Causes of pain in patients with axial spondyloarthritis U. Kiltz, X. Baraliakos, A. Regel, B. Bühring, J. Braun

Rheumazentrum Ruhrgebiet, Herne, ABSTRACT entiated: axial SpA (axSpA), psoriatic Germany. Back pain, most frequently of the in- arthritis (PsA), reactive arthritis, arthri- Uta Kiltz, MD flammatory type, is the leading symp- tis associated with inflammatory bowel Xenofon Baraliakos, MD tom in patients with axial spondyloar- disease (IBD) and undifferentiated pe- Andrea Regel, MD thritis (axSpA). Back pain in these pa- ripheral SpA (2, 3). In this review we Bjoern Bühring, MD tients is usually either due to axial in- focus on axSpA which includes both, Jürgen Braun, MD flammation or structural changes based classification as Please address all correspondence to: on new bone formation. However, there (AS) or non-radiographic axSpA (nr- Dr Uta Kiltz, Rheumazentrum Ruhrgebiet, are other possible causes of pain in axSpA). The disease course of axSpA Claudiusstraße 45, these patients. There is, for example, is highly variable and often character- 44649 Herne, Germany. a strongly increased risk of vertebral ised by persistent or fluctuating axial E-mail: [email protected] fractures, and, especially in patients inflammation as assessed by magnetic Received and accepted on September 3, with longstanding disease, degenera- resonance imaging (MRI) and structur- 2017. tive spinal changes may play an addi- al progression as assessed by conven- Clin Exp Rheumatol 2017; 35 (Suppl. 107): tional role as a cause of pain. Rarely, tional . Both, inflammation S102-S107. but rather specifically, patients with an- and new bone formation, may lead to © Copyright Clinical and kylosing spondylitis may develop suba- pain, restricted mobility, reduced func- Experimental 2017. rachnoidal cysts that often cause neu- tion and disability leading to an im- rologic symptoms, in extreme cases a paired quality of life. Ongoing inflam- Key words: axial spondyloarthritis, cauda equina syndrome. It is therefore mation is associated with new bone pain, ankylosing spondylitis mandatory to always carefully evaluate formation. AxSpA is characterised by a the origin of back pain in these patients strong association with HLA-B27 and and to consider all possible differen- other genes such as ERAP-1 and the IL- tial diagnoses. The correct diagnosis 23 receptor. SpA is a common chronic is of major importance because treat- inflammatory joint disorder, with a re- ments may differ considerably. In the cently estimated prevalence of 1–2% monitoring of patients with axSpA it is in Caucasian populations. Typically especially important to consider that starting in the second and third decade pain may have a different origin and it of life the life expectancy is decreased is crucial to notice changes in the na- mainly due to cardiovascular comor- ture of the reported back pain. Accord- bidity. Pain and disease activity may ingly, the recently updated Assessment persist for several decades in life. Male of Spondyloarthritis international So- gender and smoking are additional risk ciety (ASAS)/European League Against factors for radiographic progression. Rheumatism (EULAR) and the treat-to- Treatment options include non-steroi- target recommendations both define im- dal anti-inflammatory agents, biologics provement of symptoms, a reduction of and physiotherapy. pain and abrogation of inflammation as important targets in axSpA that can be Presentation of pain in patients achieved by pharmacological and non- with axial SpA in routine care pharmacological treatments, in rare The most significant clinical symptoms cases including surgical methods. are inflammatory back pain and periph- eral, usually asymmetric oligoarthritis Introduction and enthesitis which are often accom- Spondyloarthritis (SpA) is a hetero- panied by pain and swelling. Clinical geneous group of rheumatic diseases symptoms range from isolated pain in characterised by inflammatory back the spine to pain in the joints caused by pain, peripheral arthritis and enthesitis, inflammation in the joint or in the en- axial inflammation, joint erosions and theses (1). new bone formation, especially in the The most prevalent health-related qual- Competing interests: none declared. spine (1). Several sub forms are differ- ity of life (HRQoL) concerns include

