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High prevalence of spondyloarthritis in sarcoidosis patients with chronic back pain
Seminars in Arthritis and Rheumatism 49 (2019) 246 250
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Seminars in Arthritis and Rheumatism journal homepage: www.elsevier.com/locate/semarthrit
High prevalence of spondyloarthritis in sarcoidosis patients with chronic back pain Johanna Sigauxa,b,c,*, Luca Semeranoa,b,c, Toufik Nasrallahc, Hilario Nunesb,d,e, Diane Bouvryb,d,e, Dominique Valeyreb,d,e, Marie-Christophe Boissiera,b,c, Nathalie Saidenberg-Kermanac’ha,b,c a
Inserm UMR 1125, 1 rue de Chablis, 93009 Bobigny, France Sorbonne Paris Cite, Universite Paris 13, 1 rue de Chablis, 93009 Bobigny, France ^pitaux de Paris (AP-HP), Service de Rhumatologie, Groupe Hospitalier “Ho ^pitaux Universitaires de Paris-Seine Saint-Denis”, 125, rue de Assistance Publique-Ho Stalingrad, 93009 Bobigny, France d ^pitaux de Paris (AP-HP), Service de Pneumologie, Groupe Hospitalier “Ho ^pitaux Universitaires de Paris-Seine Saint-Denis”, 125, rue de Assistance Publique-Ho Stalingrad, 93009 Bobigny, France e EA2363, 1 rue de Chablis, 93009 Bobigny, France b c
A R T I C L E
I N F O
Keywords: Sarcoidosis Spondyloarthritis Sacroiliitis Magnetic resonance imaging Sarcoid bone lesion
A B S T R A C T
Introduction: Chronic back pain (CBP) is a frequent complaint in patients with sarcoidosis, which challenges the clinician as multiples causes may potentially underlie this symptom. Interestingly, some reports suggest that the coexistence of sarcoidosis and spondyloarthritis (SpA) may be frequent. This study aimed to determine the prevalence of axial radiographic and non-radiographic SpA in patients with sarcoidosis and CBP and assess the association between patient characteristics and SpA. Methods: This cross-sectional study enrolled 64 patients with a diagnosis of sarcoidosis and CBP. Patients describing CBP underwent a full spine MRI and radiography. All patients with inflammatory CBP underwent complementary sacroiliac joint MRI. The diagnosis of axial SpA was based on the Assessment of SpondyloArthritis International Society classification criteria. Results: Among the 64 patients (49 women) with sarcoidosis and CBP, 29 had inflammatory pain; 15/64 had a diagnosis of SpA (23.4% [95% CI: 13.7 35.6], 14/29 (48.3% [95% CI: 29.5 67.5] of those with inflammatory back pain). MRI sacroiliitis was found in 13 patients. On both univariate and multivariate analysis, SpA diagnosis was associated with inflammatory CBP (OR=28.5, 95% CI: 1.91 425.4) and sarcoidosis limited to the thorax (OR=6.74, 95% CI: 1.08 42.1). SpA was associated with young age (p = 0.0093) and male sex (p = 0.021) only on univariate analysis. Besides, 12/64 patients (18.8%, 95% CI: 10.1 30.5) had a diagnosis of sarcoidosis spine bone lesions, 7/64 (10.9%, 95% CI: 4.5 21.2) symptomatic vertebral fracture and 30/64 (46.9%, 95% CI: 34.3 59.8) degenerative spine. Conclusions: The prevalence of SpA is increased in sarcoidosis patients with inflammatory back pain. The systematic use of spine and sacroiliac MRI in this subgroup is justified. The association between other patient features and SpA needs further confirmation. © 2019 Elsevier Inc. All rights reserved.
Introduction Sarcoidosis is a systemic granulomatous disease with a broad spectrum of clinical features and organ involvement. The lung is the most commonly involved organ: at least 90% of sarcoidosis patients have Abbreviations: ASAS, Assessment of SpondyloArthritis International Society classification; CBP, chronic back pain; CI, confidence interval; CRP, C-reactive protein; HLAB27, human leukocyte antigen B27; MRI, magnetic resonance imaging; OR, odds ratio; SD, standard deviation; SpA, spondyloarthritis. ^ pitaux de Paris (AP-HP), Service de *Corresponding author at: Assistance Publique-Ho ^pitaux Universitaires de Paris-Seine SaintRhumatologie, Groupe Hospitalier “Ho Denis”, 125, rue de Stalingrad, 93009 Bobigny cedex, France. E-mail address: [email protected] (J. Sigaux). https://doi.org/10.1016/j.semarthrit.2019.03.006 0049-0172/© 2019 Elsevier Inc. All rights reserved.
