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Clinical presentation of patients suffering from recent onset chronic inflammatory back pain suggestive of spondyloarthritis: The DESIR cohort
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Original article
Clinical presentation of patients suffering from recent onset chronic inflammatory back pain suggestive of spondyloarthritis: The DESIR cohort Maxime Dougados a,b , Adrien Etcheto b , Anna Molto a,b , Sandrine Alonso c , Sophie Bouvet c , Jean-Pierre Daurès c , Paul Landais c , Maria-Antonietta d’Agostino d , Francis Berenbaum e , Maxime Breban d , Pascal Claudepierre f , Bernard Combe g , Bruno Fautrel h , Antoine Feydy i , Philippe Goupille j , Pascal Richette k , Thao Pham l , Christian Roux a , Jean-Marc Treluyer a , Alain Saraux m , Désirée van der Heijde n , Daniel Wendling o,∗ a Paris Descartes University, Department of Rheumatology, hôpital Cochin, Assistance publique–Hôpitaux de Paris, 27, rue du Faubourg-Saint-Jacques, 75014 Paris, France b Inserm (U1153), Clinical Epidemiology and Biostatistics, PRES Sorbonne Paris-Cité, 109, avenue de France, 75013 Paris, France c Département d’information médicale, CHU de Nîmes, 30029 Nîmes, France d Department of Rheumatology, Ambroise Paré Hospital, Assistance publique–Hôpitaux de Paris, 92100 Boulogne-Billancourt, France e Department of Rheumatology, hôpital Saint-Antoine, Assistance publique–Hôpitaux de Paris, 75012 Paris, France f Department of Rheumatology, hôpital Henri-Mondor, Assistance publique–Hôpitaux de Paris, 94010 Créteil, France g Department of Rheumatology, CHU de Montpellier, 34295 Montpellier, France h Department of Rheumatology, hôpital de la Pitié-Salpêtrière, Assistance publique–Hôpitaux de Paris, 75013 Paris, France i Department of Radiology, hôpital Cochin, Assistance publique–Hôpitaux de Paris, 75013 Paris, France j Department of Rheumatology, CHU de Tours, 37044 Tours cedex 9, France k Department of Rheumatology, hôpital Lariboisière, Assistance publique–Hôpitaux de Paris, 75010 Paris, France l Department of Rheumatology, CHU, Assistance publique–Hôpitaux de Marseille, 13005 Marseille, France m Department of Rheumatology, CHU de Brest, 29609 Brest cedex, France n Department of Rheumatology, Leiden University Medical Center, 2311 Leiden, The Netherlands o Université de Franche-Comté, Department of Rheumatology, CHRU de Besanc¸on, 25030 Besanc¸on, France
a r t i c l e
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Article history: Accepted 4 February 2015 Available online xxx Keywords: Spondyloarthritis Epidemiology Classification criteria Cohort
a b s t r a c t Objectives: DESIR is a prospective longitudinal multicentric French cohort of patients with inflammatory back pain suggestive of spondyloarthritis, with a 10-year-follow-up. The purpose is to evaluate the performances of the different sets of classification criteria for axial spondyloarthritis, and to describe the frequency and characteristics of the clinical features of axial spondyloarthritis. Methods: Demographic data and items allowing classification and indices calculation were collected, as well as biologic and imaging data. Baseline data are analyzed. The performance of the several classification criteria sets was evaluated (likelihood ratio) with the physician’s diagnosis as external gold standard. For the clinical presentation of axial spondyloarthritis, a descriptive analysis was conducted. Results: Seven hundred and eight patients are included. Ninety-two percent of them satisfy at least one set of classification criteria: mNY 26%, Amor 79%, ESSG 78%, ASAS 70%; physician’s confidence level 6.8 ± 2.7. 81 and 83% of patients fulfil modified (including MRI) Amor or ESSG criteria. Axial involvement is present in 100% of the cases. NSAIDs are taken by 90%, with an NSAID sore of 50 ± 46. BASDAI over 40 is noted in 60% and elevated CRP in 30% of the cases. HLA-B27 is present in 58%. According to ASDAS CRP levels, 12.7% are in inactive disease, 63% in high disease activity; mean BASFI was 30. Peripheral involvement is present in 57%, with arthritis in 37% of these. Enthesitis is noted in 49% of the patients, and first symptom in 22.5%; anterior chest wall involvement is noted in 44.6%, and dactylitis in 13%. For extra articular manifestations, psoriasis is recorded in 16%, uveitis in 8.5% and IBD in 5.1%. Smoking is present in 36.3% and hypertension in 5.1% of the cases. Conclusion: These data represent the base of evaluation of the follow-up of this cohort, allowing future specific studies. © 2015 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
∗ Corresponding author. Université de Franche-Comté, Department of Rheumatology, CHRU de Besanc¸on, 25030 Besanc¸on, France. E-mail address: [email protected] (D. Wendling). http://dx.doi.org/10.1016/j.jbspin.2015.02.006 1297-319X/© 2015 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Dougados M, et al. Clinical presentation of patients suffering from recent onset chronic inflammatory back pain suggestive of spondyloarthritis: The DESIR cohort. Joint Bone Spine (2015), http://dx.doi.org/10.1016/j.jbspin.2015.02.006
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1. Introduction
2. Methods
Spondyloarthritis is probably the first diagnosis to evoke in case of chronic inflammatory back pain occurring before the age of 40 years old [1]. The terminology has changed over the years: Betcherew’s disease for our German colleagues [2], ankylosing spondylitis, axial spondyloarthritis [3]. The major difference between ankylosing spondylitis and spondyloarthritis is that ankylosing spondylitis is focused only on the axial symptoms of the disease with structural damage observed on plain X-Rays at the sacroiliac joint level, whereas spondyloarthritis refers not only to the axial symptoms of the disease but also to its other different clinical presentations (e.g. peripheral articular involvement, peripheral enthesitis, extra-rheumatological features such as psoriasis, uveitis, inflammatory bowel disease). Moreover, concerning the axial symptoms, the so called disease “spondyloarthritis” can include patients without structural damage of the sacroiliac joints [4]. Concerning the criteria proposed to classify the patients suffering from this disease, the conventional ones are the modified New York criteria [5]. Such criteria are making as mandatory the presence of structural damage of the sacroiliac joints on pelvic Xrays (commonly but wrongly named “sacroiliitis” since “itis” should refer to an inflammation whereas the pelvic X-rays are only able to detect structural damage such as joint erosions and sub-chondral bone sclerosis). In the 1980s, criteria have been proposed with the possibility to recognize patients without structural damage at the sacroiliac joints and with the recognition of the importance of the different clinical manifestations observed in such patients (e.g. the Amor criteria [6] and the European Spondyloarthritis Study group criteria [7]). It must be recognized that despite their relevant psychometric properties, in particular the ones of the Amor criteria [8], such criteria have not been used so widely and in particular, only rare therapeutical trials have been conducted by pharmaceutical companies with reference to this criteria for enrolling the patients [9,10]. The international society focused on the different outcome measures/criteria in the area of spondyloarthritis (e.g. Assessment of Spondylo Arthritis [ASAS]) has elaborated a new set of criteria for spondyloarthritis [11] including not only the previous items (e.g. all the different clinical features of spondyloarthritis, the possibility to recognize patients without objective structural damage of the sacroiliac joints on pelvic X-rays) but also considering the importance of objective signs of inflammation (e.g. subchondral bone edema of the sacroiliac joints at MRI [12]). Such criteria have been widely used in particular by pharmaceutical companies who have started to conduct studies referring to such new criteria. Some recent trials have even been focused on patients with non-radiographic axial spondyloarthritis [13,14]. Such criteria are classification criteria and therefore are performing well in patients with established disease. However, their performances at an early stage of the disease have been less investigated. Moreover, in case of a patient presenting with axial symptoms, the frequency of other clinical spondyloarthritis features remains to be investigated. The French Society of Rheumatology has recently initiated a huge national multicenter cohort, the so-called “DESIR cohort study” (Devenir des spondyloarthrites indifférenciées récentes [DESIR]) to facilitate investigations on diagnostic and prognostic markers but also aetiologic, pathogenic and socio-economic factors among patients with early inflammatory back pain suggestive of axial spondyloarthritis [15]. These preliminary remarks prompted us to conduct an analysis of the patients enrolled in the DESIR cohort in order to evaluate the properties of the different sets of criteria and to describe the frequency and the characteristics of the different clinical features of spondyloarthritis.