S-102 Clinical and Experimental Rheumatology 2017 Causes of pain with patients with axSpA / U. Kiltz et al. pain and stiffness as well as fatigue and SpA was performed, focusing on items • duration - >3 months sleep problems (4). The majority of AS of the ASAS Health Index (ASAS HI) • age at onset - <45 years patients (83%) report different degrees (18). This disease-specific question- (or younger) of pain and associated problems, for naire contains items addressing catego- • localisation - lower back one third of them stating that pain is a ries of pain, emotional functions, sleep, • mode of onset - insidious very important symptom (5). Women sexual function, mobility, self-care, and • inflammatory - morning stiffness are 2-3 times more likely than men to community life (19). The five most im- >30 minutes report high levels of pain. Female pa- portant items are pain, sleep, exhaus- • time - wakening up in the tients also report smaller reductions tion, and the ability to stand (Table I). 2nd half of the night of pain in randomised controlled trials These findings were robust and the rel- • response to - improvement by with approved drugs (6). Furthermore, ative importance of health aspects was intervention movement, not by rest substantial fluctuations in pain can be similar across subgroups of patients These items are used as sets for diagno- found in individuals but on the group (disease subgroups AS / nr-axSpA, age, sis and preselection of patients to opti- level the outcome measures remained disease duration, work status and dis- mise referral processes (26). The defini- constant over time (7). However, rec- ease activity). Similar levels of pain in tions of IBP used in these criteria sets ognition of a disease flare in clinical patients with AS as well as in nr-axSpA are variable, and views on the clinical care requiring a change in medication patients was also found to be present in usefulness, sensitivity and specificity of is influenced by several factors. As another prospective cohort some years the items are contradictory (Table II). shown in a recent ASAS initiative, a ago (20). While both groups do not However, no single parameter has change in pain or a change in Anky- differ regarding health status, disease shown the ability to differentiate the losing Spondylitis Disease Activity activity and physical function, they do various possible reasons for back pain Score (ASDAS) or the Bath Ankylos- differ in signs of inflammation – all (27). IBP is more often present in pa- ing Spondylitis Disease Activity Index were higher in patients with AS. tients with AS compared to patients (BASDAI) is the most frequent defini- with other forms of SpA (28). Because tion according to a case vignette exer- Inflammatory back pain back pain is such a common symptom cise (8). The most characteristic symptom of in patients presenting in the offices of Pain has a substantial impact on the axSpA is chronic back pain, frequently general practitioners (GPs) and orthope- life of patients in several ways. Most of inflammatory nature (IBP), which is dic surgeons, IBP is not only important studies have focused on the influence clinically well defined (21-23). Howev- to rheumatologists (29). However, the of pain on physical function, some also er, since the sensitivity and specificity diagnostic value of the IBP criteria sets on emotional components (9). How- of IBP for diagnosis and classification has been evaluated in specialised rheu- ever, the origin of back pain in patients of axSpA is limited, the combination matology care. Since the perception of with axSpA needs to be diagnosed in- of chronic back pain lasting >3 months IBP in GP care is weak it can be hypoth- dividually in every patient. Back pain and onset of typical symptoms before esised that the diagnostic value of the in patients with axSpA is commonly the age of 45 years have been chosen IBP criteria sets in GP care is even much either due to inflammation or due to for classification criteria and referral lower (30). In addition, the performance new bone formation. This differentia- recommendations (24, 25). Indeed, the of IBP criteria sets differ between GP’s tion can be a challenge for the treating sensitivity of IBP for a diagnosis of AS and rheumatologist’s offices because the because treatment approach- has been shown to be about 70% (21). pretest probability of axial SpA is rela- es for the different causes of back pain In the ASAS classification criteria for tively low in primary care, as compared may differ fundamentally (10). The axial SpA IBP is on the list of items in- to a more specialised care. interaction between inflammation and dicative of axSpA (25). When talking about differential diag- structural damage also influence physi- Patients with IBP complain about nosis, referral of patients to the respec- cal function (10-12). Rarely, but rather morning stiffness (>30 minutes dura- tive specialists is an important topic, specifically, patients with AS may de- tion), insidious onset of back pain, since back pain is a frequent complaint velop subarachnoidal cysts that often awakening because of back pain during and the capacity of rheumatologists cause neurologic symptoms, in ex- the second half of the night and alter- to see patients with back pain in gen- treme cases a cauda equine syndrome nating buttock pain. Many patients re- eral for screening purposes is limited. (13-15). Other frequent causes of back port that pain improves by movement Therefore, preselection of patients is pain are vertebral fractures and disc rather than by rest and the proportion very important. Several referral sys- and joint degeneration (see Differential of patients who have significant benefit tems for considering a rheumatologic diagnosis) (16, 17). from non-steroidal anti-inflammatory consultation have been proposed. The Which clinical symptoms of axSpA are drugs (NSAIDs) is considerably high- simplest one that has been developed important for affected patients is not er than in those with non-specific low on a data driven basis concentrates on well known. Recently a prospective as- back pain (22). The following items just three items: buttock pain, improve- sessment of the relative importance of have been shown to be relevant in that ment of the pain by movement and oc- aspects of health for patients with ax- regard: currence of psoriasis at any time point

Clinical and Experimental Rheumatology 2017 S-103 Causes of pain with patients with axSpA / U. Kiltz et al.

Table I. Relative importance of health represented in the ASAS Health Index (ASAS HI).