pulmonary lesions in most series [1]. Locomotor involvement is usually not the presenting clinical feature, but it affects 40% of the sarcoidosis population, with a reported higher frequency among African Americans and women [2]. Locomotor involvement may be asymptomatic but is usually associated with pain (arthralgia, myalgia, arthritis, dactylitis, chronic back and peripheral pain) and loss of quality of life [3]. The term spondyloarthritis (SpA) is used to indicate a heterogeneous group of chronic inflammatory rheumatic diseases that can affect the axial skeleton (namely the spine and sacroiliac joints), the entheses and peripheral joints. A common genetic background is found in some patients and depends mainly on human leukocyte antigen B27 (HLA-B27), but other genetic determinants of the disease have been identified.
J. Sigaux et al. / Seminars in Arthritis and Rheumatism 49 (2019) 246 250
The coexistence of sarcoidosis and SpA, notably sacroiliitis, has been reported in case series [4,5] and in two cross-sectional studies [6,7] in which the prevalence of radiographic sacroiliitis varied from 6.6% to 14.2%. The presence of radiographic sacroiliitis was associated with inflammatory back pain, and all patients with these radiological features had a diagnosis of SpA according to both the Assessment of SpondyloArthritis International Society (ASAS) and European Spondyloarthropathy Study Group (ESSG) criteria [8]. At present, imaging tools such as MRI can detect sacroiliitis in patients with no or minimal radiographic sacroiliac abnormalities [9]. Hence, to account for the entire spectrum of axial SpA, the ASAS classification criteria involve both radiographic and non-radiographic forms of the disease. The aim of this cross-sectional study was to determine the prevalence of axial radiographic and non-radiographic SpA in patients with sarcoidosis and chronic back pain (CBP) and assess the association between patient characteristics and SpA. Material and methods Patients This cross-sectional study enrolled 64 patients, collaboratively monitored by rheumatologists and pulmonologists at Avicenne University Hospital, Bobigny, France, with a diagnosis of sarcoidosis and with CBP (for >6 weeks) from January 2016 to May 2018. This sample, which constituted the study population, was selected on the basis of CBP inside a wider sample of 337 patients with sarcoidosis who attended the pulmonology clinic in the same time-period. Subjects were diagnosed with sarcoidosis according to the criteria of the American Thoracic Society/European Respiratory Society/WorldAssociation of Sarcoidosis and Other Granulomatous Dis-orders statement on sarcoidosis [10]. Sarcoidosis was classified as “limited to the thorax” when involvement was limited to thoracic lymph nodes and the lungs or as “multivisceral” with both intra- and extra-thoracic involvement. The diagnosis of sarcoidosis predated the beginning of the study. Patients describing chronic low back pain (i.e., lasting for > 6 weeks) underwent a full spine MRI (if not contraindicated) and radiography. MRI involved the short T1 inversion recovery (STIR) method to identify bone oedema and/or vertebral enthesitis in the cervical, thoracic and lumbar spine region. MRI lesions considered typical for SpA (anterior/ posterior spondylitis, enthesitis of spinal ligaments) were defined as vertebral inflammatory lesions (VILs) according to the definition of the ASAS/OMERACT MRI study group [11]. A complementary sacroiliac joint MRI and enthesis ultrasonography were performed for all patients with inflammatory back pain and patients with noninflammatory pain for whom spinal MRI revealed VILs suggestive of SpA or at least one additional feature of SpA included in ASAS criteria. Patients with at least 4 of the 5 following pain features were considered to have inflammatory back pain: pain onset before age 40 years, insidious onset, improvement with exercise, no improvement with rest, pain at night (with improvement on getting up) [12]. Radiography and MRI images were evaluated separately by at least one radiologist and one rheumatologist experienced in musculoskeletal imaging and, in case of discordance, consensus was reached after discussion between the two readers. Inflammatory sacroiliitis was diagnosed according to 2009 ASAS criteria, in particular the presence of bone oedema in the subchondral or peri-articular compartment of the sacroiliac joint on one slice for bilateral lesions or on two consecutive slices for unilateral localisation [13]. The following laboratory tests were performed for all patients: routine blood biochemistry (including serum calcium) and cytology, acute phase reactants (erythrocyte sedimentation rate, C-reactive protein [CRP]), HLAB27 typing, serum angiotensin converting enzyme (ACE) and 25hydroxyvitamin D3. Complete history of sarcoidosis was assessed in detail (mean disease duration, mean disease duration at CBP onset, organ involvement, current and past systemic treatment).