2.1. Study design. Inclusion criteria DESIR is a French prospective multi-center, longitudinal cohort aiming to study patients with early inflammatory back pain suggestive of Spondyloarthritis (clinicaltrials.gov: NCTO 164 8907). This study fulfilled the current Good Clinical Practices and has obtained the approval of the appropriate ethical committee. Participants at the study gave their written informed consent. A specific website (www.lacohortedesir.fr) contains the detailed description of the centers, the organization of the cohort but also the full detailed protocol and case-report form. Patients were enrolled (inclusion period 2007 to April 2010) if they were aged > 18 years and <50 years and suffering from back pain involving the thoracic, lumbar spine or buttock area from more than 3 months less than 3 years. Such back pain had to fulfil the characteristics of “inflammatory” in accordance to either the Berlin [16] or the Calin criteria [17]. Moreover, the physician in charge of the enrolment of the patients had to score his/her level of confidence about the diagnosis of spondyloarthritis on a 0–10 scale (where 0 = not confident and 10 = very confident). A score ≥ 5 was mandatory to permit the inclusion of the patients. 2.2. Collected data A part from the data checking the inclusion criteria, the collected data comprised both patient demographics and clinical presentation of the disease. Demographics included age, gender and body mass index (BMI). Moreover, all the items permitting to adequately classify a patient according to the different sets of criteria (e.g. modified New York, Amor, ESSG and ASAS) were collected. The activity of the disease was evaluated using the following: Back Ankylosing Spondylitis Disease Activity Index (BASDAI) [18] and Ankylosing Spondylitis Disease Activity Score–C Reactive Protein (ASDAS-CRP) [19]. Moreover, inflammatory lesions according to the OMERACTASAS definition were recorded at the MRI of the Spine and the sacroiliac joints [12]. Such evaluation (binary variable: yes/no) was performed by the local radiologist or rheumatologist. The severity of the disease was assessed using the following: Bath Ankylosing Spondylitis Functional Index (BASFI) [20] and BathAnkylosing Spondylitis Metrology Index (BASMI) [21]. Moreover, plain X-rays of the spine and the pelvis permitted to score the structural damage of the sacroiliac joints. Radiologists or rheumatologists at each study center scored each sacroiliac joint as follow: 0 = normal, 1 = doubtful, 2 = obviously abnormal, or 3 = fused. For this present analysis, sacroiliac joints were considered abnormal if at least one sacroiliac joint was scored 2 or 3. This scoring method used for the local reading in DESIR is derived from the modified New York criteria for radiographic sacroiliitis changes [5] with one modification: grade 2 and 3 of New York criteria were pooled in one sole grade. The modified Stoke Ankylosing Spondylitis Spine Score [22] was calculated from the conventional X-rays of the cervical and lumbar spine. At MRI, local investigators evaluated the presence of chronic changes at the sacroiliac joint level. Such changes were defined by the presence of clear characteristic lesion such as sclerosis, erosions, bone bridges or ankylosis of the joints. The different clinical features of the disease were also collected: enthesitis, dactylitis, peripheral arthritis, extra-articular features, family history. Moreover, ultra sound examination of the entheses as well as bone mineral density and body composition assessments were performed in selected centers. The impact of the disease was evaluated according to the number of jobs paid missed days and also by the quality of life index (SF36) [23].
Please cite this article in press as: Dougados M, et al. Clinical presentation of patients suffering from recent onset chronic inflammatory back pain suggestive of spondyloarthritis: The DESIR cohort. Joint Bone Spine (2015), http://dx.doi.org/10.1016/j.jbspin.2015.02.006
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Finally, comorbidities were evaluated by checking the history of cardiovascular, infectious and malignant diseases. 2.3. Statistical analysis The statistical analysis was conducted in two consecutive steps with regard to the two main objectives of this study. For these analyses, only data of the baseline visit of DESIR were used, the database used was the one locked on 15/09/2014. 2.3.1. Performances of the different sets of classification criteria of axial spondyloarthritis First, it was investigated how many patients fulfilled at least one of the classification criteria sets of spondyloarthritis, shown in Venn diagrams. For the Amor and ESSG criteria, we also investigated the possibility to include the MRI findings in terms of inflammatory lesions observed at the sacroiliac level. For this purpose, for each criteria, we considered the item “sacroiliitis” fulfilled in case of either radiologic or MRI sacroiliitis. We called these criteria modified AMOR (mAmor) or ESSG (mESSG) criteria. The ASAS criteria for axial SpA were used. Next, the performances of the different sets of criteria were tested. For this purpose, the diagnosis of the physician served as external gold standard. For this present analysis, we considered as a positive diagnosis a score above 7 (e.g. 8,9 or 10) on the 0–10 scale. The performances of each set of criteria were determined by calculating sensitivity, specificity, positive likelihood ratio (LR+) and negative likelihood ratio (LR–). Thereafter, the main clinical characteristics of the patients were described per sets of criteria. 2.3.2. Clinical presentation of axial spondyloarthritis For this purpose, descriptive analyses were conducted. For each clinical rheumatological feature of spondyloarthritis (e.g. axial symptoms, peripheral arthritis, peripheral enthesitis) the frequency; the localization and the activity at baseline were depicted. For the other features of spondyloarthritis (e.g. family history, extra-rheumatological features) only the frequency was calculated. Finally, the percentage of patients with specific co-morbidities was also calculated and especially cardiovascular, infectious and malignant diseases. 3. Results
Fig. 1. Venn diagram representing the overlap between the various classification criteria for axial spondylo arthritis.
26 patients with regard to the ASAS criteria, such patients were considered as not fulfilling the ASAS criteria in this current analysis. The classification in accordance to the other sets of criteria was possible in all the 708 patients. The modified New York criteria, Amor criteria, ESSG and ASAS criteria were fulfilled by 26.4%, 79.1%, 77.8% and 70.3% of the patients respectively. All the 187 patients fulfilling the modified New York criteria fulfilled the other sets of criteria; 183 patients fulfilled all four criteria sets; a part from the modified New York criteria 192 patients fulfilled the three other sets of criteria. The modified Amor criteria and modified ESSG criteria were fulfilled by 81.8% and 83.0% of the patients respectively. The detailed description of the number of patients per set of criteria is given in Figs. 1 and 2. The level of confidence of the rheumatologist about the diagnosis of SpondyloArthritis was higher in the modified New York criteria group (Table 1). The modified New York criteria showed the lowest sensitivity (40.2%) but also the highest specificity (85.5%). The detailed performances of the various sets of criteria are summarized in Table 1. The baseline characteristics of the patients according to the various sets of criteria are summarized in Table 2.
3.1. Baseline demographics In total, 708 patients were included in the DESIR cohort. Back pain involved the thoracic, lumbar spine and buttock area in 54.8%, 89.8% and 74.7% respectively. Isolated area involvement (e.g. only thoracic, lumbar spine or buttock) was observed in 2.7%, 10.4% or 4.4% respectively. The “inflammatory” component of such back pain was based on the fulfilment of the Calin (97.7%) or Berlin (88.6%) criteria, 86.3% fulfilled both criteria, 2.3% only the Calin criteria and 11.4% only the Berlin criteria. The level of confidence of the rheumatologist about the diagnosis of SpA was 6.8 ± 2.7. The mean age at inclusion was 33.8 ± 8.6 years, the mean axial symptoms duration was 18.1 ± 10.4 months, 46.2% (n = 327) were males and 89.8% were Caucasians. The majority of the non-Caucasians (n = 72) were native from North Africa 61.1% (n = 44). 3.2. Performances of the classification criteria Of the 708 patients, 652 (92.09%) fulfilled at least one classification criteria set at baseline. Missing data did not permit to classify
Fig. 2. Venn diagram representing the overlap between the various classification (modified) criteria for axial spondylo arthritis.
Please cite this article in press as: Dougados M, et al. Clinical presentation of patients suffering from recent onset chronic inflammatory back pain suggestive of spondyloarthritis: The DESIR cohort. Joint Bone Spine (2015), http://dx.doi.org/10.1016/j.jbspin.2015.02.006
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Table 1 Performances of various axial spondyloarthritis criteria with the diagnosis of the rheumatologist as external standard in 708 patients suffering from recent onset (<3 years) chronic (≥3 months) inflammatory back pain. Criteria set
Sensitivitya
Specificityb
LR+c
LR–c
Confidence about the diagnosisd
mNY Amor mAmore ESSG mESSGe ASAS
40.2 [34.9; 45.8] 88.5 [84.5; 91.8] 90.4 [86.6; 93.4] 87.2 [83.1; 90.6] 91.2 [87.5; 94.0] 81.1 [76.3; 85.2]
85.5 [81.6; 88.9] 29.2 [24.6; 34.2] 25.7 [21.3; 30.5] 30.3 [25.7; 35.1] 23.9 [19.7; 28.6] 39.0 [34.0; 44.2]
2.78 [2.11; 3.67] 1.25 [1.16; 1.35] 1.22 [1.13; 1.30] 1.25 [1.16; 1.35] 1.20 [1.12; 1.28] 1.33 [1.21; 1.47]
0.70 [0.63; 0.77] 0.39 [0.28; 0.55] 0.37 [0.26; 0.55] 0.42 [0.31; 0.58] 0.37 [0.25; 0.55] 0.49 [0.37; 0.63]
8.2 (1.8) 7.3 (2.3) 7.2 (2.4) 7.1 (2.5) 7.1 (2.5) 7.3 (2.3)
a Sensitivity: % of patients fulfilling the evaluated set of criteria among the X patients with a confidence of the rheumatologist about the diagnosis of SpA above 7 on a 0–10 Numerical Rating Scale. b Specificity: % of patients not fulfilling the evaluated set of criteria among the y patients with a confidence of the rheumatologist about the diagnosis of SpA below 8 on a 0–10 Numerical Rating Scale. c Data provided are % and 95% confidence internal. LR+: positive likelihood ratio; LR–: negative likelihood ratio. d Evaluated ona 0–10 scale (0 = not confident at all and 10 = very confident). e mAmor and mESSG = the modification consisted in considering the items sacroiliitis fulfilled in case of structural damage observed at pelvic X-rays or inflammatory lesions observed at MRI of the sacroiliac joints.