Item of the ASAS Health Index Aspect Relative importance Number of patients (of 192) Mean score 95%-CI with problems (%)

Pain sometimes disrupts my normal activities Pain 14.20 (13.80 to 14.60) 157 (78.9%) I sleep badly at night Sleep 10.28 (9.59 to 10.96) 113 (56.8%) I am often exhausted Being exhausted 9.63 (9.01 to 10.25) 115 (57.8%) I find it hard to stand for long Standing 9.25 (8.53 to 9.98) 142 (72.1%) I am less motivated to do anything that requires physical effort Motivation 8.70 (8.05 to 9.34) 110 (55.3%) I often get frustrated Frustration 6.05 (5.42 to 6.67) 86 (43.2%) I have problems running Running 5.88 (5.10 to 6.70) 131 (65.8%) I have experienced financial changes because of AS Financial changes 5.45 (4.67 to 6.22) 88 (44.2%) I am restricted in traveling because of my mobility Travel 5.30 (4.65 to 5.95) 83 (41.7%) I cannot overcome my difficulties Be able to overcome difficulties 4.82 (4.23 to 5.41) 56 (28.1%) I find it hard to concentrate Concentration 4.42 (3.81 to 5.03) 64 (32.2%) I am not able to walk outdoors on flat ground Walking outdoors 3.89 (3.37 to 4.41) 40 (20.1%) I lost interest in sex Sexual relationships 3.20 (2.65 to 3.74) 52 (26.1%) I have problems using the toilet Toileting 3.17 (2.58 to 3.75) 49 (24.6%) I am finding it hard to make contact with people Contact with people 2.36 (1.89 to 2.82) 33 (16.6%) I have difficulty operating the pedals in my car Driving 1.78 (1.39 to 2.17) 26 (13.1%) I find it difficult to wash my hair Washing hair 1.63 (1.25 to 2.01) 28 (14.1%)

Table II. Variables of different definitions for IBP.

Calin A et al.: first historical Rudwaleit M et al.: Based on Sieper J et al.: Based on expert definition [23] study data [21] consensus [22]

Age at onset <40 years <45 years ≤40 years (odds ratio (OR): 9.9) Duration ≥3 months ≥3 months Onset insidious insidious (OR: 12.7) Clinical features Morning stiffness Morning stiffness > 30 minutes Response to interventions Improvement by movement Improvement by movement (OR: 23.1) No improvement by rest No improvement by rest (OR 7.7) Alternating buttock pain Wakening up in the 2nd half of the night Night pain (OR: 20.4) Sensitivity# If 4/5 criteria: 90% if 2/4 criteria: 70% if 4/5 criteria: 80% Specificity# if 4/5 criteria: 52% if 2/4 criteria: 81% if 4/5 criteria: 72%

# Data of the Validation cohort (n=648) as reported in (ref. 22).

(31). If less than 2 of these items are Table III. Causes of back pain in patients with SpA. present, determination of HLA B27 is Axial inflammation including , spondylitis, spondylodiscitis, enthesitis recommended prior to referral to the Structural damage (new bone formation, ankylosis, hyperkyphosis) rheumatologist. This proposal is cur- Vertebral fractures rently being evaluated in a larger study. Spinal instability due to atlantoaxial dislocation Subarachnoidal cysts

Differential diagnosis based Degenerative spinal changes on pain in patients with axSpA Disc herniation The correct diagnosis of axSpA includ- Spinal stenosis ing the differentiation of the many dif- Fibromyalgia, myofascial pain syndromes ferent causes of back pain is of major Muscular dysbalance importance because treatments may Non-specific (low) back pain differ considerably (Table III). How- ever, the differential diagnosis of back All other causes of back pain (myocardial infarction, aneurysm, pleuritis, paptic ulcer, etc. pain in an unselected patient group may be challenging. When present- ous diseases such as degenerative disk spinal stenosis and hypermobility have ing in a primary care setting, only a disease, degenerative changes in the to be considered and interpreted to- small proportion of patients will have intervertebral (facet) joints and the as- gether with imaging of the spine (33). axial inflammation as the major cause sociated ligaments, spinal instability, A recent study from the Netherlands of their back complaints (32). Numer- herniation of the intervertebral disk, showed that the prevalence of degen-

