disease subtype were not but the authors that there was no in between disease classifications. the group was for yr there had been two from the one of was a uSpA patient who due to disease at 12 therapy. A recent study of SpA patients with 10 with uSpA, that to yr with The group reported good clinical in a of in 40 patients with spondyloarthropathy but in both studies only were The first of in uSpA was a small study reported by a Berlin group uSpA patients with disease who had been either to or had not it of 3 or at 2 and patients the ESSG criteria for SpA, but the criteria for a PsA, was yr and disease duration patients had IBP in the sacroiliac at the of the four had radiographic sacroiliitis grade three had and three patients had involvement in the was seen in of the patients the first 12 disease and pain by had improved in all with more in the three patients the of The number of joints improved by enthesitis improved in two and as by the Study in pain and in this study were seen to to with early AS A group has recently reported an study of in 10 uSpA patients patients the study at a of at 2 and 12 patients reported an improvement in and disease improved in The to was not as as with previous AS but the for this is studies are to there is a in between the two of or there are disease features common to both that to a with in AS have shown clinical improvement with therapy. is reduced with and both disease and physical over 2 yr with is but there is early evidence of a on of is a of the to the of As with the of the use of in uSpA are for a of a larger study in et al. reported an study of at a of for in 10 patients with SpA, one of was defined as uSpA. was at a in patients already this but not improved over patient and joint pain enthesopathy in the study The only patient with uSpA had early disease duration of and in clinical more than therapy. of the of the it is not to that early disease gives a but this certainly the does early disease more or more to and if is it to the of uSpA to AS or other more with This is an important with to current for in the at present, only patients criteria for AS for any of the and there is a need to address their in other such as disease. The only study of in uSpA was recently published by et al. uSpA patients were included in an which that at 12 similar to seen in AS the ESSG criteria for SpA but of the criteria. had disease for at months, with a pain of or more a of to had at the of the one patients had evidence of enthesitis and three had current or of the 10 patients more than improvement in at disease manifestations including IBP, peripheral arthritis and enthesitis, of as by the and the and as by the patients to an improvement at of therapy. of the patients who to was at an of recent studies of in AS have shown clinical improvement with with in morning stiffness and nocturnal spinal pain improvement in disease and a is the currently for the of rheumatoid arthritis. A recent study in AS suggests that may have similar to other in AS, although in both AS and uSpA are at a different in the inflammatory is a interleukin-1 the only study of in SpA to any of on manifestations in AS As the ESSG classification criteria for SpA are more used in clinical practice, it is important that more with the concept of uSpA, if in it can be considered as early AS. we the natural of the patient and the of that are in spinal and peripheral joint the is for in the early of disease, and for to the of The authors have no of