3.3. Clinical presentation of axial spondyloarthritis
12.7%, 24.0% and 63.3% respectively. The impact of the disease was important with a BASFI of 30.4± 22.7 and a BASMI of 23 ± 10.
3.3.1. Axial involvement Because of the inclusion criteria, 100% of the patients were complaining of axial involvement. The first affected area was either the cervical, thoracic, lumbar spine or buttock in 11.1%, 23.3%, 67.1%, 39.5% respectively. Between the first localization and baseline visit, another localization was affected in 96.3%. For the ones with buttock pain as the first manifestation, before baseline visit, they also reported an involvement of cervical, thoracic or lumbar spine in 33.2%, 47.1% or 86.7% respectively. For the ones with lumbar spine as the first manifestation, they also reported an involvement before baseline visit of either cervical, thoracic spine or buttock area in 39.4%, 52.6%, 70.5% respectively. The onset type was either explosive (e.g. occurring within two weeks), sub-acute (e.g. occurring within 1 month), insidious or intermittent in 16.7%, 16.0% or 68.4% respectively. The axial symptoms were responsible of nocturnal awakenings in 89.0%, associated with a morning stiffness of at least 20 minutes in 88.0%, continuous (e.g. nocturnal and diurnal) in 47.6% and occurring mainly after physical activities in 24.0%. NSAID therapy was effective in improving such axial symptoms in 79.6%. At baseline, despite an NSAID intake in 90.2% of the patients with an ASAS-NASAID score of 50.8 ± 46.7, in the whole population the disease was active with a BASDAI over 40 in 60.4% (mean 44.7 ± 20.0) and an increased CRP in 30.1% (8.1 ± 13.5). According to the ASDAS-CRP, the percentage of patients in remission, moderately active disease, and high active disease was
3.3.2. Peripheral articular involvement Such involvement has been considered as present in 57.2% of the patients with an onset prior to the axial symptoms in 39.2% and prior any other clinical feature of SpA in 22.2%. The first affected symptomatic joint was any joint of the hand (33.6%), the feet (25.7%), knee (21.0%), elbow (8.9%), shoulder (16.0%); hips (12.1%). From onset to baseline, an oligo (≤3) arthritis predominant in the lower limbs was observed in 12.0%. Finally, among the 405 patients complaining of peripheral articular involvement, objective signs of arthritis was present in 151 (37.3%). At the baseline visit physical examination, the % of patients with any tender joint or swollen was 56.8% and 7.2% respectively with a mean number of tender and swollen joint of 4.3 ± 8.5and 0.1 ± 0.8 respectively. 3.3.3. Peripheral enthesitis Such involvement has been considered as clinical feature present in 49.2% of the patients with an onset prior to the axial symptoms in 41.2% and prior to any other clinical features of SpA in 22.5%. The first affected area was the posterior part of the heel (17.6%), inferior part of the heel (26.4%) anterior tibial tuberosity (3.7%), other sites of the lower limb (5.2%) and other sites of the upper limb (3.7%). From onset to baseline, any heel involvement (left or right, inferior or posterior) was observed in 41.7%. At the baseline visit
Table 2 Baseline characteristics of the 708 enrolled patients suffering from recent onset (<3 years) chronic (≥3 months) inflammatory back pain. Characteristics
mNY
Amor
Criteria mAmor
Fulfilled ESSG
mESSG
ASAS
Whole group
Number of patients Age at inclusion Male (%) Duration of back pain in months (SD) HLA B27 positivity (%) Positive family of SpA (%) Sacroiliitis, radiography (%) Sacroiliitis, MRI (%) Increased CRP (%) Past history or current symptoms Peripheral arthritis (%) Enthesitis (%) Uveitis (%) Psoriasis (%) IBDa (%)
187 31.3 (8.9) 110 (58.8) 18.9 (10.1) 137 (73.3) 43 (23.0) 187 (100) 132 (70.6) 87 (48.6)
544 33.3 (8.5) 258 (47.4) 18.3 (10.6) 363 (66.7) 122 (22.4) 183 (33.6) 205 (38.3) 175 (33.3)
563 33.4 (8.5) 268 (47.6) 18.4 (10.6) 370 (65.7) 122 (21.7) 183 (32.5) 224 (40.4) 180 (33.1)
551 33.3 (8.7) 260 (47.2) 18.4 (10.6) 327 (59.3) 131 (23.8) 187 (33.9) 194 (35.7) 172 (32.3)
588 33.2 (8.7) 283 (48.1) 18.3 (10.6) 352 (59.9) 133 (22.6) 187 (31.8) 231 (39.8) 184 (32.4)
486 33.0 (8.6) 244 (50.2) 18.5 (10.6) 406 (83.5) 117 (24.1) 187 (38.5) 231 (48.4) 162 (34.5)
708 33.8 (8.6) 327 (46.2) 18.1 (10.4) 410 (57.9) 139 (19.6) 187 (26.4) 231 (33.3) 206 (30.1)
99 (52.9) 78 (41.7) 20 (10.6) 27 (14.1) 8 (4.3)
328 (60.3) 302 (55.5) 47 (8.6) 100 (18.3) 30 (5.5)
337 (59.9) 304 (54.0) 50 (8.8) 101 (17.9) 31 (5.5)
339 (61.5) 348 (63.2) 50 (9.0) 110 (19.9) 34 (6.2)
351 (59.7) 348 (59.2) 52 (8.8) 111 (18.8) 34 (5.8)
267 (54.9) 227 (46.7) 46 (9.4) 78 (16.0) 23 (4.7)
405 (57.2) 348 (49.1) 60 (8.5) 112 (15.8) 35 (4.9)
Please cite this article in press as: Dougados M, et al. Clinical presentation of patients suffering from recent onset chronic inflammatory back pain suggestive of spondyloarthritis: The DESIR cohort. Joint Bone Spine (2015), http://dx.doi.org/10.1016/j.jbspin.2015.02.006
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Past history or current symptoms
5
3.5. Impact of spondyloarthritis
80 70 60 50 40 30 20 10 0
Among the 609 patients with a paid job, 59.1% had at least one missed working day with a mean number of missed working days of 32.8 ± 67 during that last year in the whole population and of 32.8 ± 68.2 in the population with a paid job. The occurrence of SpA had no consequence on the paid jobs in 60.7% but resulted in changing jobs in 2.0%, stopping jobs (fired) in 1.2% and in incapacity in 0.5%. Because of the disease, the quality of life was impaired with a mean SF 36 mental and physical score of 40.2 ± 11.2 and 39.9 ± 9.3 respectively. 3.6. Co-morbidities
percentage of paents Fig. 3. Spondyloarthritis clinical features observed in 708 patients suffering from recent onset (<3 years) chronic (≥3 months) inflammatory back pain. Enth any: enthesiris, any location. Periph. Arthr: peripheral arthritis. ACW: anterior chest wall involvement. IBD: inflammatory bowel disease. Oligoarthr.: oligoarthritis predominantly. Fam.Hist: familial history. Enth heel: enthesitis, heel.
physical examination, the enthesitis index was 0 in 34.9% with a mean and SD of 4.3 and 5.8 in the whole population. 3.3.4. Anterior chest wall pain Such involvement has been considered as present in 44.6% of the patients with an onset prior the axial symptoms in 41.4% and prior to any other clinical feature of SpA in 8.2%. The first affected area was sterno-clavicular (6.9%), sterno-costal (16.7%), manubrio-sternal joint (11.9%) or diffuse (16.8%). 3.3.5. Dactylitis Such involvement has been considered as present in 13.0% with an onset prior the axial symptoms in 41.3% and prior to any other clinical features of SpA in 14.1%. The most frequent affected digits were finger I (1.1%), II (2.4%), III (2.5%), IV (0.9%), V (0.7%) and toes I (2.3%), II (4.1%), III (2.6%), IV (2.4%), V (1.7%). From onset to baseline, the most affected digits were fingers I (1.7%), II (3.1%), III (3.1%), IV (1.3%), V (1.1%). 3.3.6. Extra-articular features Uveitis was observed in 8.5% of the patients with an onset prior the axial symptoms in 53.3% and prior to any other clinical feature of SpA in 15.0%. Skin psoriasis was observed in 16.1% with an onset prior the axial symptoms in 73.7% and prior to any other clinical feature of SpA in 34.2%. Palmo-plantar pustulosis was rarely noticed: 8 (1.1%). Crohn’s disease (2.54%) and/or ulcerative colitis was noticed prior the axial symptoms in 66.7% and prior to any other SpA clinical feature in 5.5%. 3.4. Family history of SpA At baseline, a family history of the following ankylosing spondylitis, psoriatic arthritis, IBD related arthritis, reactive arthritis, skin psoriasis, uveitis, IBD has been noticed in 19.6%, 2.8%, 1.1%, 1.0%, 19.9%, 4.5% and 5.1% respectively resulting in a “positive” family history of 24.3%. The Fig. 3 summarizes the different findings at baseline concerning such SpA clinical features. Focusing on the items included in the ASAS criteria (e.g. oligarthritis predominantly in the lower limbs, enthesitis of the heel, psoriasis, uveitis, IBD, family history, increased CRP) at least one of them was noticed in 73.4% of the patients and at least two of them in 33.5%.