S-104 Clinical and Experimental Rheumatology 2017 Causes of pain with patients with axSpA / U. Kiltz et al. erative changes in the spine is similar ticipation (42). ASAS recommends in- pharmacological . Several in patients with SpA and no SpA, es- dividualising the treatment of patients trials showed a reduction of pain and pecially in patients with younger age with axSpA according to the current preservation or amelioration of function (16). This is one reason why the di- signs and symptoms of the disease when AS patients performed regular agnosis of axSpA is often delayed, as (axial, peripheral, extra-articular mani- exercises (47). However, the effect size symptoms can be confused with other festations). The assessment of pain, was moderate and improvements didn’t more common but usually less serious patient global and physical function last for longer periods of time. NSAIDs disorders such as chronic low back is recommended as core domains in and biologics have demonstrated ef- pain (34). Pain in patients with SpA is clinical record keeping according to ficacy and efficiency including reduc- not only present as back pain but also ASAS/ Outcome Measures in Rheu- tion of pain in patients with axSpA. If as widespread pain which can mislead matology (OMERACT) (43). In the taken in proper dosages, NSAIDs are to the diagnosis of fibromyalgia (FM) monitoring of patients with axSpA it efficacious and relief pain and stiffness (35). Similarly, patients with FM may is especially important to consider that in 70–80% of patients (48). A meta- also present with chronic back pain, pain may have a different origin and it analysis of trials investigating the effect morning stiffness and functional im- is crucial to notice changes in the na- of NSAIDs showed a high effect size pairment, which may be a challenge ture of the reported symptoms of back for the domain pain (1.07), but only for a diagnostic differentiation to ax- pain. Therefore, assessment of pain is a medium effect size for the domain SpA (36). It has been shown that pa- crucial in the management of patients physical function (0.54) (49, 50). The tients with axSpA fulfill ASAS classi- with axSpA. Pain as a single measure role of analgesics has not been formally fication criteria for axial SpA and in a can be assessed by using a numerical studied so far. According to the ASAS quarter also the FM classification cri- rating scale (NRS) or visual analogue recommendations, analgesics such as teria, but that FM patients in most cas- scale (VAS) for pain in general or for paracetamol might be considered for es did not fulfill ASAS classification spinal pain in particular. Most dis- residual pain in axSpA patients after criteria for axial SpA (37) (Rheuma- ease activity instruments also include previously recommended treatments tology 2017, accepted). In this context a question about pain. Different types have failed, are contraindicated, and/or it is important to understand that pa- of disease activity measures are avail- poorly tolerated (42). tients with axial and/or peripheral pain able: self-report (patient) instruments The introduction of tumour-necrosis- might suffer from an enthesitis as well, (e.g., BASDAI and composite indices factor inhibitors (TNFi) has clearly since these issues presence can easily (e.g., ASDAS) (44, 45). The patients opened a new era of treatment of pa- be overlooked in a clinical setting (38). should report the level of back pain and tients with axSpA. TNFi show strong The disease course in patients with level of pain in the joints, overall level therapeutic effects in both, peripheral axSpA can be complicated by an in- of fatigue and morning stiffness. The 6 and axial SpA. Anti-TNF leads creased risk of vertebral fractures items of the BASDAI sum up to a score to a marked reduction of pain and im- which adds another aspect of pain between 0–10, higher values indicate provement of function, as shown in aetiology in patients with an estab- more active disease. However, it is well many clinical trials and different meta- lished disease (39). Many fractures are known that the BASDAI is a subjec- analyses (49-51). For the domains pain missed in clinical setting because back tive measure based on patient’s percep- and patient’s global assessment, the pain has been interpreted as a disease tions reporting their pain at different treatment effect for TNFi was large flare of spondylitis (40). Moreover, the locations, its duration and intensity, (standardised mean difference (SMD) fact that more AS patients with syn- the extent of morning stiffness and the (95% confidence interval (CI)) -0.9 desmophytes had reduced bone den- overall level of fatigue. The composite (-1.07, -0.73)) (49). Patients treated sity than those without suggests that index Ankylosing Spondylitis Disease with TNFi were more likely to achieve bone growth and bone loss occur in Activity Score (ASDAS) is using three an ASAS 20 response after 12 weeks in parallel in axSpA patients (41). questions of the BASDAI (Question 2 all randomised controlled trials (RCTs) about total back pain, Question 3 about performed so far in axSpA (52). A Assessment of pain in patients peripheral pain and Question 6 about marked pain reduction as assessed by with SpA morning stiffness) but also inflammato- ASAS 20 or BASDAI50 response rates As already mentioned, pain and es- ry markers (C-reactive protein (CRP) or was also seen in trials with the interleu- pecially back pain is one of the major erythrocyte sedimentation rate (ESR)) kin-17A inhibitor secukinumab in AS symptom of patients with SpA. ASAS/ and patient’ global assessment. ASDAS (53, 54). EULAR management recommenda- was shown to be highly discriminatory Improvement of symptoms and reduc- tions focus primarily on reducing and in differentiating patients with different tion of pain can be achieved not only by controlling signs and symptoms and levels of disease activity (46). pharmacological and non-pharmaco- therefore maximising health-related logical treatments, but also with surgi- quality of life by preventing progres- Treatment cal methods in patients with severe hip sive structural damage and preserving/ Improvement of pain can be achieved involvement or spinal hyperkyphosis. normalising function and social par- by pharmacological, surgical and non- In patients with refractory pain and/or

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