3.6.1. Gastro-intestinal tract A past history of ulcers was noticed in 3.9% with a perforation in 0%. 3.6.2. Cardiovascular disease Hypertension was noticed in 5.1%. Cardiovascular events were rarely noticed (e.g. myocardial infarction (0.0%), stroke (0.0%)). 3.6.3. Malignant diseases A history of lymphoma was only noticed in two patients and of any solid cancer in four patients. 3.6.4. Infectious diseases An history of tuberculosis was noticed in six patients, Human immunodeficiency viral (HIV) infection in two (0.3%), hepatitis B and C in three (0.4%) and one (0.1%) respectively. 3.6.5. Smoking and alcohol intake It was noticed in 257 (36.3%) and 104 (14.7%) respectively. 4. Discussion This study emphasizes the importance of the criteria sets for the whole spectrum of spondyloarthritis (e.g. Amor, ESSG, ASAS) in comparison to the conventional modified NY criteria. Such importance is mainly related to the meaningful body of information from the imaging modalities but also the frequency of the other clinical features of SpA even at an early stage of the disease. Finally, this study has considered not only the rheumatological disorder but also other diseases, which can occur concomitantly. This study has some weakness but also relevant strengths. The performances of the different sets of criteria have been evaluated by considering the level of confidence of the rheumatologist about the diagnosis of SpA according to a 11 Numerical Rating Scale from 0 (0 = not confident at all) to 10 (10 = very confident). In this study, the choice of the threshold above 7 to classify a patient as suffering from axial SpA can be considered as arbitrarily and therefore as a potential weakness of the study. Moreover, the so-called “control group” (e.g. the patients with a level of confidence of the rheumatologist below 8) could be considered as a potential “disease group” since the inclusion criteria made mandatory a level of confidence above 5. However, it should be noticed that such methodology has been previously used in this area [24]. Moreover, such study permitted at least to compare the sensitivity of the different sets of criteria by comparing the percentage of patients fulfilling such criteria without any reference to the level of confidence of the rheumatologist. Such analysis clearly showed that at an early stage of the disease the mNY criteria are useless since able to correctly classify only 15.8% of the patients. This is due to the fact that in order to fulfil such criteria, the patient had to present
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structural damage of the sacroiliac joints. There is still a debate whether the absence of structural damage is a pre-stage of the disease (e.g. all the patients will present such structural damage since the % of patients with such structural damage of sacroiliac joint is decreasing overtime [25,26] or a specific characteristic of some patients who will never present structural damage of the sacroiliac joints. This is the reason why such patients are not designated as pre-radiographic axial SpA but as non-radiographic axial SpA [3]. Moreover, our study emphasizes the relative high frequency of the other clinical features of SpA in patients presenting with axial symptoms (Fig. 3). Such data are strongly supporting the use of the spondyloarthritis criteria set instead of the one of the mNY criteria. The performances of the three sets of SpA criteria were similar, particularly when including positive sacro iliac MRI in Amor and ESSG criteria. Our study also improves our knowledge about the clinical presentation of patients presenting with axial involvement of spondyloarthritis. As suspected, the axial localization of the symptoms at onset were mainly in the buttock or lumbar spine area (39.5 and 67.1% respectively) and rarely the cervical level (11.1%). Some particular information have been extracted from the baseline data of the DESIR Cohort. Patients with psoriasis have more frequently enthesitis, elevated BASDAI and BASFI scores, increased CRP and cholesterol levels, without differences in imaging data with patients without psoriasis [27]. Female gender is associated with higher BASDAI, fatigue and function scores despite less radiographic and MRI modifications than men. Women with radiographic sacro ileitis have more peripheral involvement [28]. Uveitis is associated with cervical involvement, a preceding history of infection and presence of IBD [29]. Anterior chest wall involvement is associated with greater severity of the disease, enthesitis, and radiographic modification of sacro iliac joints, irrespective of the symptoms duration [30]. HLA-B27 is associated with an earlier onset of IBP, a shorter diagnosis delay, axial MRI inflammation, sacro iliac radiographic changes, reduced disease activity and psoriasis frequency [31]. Analyzing patients characteristics pending the clinical or imaging arm of the ASAS classification, Molto demonstrated that only minor differences were obvious, patients classified through the imaging arm (i.e. entry by radiographic or MRI sacroiliitis) are younger, more frequently male and have more frequently elevated CRP [32]. Finally, the main clinical features of the disease may be grouped in particular phenotypes or clusters [33]. Since early diagnosis or correct classification may be important for optimized management [34], overdiagnosis may also be inconvenient [35], and the matter of early diagnosis criteria is still under debate. Under these circumstances, performance of the different sets of classification criteria applied in early disease give some information upon accuracy of their use as diagnosis tools. It is noteworthy that these performances in the DESIR cohort are not so different that those observed in other similar cohorts of early possible spondyloarthritis [24,36]. In established SpA disease, an increased risk of comorbidities and especially cardiovascular diseases, and osteoporosis are well recognized. However, the pathophysiology of such comorbidities is not clear (e.g. related to the inflammatory process of the disease, its treatments and in particular long term intake of NSAIDs or other factors such as immobilization of the spine due to ankylosis). In our study focused on patients observed at disease onset, the prevalence of such co-morbidities was low. The results observed in this study will necessitate to be confirmed in other cohorts of patients and also to be further analyzed in particular in the long term since all the enrolled patients will be closely monitored during at least 10 years after the baseline visit.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgements The DESIR cohort is conducted under the control of Assistance publique–Hopitaux de Paris via the Clinical Research Unit Paris-Centre and under the umbrella of the French Society of Rheumatology and Inserm (Institut national de la santé et de la recherche médicale). The database management is performed within the department of epidemiology and biostatistics (Professor Jean-Pierre Daurès, D.I.M., Nîmes, France). An unrestricted grant from Wyeth Pharmaceuticals was allocated for the first 5 years of the follow-up of the recruited patients. We also wish to thank the different regional participating centres: Pr Maxime Dougados (Paris–Cochin B), Pr André Kahan (Paris–Cochin A), Pr Olivier Meyer (Paris–Bichat), Pr Pierre Bourgeois (Paris–La Pitié-Salpetrière), Pr Francis Berenbaum (Paris–Saint Antoine), Pr Pascal Claudepierre (Créteil), Pr Maxime Breban (Boulogne Billancourt), Dr Bernadette Saint-Marcoux (Aulnay-sous-Bois), Pr Philippe Goupille (Tours), Pr Jean-Francis Maillefert (Dijon), Dr Xavier Puéchal (Le Mans), Pr Daniel Wendling (Besanc¸on), Pr Bernard Combe (Montpellier), Pr Liana Euller-Ziegler (Nice), Pr Philippe Orcel (Paris–Lariboisière), Pr Pierre Lafforgue (Marseille), Dr Patrick Boumier (Amiens), Pr Jean-Michel Ristori (ClermontFerrand), Dr Nadia Mehsen (Bordeaux), Pr Damien Loeuille (Nancy), Pr René-Marc Flipo (Lille), Pr Alain Saraux (Brest), Pr Corinne Miceli (Le Kremlin Bicêtre), Pr Alain Cantagrel (Toulouse), Pr Olivier Vittecoq (Rouen). Funding: the DESIR-cohort is financially supported by unrestricted grants from both the French Society of Rheumatology, and Pfizer Ltd, France. References [1] Calin A, Kaye B, Sternberg M, et al. The prevalence and nature of back pain in an industrial complex: a questionnaire and radiographic and HLA analysis. Spine (Phila Pa 1976) 1980;5:201–5. [2] Rudwaleit M, Sieper J. [Diagnosis and treatment of ankylosing spondylitis (Bechterew disease)]. Dtsch Med Wochenschr 2005;130:1882–6 [Review. German. No abstract available]. [3] Claudepierre P, Wendling D, Breban M, et al. Ankylosing spondylitis, spondyloarthropathy, spondyloarthritis, or spondylarthritis: what’s in a name? Joint Bone Spine 2012;79:534–5. [4] Wendling D, Prati C, Claudepierre P, et al. Non-radiographic spondyloarthritis: a theoretical concept or a real entity? Joint Bone Spine 2012;79:531–3. [5] Vander Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York Criteria. Arthritis Rheum 1984;27:361–8. [6] Amor B, Dougados M, Mijiyawa M. Criteria of the classification of spondylartropathies. Rev Rhum Mal Osteoart 1990;57:85–9. [7] Dougados M, van der Linden A, Juhlin R, et al. The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy. Arthritis Rheum 1991;34:1218–27. [8] Amor B, Dougados M, Listrat V, et al. [Evaluation of the Amor criteria for spondylarthropathies and European Spondylarthropathy Study Group (ESSG). A cross-sectional analysis of 2228 patients]. Ann Med Interne (Paris) 1991;142:85–9. [9] Dougados M, vam der Linden S, et al. Sulfasalazine in the treatment of spondylarthropathy. A randomized, multicenter, double-blind, placebo-controlled study. Arthritis Rheum 1995;38:618–27. [10] Clegg DO, Reda DJ, Weisman MH, et al. Comparison of sulfasalazine and placebo in the treatment of ankylosing spondylitis. A Department of Veterans Affairs Cooperative Study. Arthritis Rheum 1996;39:2004–12. [11] Rudwaleit M, van der Heijde D, Landewé R, et al. The development of Assessment of Spondyloarthritis International Society classification criteria for axial spondyloarthritis (part II): validation and final selection. Ann Rheum Dis 2009;68:777–83. [12] Rudwaleit M, Jurik AG, Hermann KG, et al. Defining active sacroiliitis on magnetic resonance imaging (MRI) for classification of axial spondyloarthritis: a consensual approach by the ASAS/OMERACTMRI group. Ann Rheum Dis 2009;68:1520–7.
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Original article
Clinical presentation of patients suffering from recent onset chronic inflammatory back pain suggestive of spondyloarthritis: The DESIR cohort Maxime Dougados a,b , Adrien Etcheto b , Anna Molto a,b , Sandrine Alonso c , Sophie Bouvet c , Jean-Pierre Daurès c , Paul Landais c , Maria-Antonietta d’Agostino d , Francis Berenbaum e , Maxime Breban d , Pascal Claudepierre f , Bernard Combe g , Bruno Fautrel h , Antoine Feydy i , Philippe Goupille j , Pascal Richette k , Thao Pham l , Christian Roux a , Jean-Marc Treluyer a , Alain Saraux m , Désirée van der Heijde n , Daniel Wendling o,∗ a Paris Descartes University, Department of Rheumatology, hôpital Cochin, Assistance publique–Hôpitaux de Paris, 27, rue du Faubourg-Saint-Jacques, 75014 Paris, France b Inserm (U1153), Clinical Epidemiology and Biostatistics, PRES Sorbonne Paris-Cité, 109, avenue de France, 75013 Paris, France c Département d’information médicale, CHU de Nîmes, 30029 Nîmes, France d Department of Rheumatology, Ambroise Paré Hospital, Assistance publique–Hôpitaux de Paris, 92100 Boulogne-Billancourt, France e Department of Rheumatology, hôpital Saint-Antoine, Assistance publique–Hôpitaux de Paris, 75012 Paris, France f Department of Rheumatology, hôpital Henri-Mondor, Assistance publique–Hôpitaux de Paris, 94010 Créteil, France g Department of Rheumatology, CHU de Montpellier, 34295 Montpellier, France h Department of Rheumatology, hôpital de la Pitié-Salpêtrière, Assistance publique–Hôpitaux de Paris, 75013 Paris, France i Department of Radiology, hôpital Cochin, Assistance publique–Hôpitaux de Paris, 75013 Paris, France j Department of Rheumatology, CHU de Tours, 37044 Tours cedex 9, France k Department of Rheumatology, hôpital Lariboisière, Assistance publique–Hôpitaux de Paris, 75010 Paris, France l Department of Rheumatology, CHU, Assistance publique–Hôpitaux de Marseille, 13005 Marseille, France m Department of Rheumatology, CHU de Brest, 29609 Brest cedex, France n Department of Rheumatology, Leiden University Medical Center, 2311 Leiden, The Netherlands o Université de Franche-Comté, Department of Rheumatology, CHRU de Besanc¸on, 25030 Besanc¸on, France
a r t i c l e
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Article history: Accepted 4 February 2015 Available online xxx Keywords: Spondyloarthritis Epidemiology Classification criteria Cohort
a b s t r a c t Objectives: DESIR is a prospective longitudinal multicentric French cohort of patients with inflammatory back pain suggestive of spondyloarthritis, with a 10-year-follow-up. The purpose is to evaluate the performances of the different sets of classification criteria for axial spondyloarthritis, and to describe the frequency and characteristics of the clinical features of axial spondyloarthritis. Methods: Demographic data and items allowing classification and indices calculation were collected, as well as biologic and imaging data. Baseline data are analyzed. The performance of the several classification criteria sets was evaluated (likelihood ratio) with the physician’s diagnosis as external gold standard. For the clinical presentation of axial spondyloarthritis, a descriptive analysis was conducted. Results: Seven hundred and eight patients are included. Ninety-two percent of them satisfy at least one set of classification criteria: mNY 26%, Amor 79%, ESSG 78%, ASAS 70%; physician’s confidence level 6.8 ± 2.7. 81 and 83% of patients fulfil modified (including MRI) Amor or ESSG criteria. Axial involvement is present in 100% of the cases. NSAIDs are taken by 90%, with an NSAID sore of 50 ± 46. BASDAI over 40 is noted in 60% and elevated CRP in 30% of the cases. HLA-B27 is present in 58%. According to ASDAS CRP levels, 12.7% are in inactive disease, 63% in high disease activity; mean BASFI was 30. Peripheral involvement is present in 57%, with arthritis in 37% of these. Enthesitis is noted in 49% of the patients, and first symptom in 22.5%; anterior chest wall involvement is noted in 44.6%, and dactylitis in 13%. For extra articular manifestations, psoriasis is recorded in 16%, uveitis in 8.5% and IBD in 5.1%. Smoking is present in 36.3% and hypertension in 5.1% of the cases. Conclusion: These data represent the base of evaluation of the follow-up of this cohort, allowing future specific studies. © 2015 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
∗ Corresponding author. Université de Franche-Comté, Department of Rheumatology, CHRU de Besanc¸on, 25030 Besanc¸on, France. E-mail address: [email protected] (D. Wendling). http://dx.doi.org/10.1016/j.jbspin.2015.02.006 1297-319X/© 2015 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
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1. Introduction
2. Methods
Spondyloarthritis is probably the first diagnosis to evoke in case of chronic inflammatory back pain occurring before the age of 40 years old [1]. The terminology has changed over the years: Betcherew’s disease for our German colleagues [2], ankylosing spondylitis, axial spondyloarthritis [3]. The major difference between ankylosing spondylitis and spondyloarthritis is that ankylosing spondylitis is focused only on the axial symptoms of the disease with structural damage observed on plain X-Rays at the sacroiliac joint level, whereas spondyloarthritis refers not only to the axial symptoms of the disease but also to its other different clinical presentations (e.g. peripheral articular involvement, peripheral enthesitis, extra-rheumatological features such as psoriasis, uveitis, inflammatory bowel disease). Moreover, concerning the axial symptoms, the so called disease “spondyloarthritis” can include patients without structural damage of the sacroiliac joints [4]. Concerning the criteria proposed to classify the patients suffering from this disease, the conventional ones are the modified New York criteria [5]. Such criteria are making as mandatory the presence of structural damage of the sacroiliac joints on pelvic Xrays (commonly but wrongly named “sacroiliitis” since “itis” should refer to an inflammation whereas the pelvic X-rays are only able to detect structural damage such as joint erosions and sub-chondral bone sclerosis). In the 1980s, criteria have been proposed with the possibility to recognize patients without structural damage at the sacroiliac joints and with the recognition of the importance of the different clinical manifestations observed in such patients (e.g. the Amor criteria [6] and the European Spondyloarthritis Study group criteria [7]). It must be recognized that despite their relevant psychometric properties, in particular the ones of the Amor criteria [8], such criteria have not been used so widely and in particular, only rare therapeutical trials have been conducted by pharmaceutical companies with reference to this criteria for enrolling the patients [9,10]. The international society focused on the different outcome measures/criteria in the area of spondyloarthritis (e.g. Assessment of Spondylo Arthritis [ASAS]) has elaborated a new set of criteria for spondyloarthritis [11] including not only the previous items (e.g. all the different clinical features of spondyloarthritis, the possibility to recognize patients without objective structural damage of the sacroiliac joints on pelvic X-rays) but also considering the importance of objective signs of inflammation (e.g. subchondral bone edema of the sacroiliac joints at MRI [12]). Such criteria have been widely used in particular by pharmaceutical companies who have started to conduct studies referring to such new criteria. Some recent trials have even been focused on patients with non-radiographic axial spondyloarthritis [13,14]. Such criteria are classification criteria and therefore are performing well in patients with established disease. However, their performances at an early stage of the disease have been less investigated. Moreover, in case of a patient presenting with axial symptoms, the frequency of other clinical spondyloarthritis features remains to be investigated. The French Society of Rheumatology has recently initiated a huge national multicenter cohort, the so-called “DESIR cohort study” (Devenir des spondyloarthrites indifférenciées récentes [DESIR]) to facilitate investigations on diagnostic and prognostic markers but also aetiologic, pathogenic and socio-economic factors among patients with early inflammatory back pain suggestive of axial spondyloarthritis [15]. These preliminary remarks prompted us to conduct an analysis of the patients enrolled in the DESIR cohort in order to evaluate the properties of the different sets of criteria and to describe the frequency and the characteristics of the different clinical features of spondyloarthritis.
2.1. Study design. Inclusion criteria DESIR is a French prospective multi-center, longitudinal cohort aiming to study patients with early inflammatory back pain suggestive of Spondyloarthritis (clinicaltrials.gov: NCTO 164 8907). This study fulfilled the current Good Clinical Practices and has obtained the approval of the appropriate ethical committee. Participants at the study gave their written informed consent. A specific website (www.lacohortedesir.fr) contains the detailed description of the centers, the organization of the cohort but also the full detailed protocol and case-report form. Patients were enrolled (inclusion period 2007 to April 2010) if they were aged > 18 years and <50 years and suffering from back pain involving the thoracic, lumbar spine or buttock area from more than 3 months less than 3 years. Such back pain had to fulfil the characteristics of “inflammatory” in accordance to either the Berlin [16] or the Calin criteria [17]. Moreover, the physician in charge of the enrolment of the patients had to score his/her level of confidence about the diagnosis of spondyloarthritis on a 0–10 scale (where 0 = not confident and 10 = very confident). A score ≥ 5 was mandatory to permit the inclusion of the patients. 2.2. Collected data A part from the data checking the inclusion criteria, the collected data comprised both patient demographics and clinical presentation of the disease. Demographics included age, gender and body mass index (BMI). Moreover, all the items permitting to adequately classify a patient according to the different sets of criteria (e.g. modified New York, Amor, ESSG and ASAS) were collected. The activity of the disease was evaluated using the following: Back Ankylosing Spondylitis Disease Activity Index (BASDAI) [18] and Ankylosing Spondylitis Disease Activity Score–C Reactive Protein (ASDAS-CRP) [19]. Moreover, inflammatory lesions according to the OMERACTASAS definition were recorded at the MRI of the Spine and the sacroiliac joints [12]. Such evaluation (binary variable: yes/no) was performed by the local radiologist or rheumatologist. The severity of the disease was assessed using the following: Bath Ankylosing Spondylitis Functional Index (BASFI) [20] and BathAnkylosing Spondylitis Metrology Index (BASMI) [21]. Moreover, plain X-rays of the spine and the pelvis permitted to score the structural damage of the sacroiliac joints. Radiologists or rheumatologists at each study center scored each sacroiliac joint as follow: 0 = normal, 1 = doubtful, 2 = obviously abnormal, or 3 = fused. For this present analysis, sacroiliac joints were considered abnormal if at least one sacroiliac joint was scored 2 or 3. This scoring method used for the local reading in DESIR is derived from the modified New York criteria for radiographic sacroiliitis changes [5] with one modification: grade 2 and 3 of New York criteria were pooled in one sole grade. The modified Stoke Ankylosing Spondylitis Spine Score [22] was calculated from the conventional X-rays of the cervical and lumbar spine. At MRI, local investigators evaluated the presence of chronic changes at the sacroiliac joint level. Such changes were defined by the presence of clear characteristic lesion such as sclerosis, erosions, bone bridges or ankylosis of the joints. The different clinical features of the disease were also collected: enthesitis, dactylitis, peripheral arthritis, extra-articular features, family history. Moreover, ultra sound examination of the entheses as well as bone mineral density and body composition assessments were performed in selected centers. The impact of the disease was evaluated according to the number of jobs paid missed days and also by the quality of life index (SF36) [23].
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Finally, comorbidities were evaluated by checking the history of cardiovascular, infectious and malignant diseases. 2.3. Statistical analysis The statistical analysis was conducted in two consecutive steps with regard to the two main objectives of this study. For these analyses, only data of the baseline visit of DESIR were used, the database used was the one locked on 15/09/2014. 2.3.1. Performances of the different sets of classification criteria of axial spondyloarthritis First, it was investigated how many patients fulfilled at least one of the classification criteria sets of spondyloarthritis, shown in Venn diagrams. For the Amor and ESSG criteria, we also investigated the possibility to include the MRI findings in terms of inflammatory lesions observed at the sacroiliac level. For this purpose, for each criteria, we considered the item “sacroiliitis” fulfilled in case of either radiologic or MRI sacroiliitis. We called these criteria modified AMOR (mAmor) or ESSG (mESSG) criteria. The ASAS criteria for axial SpA were used. Next, the performances of the different sets of criteria were tested. For this purpose, the diagnosis of the physician served as external gold standard. For this present analysis, we considered as a positive diagnosis a score above 7 (e.g. 8,9 or 10) on the 0–10 scale. The performances of each set of criteria were determined by calculating sensitivity, specificity, positive likelihood ratio (LR+) and negative likelihood ratio (LR–). Thereafter, the main clinical characteristics of the patients were described per sets of criteria. 2.3.2. Clinical presentation of axial spondyloarthritis For this purpose, descriptive analyses were conducted. For each clinical rheumatological feature of spondyloarthritis (e.g. axial symptoms, peripheral arthritis, peripheral enthesitis) the frequency; the localization and the activity at baseline were depicted. For the other features of spondyloarthritis (e.g. family history, extra-rheumatological features) only the frequency was calculated. Finally, the percentage of patients with specific co-morbidities was also calculated and especially cardiovascular, infectious and malignant diseases. 3. Results
Fig. 1. Venn diagram representing the overlap between the various classification criteria for axial spondylo arthritis.
26 patients with regard to the ASAS criteria, such patients were considered as not fulfilling the ASAS criteria in this current analysis. The classification in accordance to the other sets of criteria was possible in all the 708 patients. The modified New York criteria, Amor criteria, ESSG and ASAS criteria were fulfilled by 26.4%, 79.1%, 77.8% and 70.3% of the patients respectively. All the 187 patients fulfilling the modified New York criteria fulfilled the other sets of criteria; 183 patients fulfilled all four criteria sets; a part from the modified New York criteria 192 patients fulfilled the three other sets of criteria. The modified Amor criteria and modified ESSG criteria were fulfilled by 81.8% and 83.0% of the patients respectively. The detailed description of the number of patients per set of criteria is given in Figs. 1 and 2. The level of confidence of the rheumatologist about the diagnosis of SpondyloArthritis was higher in the modified New York criteria group (Table 1). The modified New York criteria showed the lowest sensitivity (40.2%) but also the highest specificity (85.5%). The detailed performances of the various sets of criteria are summarized in Table 1. The baseline characteristics of the patients according to the various sets of criteria are summarized in Table 2.
3.1. Baseline demographics In total, 708 patients were included in the DESIR cohort. Back pain involved the thoracic, lumbar spine and buttock area in 54.8%, 89.8% and 74.7% respectively. Isolated area involvement (e.g. only thoracic, lumbar spine or buttock) was observed in 2.7%, 10.4% or 4.4% respectively. The “inflammatory” component of such back pain was based on the fulfilment of the Calin (97.7%) or Berlin (88.6%) criteria, 86.3% fulfilled both criteria, 2.3% only the Calin criteria and 11.4% only the Berlin criteria. The level of confidence of the rheumatologist about the diagnosis of SpA was 6.8 ± 2.7. The mean age at inclusion was 33.8 ± 8.6 years, the mean axial symptoms duration was 18.1 ± 10.4 months, 46.2% (n = 327) were males and 89.8% were Caucasians. The majority of the non-Caucasians (n = 72) were native from North Africa 61.1% (n = 44). 3.2. Performances of the classification criteria Of the 708 patients, 652 (92.09%) fulfilled at least one classification criteria set at baseline. Missing data did not permit to classify
Fig. 2. Venn diagram representing the overlap between the various classification (modified) criteria for axial spondylo arthritis.
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Table 1 Performances of various axial spondyloarthritis criteria with the diagnosis of the rheumatologist as external standard in 708 patients suffering from recent onset (<3 years) chronic (≥3 months) inflammatory back pain. Criteria set
Sensitivitya
Specificityb
LR+c
LR–c
Confidence about the diagnosisd
mNY Amor mAmore ESSG mESSGe ASAS
40.2 [34.9; 45.8] 88.5 [84.5; 91.8] 90.4 [86.6; 93.4] 87.2 [83.1; 90.6] 91.2 [87.5; 94.0] 81.1 [76.3; 85.2]
85.5 [81.6; 88.9] 29.2 [24.6; 34.2] 25.7 [21.3; 30.5] 30.3 [25.7; 35.1] 23.9 [19.7; 28.6] 39.0 [34.0; 44.2]
2.78 [2.11; 3.67] 1.25 [1.16; 1.35] 1.22 [1.13; 1.30] 1.25 [1.16; 1.35] 1.20 [1.12; 1.28] 1.33 [1.21; 1.47]
0.70 [0.63; 0.77] 0.39 [0.28; 0.55] 0.37 [0.26; 0.55] 0.42 [0.31; 0.58] 0.37 [0.25; 0.55] 0.49 [0.37; 0.63]
8.2 (1.8) 7.3 (2.3) 7.2 (2.4) 7.1 (2.5) 7.1 (2.5) 7.3 (2.3)
a Sensitivity: % of patients fulfilling the evaluated set of criteria among the X patients with a confidence of the rheumatologist about the diagnosis of SpA above 7 on a 0–10 Numerical Rating Scale. b Specificity: % of patients not fulfilling the evaluated set of criteria among the y patients with a confidence of the rheumatologist about the diagnosis of SpA below 8 on a 0–10 Numerical Rating Scale. c Data provided are % and 95% confidence internal. LR+: positive likelihood ratio; LR–: negative likelihood ratio. d Evaluated ona 0–10 scale (0 = not confident at all and 10 = very confident). e mAmor and mESSG = the modification consisted in considering the items sacroiliitis fulfilled in case of structural damage observed at pelvic X-rays or inflammatory lesions observed at MRI of the sacroiliac joints.
3.3. Clinical presentation of axial spondyloarthritis
12.7%, 24.0% and 63.3% respectively. The impact of the disease was important with a BASFI of 30.4± 22.7 and a BASMI of 23 ± 10.
3.3.1. Axial involvement Because of the inclusion criteria, 100% of the patients were complaining of axial involvement. The first affected area was either the cervical, thoracic, lumbar spine or buttock in 11.1%, 23.3%, 67.1%, 39.5% respectively. Between the first localization and baseline visit, another localization was affected in 96.3%. For the ones with buttock pain as the first manifestation, before baseline visit, they also reported an involvement of cervical, thoracic or lumbar spine in 33.2%, 47.1% or 86.7% respectively. For the ones with lumbar spine as the first manifestation, they also reported an involvement before baseline visit of either cervical, thoracic spine or buttock area in 39.4%, 52.6%, 70.5% respectively. The onset type was either explosive (e.g. occurring within two weeks), sub-acute (e.g. occurring within 1 month), insidious or intermittent in 16.7%, 16.0% or 68.4% respectively. The axial symptoms were responsible of nocturnal awakenings in 89.0%, associated with a morning stiffness of at least 20 minutes in 88.0%, continuous (e.g. nocturnal and diurnal) in 47.6% and occurring mainly after physical activities in 24.0%. NSAID therapy was effective in improving such axial symptoms in 79.6%. At baseline, despite an NSAID intake in 90.2% of the patients with an ASAS-NASAID score of 50.8 ± 46.7, in the whole population the disease was active with a BASDAI over 40 in 60.4% (mean 44.7 ± 20.0) and an increased CRP in 30.1% (8.1 ± 13.5). According to the ASDAS-CRP, the percentage of patients in remission, moderately active disease, and high active disease was
3.3.2. Peripheral articular involvement Such involvement has been considered as present in 57.2% of the patients with an onset prior to the axial symptoms in 39.2% and prior any other clinical feature of SpA in 22.2%. The first affected symptomatic joint was any joint of the hand (33.6%), the feet (25.7%), knee (21.0%), elbow (8.9%), shoulder (16.0%); hips (12.1%). From onset to baseline, an oligo (≤3) arthritis predominant in the lower limbs was observed in 12.0%. Finally, among the 405 patients complaining of peripheral articular involvement, objective signs of arthritis was present in 151 (37.3%). At the baseline visit physical examination, the % of patients with any tender joint or swollen was 56.8% and 7.2% respectively with a mean number of tender and swollen joint of 4.3 ± 8.5and 0.1 ± 0.8 respectively. 3.3.3. Peripheral enthesitis Such involvement has been considered as clinical feature present in 49.2% of the patients with an onset prior to the axial symptoms in 41.2% and prior to any other clinical features of SpA in 22.5%. The first affected area was the posterior part of the heel (17.6%), inferior part of the heel (26.4%) anterior tibial tuberosity (3.7%), other sites of the lower limb (5.2%) and other sites of the upper limb (3.7%). From onset to baseline, any heel involvement (left or right, inferior or posterior) was observed in 41.7%. At the baseline visit
Table 2 Baseline characteristics of the 708 enrolled patients suffering from recent onset (<3 years) chronic (≥3 months) inflammatory back pain. Characteristics
mNY
Amor
Criteria mAmor
Fulfilled ESSG
mESSG
ASAS
Whole group
Number of patients Age at inclusion Male (%) Duration of back pain in months (SD) HLA B27 positivity (%) Positive family of SpA (%) Sacroiliitis, radiography (%) Sacroiliitis, MRI (%) Increased CRP (%) Past history or current symptoms Peripheral arthritis (%) Enthesitis (%) Uveitis (%) Psoriasis (%) IBDa (%)
187 31.3 (8.9) 110 (58.8) 18.9 (10.1) 137 (73.3) 43 (23.0) 187 (100) 132 (70.6) 87 (48.6)
544 33.3 (8.5) 258 (47.4) 18.3 (10.6) 363 (66.7) 122 (22.4) 183 (33.6) 205 (38.3) 175 (33.3)
563 33.4 (8.5) 268 (47.6) 18.4 (10.6) 370 (65.7) 122 (21.7) 183 (32.5) 224 (40.4) 180 (33.1)
551 33.3 (8.7) 260 (47.2) 18.4 (10.6) 327 (59.3) 131 (23.8) 187 (33.9) 194 (35.7) 172 (32.3)
588 33.2 (8.7) 283 (48.1) 18.3 (10.6) 352 (59.9) 133 (22.6) 187 (31.8) 231 (39.8) 184 (32.4)
486 33.0 (8.6) 244 (50.2) 18.5 (10.6) 406 (83.5) 117 (24.1) 187 (38.5) 231 (48.4) 162 (34.5)
708 33.8 (8.6) 327 (46.2) 18.1 (10.4) 410 (57.9) 139 (19.6) 187 (26.4) 231 (33.3) 206 (30.1)
99 (52.9) 78 (41.7) 20 (10.6) 27 (14.1) 8 (4.3)
328 (60.3) 302 (55.5) 47 (8.6) 100 (18.3) 30 (5.5)
337 (59.9) 304 (54.0) 50 (8.8) 101 (17.9) 31 (5.5)
339 (61.5) 348 (63.2) 50 (9.0) 110 (19.9) 34 (6.2)
351 (59.7) 348 (59.2) 52 (8.8) 111 (18.8) 34 (5.8)
267 (54.9) 227 (46.7) 46 (9.4) 78 (16.0) 23 (4.7)
405 (57.2) 348 (49.1) 60 (8.5) 112 (15.8) 35 (4.9)
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Past history or current symptoms
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3.5. Impact of spondyloarthritis
80 70 60 50 40 30 20 10 0
Among the 609 patients with a paid job, 59.1% had at least one missed working day with a mean number of missed working days of 32.8 ± 67 during that last year in the whole population and of 32.8 ± 68.2 in the population with a paid job. The occurrence of SpA had no consequence on the paid jobs in 60.7% but resulted in changing jobs in 2.0%, stopping jobs (fired) in 1.2% and in incapacity in 0.5%. Because of the disease, the quality of life was impaired with a mean SF 36 mental and physical score of 40.2 ± 11.2 and 39.9 ± 9.3 respectively. 3.6. Co-morbidities
percentage of paents Fig. 3. Spondyloarthritis clinical features observed in 708 patients suffering from recent onset (<3 years) chronic (≥3 months) inflammatory back pain. Enth any: enthesiris, any location. Periph. Arthr: peripheral arthritis. ACW: anterior chest wall involvement. IBD: inflammatory bowel disease. Oligoarthr.: oligoarthritis predominantly. Fam.Hist: familial history. Enth heel: enthesitis, heel.
physical examination, the enthesitis index was 0 in 34.9% with a mean and SD of 4.3 and 5.8 in the whole population. 3.3.4. Anterior chest wall pain Such involvement has been considered as present in 44.6% of the patients with an onset prior the axial symptoms in 41.4% and prior to any other clinical feature of SpA in 8.2%. The first affected area was sterno-clavicular (6.9%), sterno-costal (16.7%), manubrio-sternal joint (11.9%) or diffuse (16.8%). 3.3.5. Dactylitis Such involvement has been considered as present in 13.0% with an onset prior the axial symptoms in 41.3% and prior to any other clinical features of SpA in 14.1%. The most frequent affected digits were finger I (1.1%), II (2.4%), III (2.5%), IV (0.9%), V (0.7%) and toes I (2.3%), II (4.1%), III (2.6%), IV (2.4%), V (1.7%). From onset to baseline, the most affected digits were fingers I (1.7%), II (3.1%), III (3.1%), IV (1.3%), V (1.1%). 3.3.6. Extra-articular features Uveitis was observed in 8.5% of the patients with an onset prior the axial symptoms in 53.3% and prior to any other clinical feature of SpA in 15.0%. Skin psoriasis was observed in 16.1% with an onset prior the axial symptoms in 73.7% and prior to any other clinical feature of SpA in 34.2%. Palmo-plantar pustulosis was rarely noticed: 8 (1.1%). Crohn’s disease (2.54%) and/or ulcerative colitis was noticed prior the axial symptoms in 66.7% and prior to any other SpA clinical feature in 5.5%. 3.4. Family history of SpA At baseline, a family history of the following ankylosing spondylitis, psoriatic arthritis, IBD related arthritis, reactive arthritis, skin psoriasis, uveitis, IBD has been noticed in 19.6%, 2.8%, 1.1%, 1.0%, 19.9%, 4.5% and 5.1% respectively resulting in a “positive” family history of 24.3%. The Fig. 3 summarizes the different findings at baseline concerning such SpA clinical features. Focusing on the items included in the ASAS criteria (e.g. oligarthritis predominantly in the lower limbs, enthesitis of the heel, psoriasis, uveitis, IBD, family history, increased CRP) at least one of them was noticed in 73.4% of the patients and at least two of them in 33.5%.
3.6.1. Gastro-intestinal tract A past history of ulcers was noticed in 3.9% with a perforation in 0%. 3.6.2. Cardiovascular disease Hypertension was noticed in 5.1%. Cardiovascular events were rarely noticed (e.g. myocardial infarction (0.0%), stroke (0.0%)). 3.6.3. Malignant diseases A history of lymphoma was only noticed in two patients and of any solid cancer in four patients. 3.6.4. Infectious diseases An history of tuberculosis was noticed in six patients, Human immunodeficiency viral (HIV) infection in two (0.3%), hepatitis B and C in three (0.4%) and one (0.1%) respectively. 3.6.5. Smoking and alcohol intake It was noticed in 257 (36.3%) and 104 (14.7%) respectively. 4. Discussion This study emphasizes the importance of the criteria sets for the whole spectrum of spondyloarthritis (e.g. Amor, ESSG, ASAS) in comparison to the conventional modified NY criteria. Such importance is mainly related to the meaningful body of information from the imaging modalities but also the frequency of the other clinical features of SpA even at an early stage of the disease. Finally, this study has considered not only the rheumatological disorder but also other diseases, which can occur concomitantly. This study has some weakness but also relevant strengths. The performances of the different sets of criteria have been evaluated by considering the level of confidence of the rheumatologist about the diagnosis of SpA according to a 11 Numerical Rating Scale from 0 (0 = not confident at all) to 10 (10 = very confident). In this study, the choice of the threshold above 7 to classify a patient as suffering from axial SpA can be considered as arbitrarily and therefore as a potential weakness of the study. Moreover, the so-called “control group” (e.g. the patients with a level of confidence of the rheumatologist below 8) could be considered as a potential “disease group” since the inclusion criteria made mandatory a level of confidence above 5. However, it should be noticed that such methodology has been previously used in this area [24]. Moreover, such study permitted at least to compare the sensitivity of the different sets of criteria by comparing the percentage of patients fulfilling such criteria without any reference to the level of confidence of the rheumatologist. Such analysis clearly showed that at an early stage of the disease the mNY criteria are useless since able to correctly classify only 15.8% of the patients. This is due to the fact that in order to fulfil such criteria, the patient had to present
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structural damage of the sacroiliac joints. There is still a debate whether the absence of structural damage is a pre-stage of the disease (e.g. all the patients will present such structural damage since the % of patients with such structural damage of sacroiliac joint is decreasing overtime [25,26] or a specific characteristic of some patients who will never present structural damage of the sacroiliac joints. This is the reason why such patients are not designated as pre-radiographic axial SpA but as non-radiographic axial SpA [3]. Moreover, our study emphasizes the relative high frequency of the other clinical features of SpA in patients presenting with axial symptoms (Fig. 3). Such data are strongly supporting the use of the spondyloarthritis criteria set instead of the one of the mNY criteria. The performances of the three sets of SpA criteria were similar, particularly when including positive sacro iliac MRI in Amor and ESSG criteria. Our study also improves our knowledge about the clinical presentation of patients presenting with axial involvement of spondyloarthritis. As suspected, the axial localization of the symptoms at onset were mainly in the buttock or lumbar spine area (39.5 and 67.1% respectively) and rarely the cervical level (11.1%). Some particular information have been extracted from the baseline data of the DESIR Cohort. Patients with psoriasis have more frequently enthesitis, elevated BASDAI and BASFI scores, increased CRP and cholesterol levels, without differences in imaging data with patients without psoriasis [27]. Female gender is associated with higher BASDAI, fatigue and function scores despite less radiographic and MRI modifications than men. Women with radiographic sacro ileitis have more peripheral involvement [28]. Uveitis is associated with cervical involvement, a preceding history of infection and presence of IBD [29]. Anterior chest wall involvement is associated with greater severity of the disease, enthesitis, and radiographic modification of sacro iliac joints, irrespective of the symptoms duration [30]. HLA-B27 is associated with an earlier onset of IBP, a shorter diagnosis delay, axial MRI inflammation, sacro iliac radiographic changes, reduced disease activity and psoriasis frequency [31]. Analyzing patients characteristics pending the clinical or imaging arm of the ASAS classification, Molto demonstrated that only minor differences were obvious, patients classified through the imaging arm (i.e. entry by radiographic or MRI sacroiliitis) are younger, more frequently male and have more frequently elevated CRP [32]. Finally, the main clinical features of the disease may be grouped in particular phenotypes or clusters [33]. Since early diagnosis or correct classification may be important for optimized management [34], overdiagnosis may also be inconvenient [35], and the matter of early diagnosis criteria is still under debate. Under these circumstances, performance of the different sets of classification criteria applied in early disease give some information upon accuracy of their use as diagnosis tools. It is noteworthy that these performances in the DESIR cohort are not so different that those observed in other similar cohorts of early possible spondyloarthritis [24,36]. In established SpA disease, an increased risk of comorbidities and especially cardiovascular diseases, and osteoporosis are well recognized. However, the pathophysiology of such comorbidities is not clear (e.g. related to the inflammatory process of the disease, its treatments and in particular long term intake of NSAIDs or other factors such as immobilization of the spine due to ankylosis). In our study focused on patients observed at disease onset, the prevalence of such co-morbidities was low. The results observed in this study will necessitate to be confirmed in other cohorts of patients and also to be further analyzed in particular in the long term since all the enrolled patients will be closely monitored during at least 10 years after the baseline visit.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgements The DESIR cohort is conducted under the control of Assistance publique–Hopitaux de Paris via the Clinical Research Unit Paris-Centre and under the umbrella of the French Society of Rheumatology and Inserm (Institut national de la santé et de la recherche médicale). The database management is performed within the department of epidemiology and biostatistics (Professor Jean-Pierre Daurès, D.I.M., Nîmes, France). An unrestricted grant from Wyeth Pharmaceuticals was allocated for the first 5 years of the follow-up of the recruited patients. We also wish to thank the different regional participating centres: Pr Maxime Dougados (Paris–Cochin B), Pr André Kahan (Paris–Cochin A), Pr Olivier Meyer (Paris–Bichat), Pr Pierre Bourgeois (Paris–La Pitié-Salpetrière), Pr Francis Berenbaum (Paris–Saint Antoine), Pr Pascal Claudepierre (Créteil), Pr Maxime Breban (Boulogne Billancourt), Dr Bernadette Saint-Marcoux (Aulnay-sous-Bois), Pr Philippe Goupille (Tours), Pr Jean-Francis Maillefert (Dijon), Dr Xavier Puéchal (Le Mans), Pr Daniel Wendling (Besanc¸on), Pr Bernard Combe (Montpellier), Pr Liana Euller-Ziegler (Nice), Pr Philippe Orcel (Paris–Lariboisière), Pr Pierre Lafforgue (Marseille), Dr Patrick Boumier (Amiens), Pr Jean-Michel Ristori (ClermontFerrand), Dr Nadia Mehsen (Bordeaux), Pr Damien Loeuille (Nancy), Pr René-Marc Flipo (Lille), Pr Alain Saraux (Brest), Pr Corinne Miceli (Le Kremlin Bicêtre), Pr Alain Cantagrel (Toulouse), Pr Olivier Vittecoq (Rouen). Funding: the DESIR-cohort is financially supported by unrestricted grants from both the French Society of Rheumatology, and Pfizer Ltd, France. References [1] Calin A, Kaye B, Sternberg M, et al. The prevalence and nature of back pain in an industrial complex: a questionnaire and radiographic and HLA analysis. Spine (Phila Pa 1976) 1980;5:201–5. [2] Rudwaleit M, Sieper J. [Diagnosis and treatment of ankylosing spondylitis (Bechterew disease)]. Dtsch Med Wochenschr 2005;130:1882–6 [Review. German. No abstract available]. [3] Claudepierre P, Wendling D, Breban M, et al. Ankylosing spondylitis, spondyloarthropathy, spondyloarthritis, or spondylarthritis: what’s in a name? Joint Bone Spine 2012;79:534–5. [4] Wendling D, Prati C, Claudepierre P, et al. Non-radiographic spondyloarthritis: a theoretical concept or a real entity? Joint Bone Spine 2012;79:531–3. [5] Vander Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York Criteria. Arthritis Rheum 1984;27:361–8. [6] Amor B, Dougados M, Mijiyawa M. Criteria of the classification of spondylartropathies. Rev Rhum Mal Osteoart 1990;57:85–9. [7] Dougados M, van der Linden A, Juhlin R, et al. The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy. Arthritis Rheum 1991;34:1218–27. [8] Amor B, Dougados M, Listrat V, et al. [Evaluation of the Amor criteria for spondylarthropathies and European Spondylarthropathy Study Group (ESSG). A cross-sectional analysis of 2228 patients]. Ann Med Interne (Paris) 1991;142:85–9. [9] Dougados M, vam der Linden S, et al. Sulfasalazine in the treatment of spondylarthropathy. A randomized, multicenter, double-blind, placebo-controlled study. Arthritis Rheum 1995;38:618–27. [10] Clegg DO, Reda DJ, Weisman MH, et al. Comparison of sulfasalazine and placebo in the treatment of ankylosing spondylitis. A Department of Veterans Affairs Cooperative Study. Arthritis Rheum 1996;39:2004–12. [11] Rudwaleit M, van der Heijde D, Landewé R, et al. The development of Assessment of Spondyloarthritis International Society classification criteria for axial spondyloarthritis (part II): validation and final selection. Ann Rheum Dis 2009;68:777–83. [12] Rudwaleit M, Jurik AG, Hermann KG, et al. Defining active sacroiliitis on magnetic resonance imaging (MRI) for classification of axial spondyloarthritis: a consensual approach by the ASAS/OMERACTMRI group. Ann Rheum Dis 2009;68:1520–7.
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Please cite this article in press as: Dougados M, et al. Clinical presentation of patients suffering from recent onset chronic inflammatory back pain suggestive of spondyloarthritis: The DESIR cohort. Joint Bone Spine (2015), http://dx.doi.org/10.1016/j.jbspin.2015.02.006