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The diagnosis of axial SpA was based on the 2009 ASAS classification criteria [14]: presence of sacroiliitis on radiography or MRI plus at least one SpA feature (inflammatory back pain, arthritis, enthesitis, uveitis, dactylitis, psoriasis, Crohn disease/ulcerative colitis, good response to non-steroidal anti-inflammatory drugs, family history of SpA, HLA-B27 positivity, elevated CRP level) or HLA-B27 positivity plus at least two SpA features. Statistical analysis Descriptive statistics are presented as mean (SD) for continuous variables and number (%) for categorical variables. To compare patients with and without SpA, a parametric or non-parametric test (Student t or Mann Whitney test) was used for quantitative variables, depending on the data distribution. Chi-square test was used to compare categorical variables. To explore the association between patient variables and the diagnosis of SpA, a backward logistic multiple regression model was used. All variables associated with the diagnosis of SpA that were significant on univariate analysis at p 0.05 (age, sex, type of sarcoidosis involvement and inflammatory back pain) plus the variables that were considered clinically pertinent (CRP level) were included in the model. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. All statistical analyses were performed with MedCalc (v10.4.0.0). Significance was set at p 0.05. Results We included 64 patients (49 women) with sarcoidosis and CBP (Fig. 1). The main patient characteristics are summarized in Table 1. Among patients with CBP, 29 (45.3%) had inflammatory pain; MRI sacroiliitis was found in 13/64 (20.3%) patients, all with inflammatory pain, and 5 of these had concomitant radiographic sacroiliitis. Hence, in this subgroup of patients, the use of MRI allowed to detect 8 additional SpA. This results in a number need to screen of 8 patients with inflammatory pain to diagnose one patient with SpA. VILs were described in 6/64 (9.4%) patients and radiographic syndesmophytes were found in 7 (10.9%). Only 2 patients with VILs had syndesmophytes on radiography. Vertebral fracture (symptomatic or not) was seen in 10/64 patients (15.6%) on radiography and/or MRI. Among the 28 patients evaluated for HLA-B27 positivity, only 2 were positive; none had sacroiliitis, so for both, the diagnosis of SpA was retained on the basis of concomitant clinical features of SpA. Overall, 15/64 patients had a diagnosis of SpA (23.4% [95% CI: 13.7 35.6]), 14/29 with inflammatory back pain (48.3% [95% CI: 29.5 67.5]) and 1 with non-inflammatory back pain. The latter patient was HLA-B27 positive and had a personal history of psoriasis and clinical peripheral enthesitis associated with enthesal abnormalities suggestive of SpA on ultrasonography. Besides, 12/64 patients (18.8%, 95% CI: 10.1 30.5) had a diagnosis of sarcoidosis spine bone lesions, 7 (10.9%, 95% CI: 4.5 21.2) symptomatic vertebral fracture (bone oedema on spine MRI) and 30 (46.9%, 95% CI: 34.3 59.8) degenerative spine. On univariate analysis, SpA was significantly associated with younger age (OR=6.32, 95% CI: 1.57 25.3), male sex (OR=4.48, 95% CI: 1.26 15.9) and inflammatory back pain (OR=31.7, 95% CI: 3.82 263.8) as well as sarcoidosis limited to the thorax (OR=4.53, 95% CI: =1.32 15.6) (Table 2). Patients with and without SpA did not differ in potentially relevant variables such as CRP, ACE or 25 hydroxyvitamin D3 level (data not shown). On multivariate analysis, SpA was associated with only inflammatory back pain (OR=28.5, 95% CI: 1.9 425.4) and sarcoidosis limited to the thorax (OR=6.74, 95% CI:1.08 42.1) (Table 2). When the form of sarcoidosis was removed from the multivariate model, the association between SpA and male sex was again significant (OR= 6.08, 95% CI: 1.0 41.1).
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Fig. 1. Flow of participants in the study.
Discussion To our knowledge, this is the first study evaluating the prevalence of SpA in patients with sarcoidosis and inflammatory back pain with systematic spine and sacroiliac MRI. We found a high prevalence of SpA (23.4%) fulfilling the ASAS classification criteria in patients with sarcoidosis and CBP. The prevalence increased to 48.3% for patients
describing inflammatory pain. On both univariate and multivariate analysis, SpA was associated with inflammatory CBP and sarcoidosis limited to the thorax. The epidemiological association between sarcoidosis and SpA and/ or radiographic sacroiliitis has been described. In 2005, Erb et al. investigated the prevalence of sacroiliitis in 61 sarcoidosis patients, 49 of whom had reported back pain at some point in their lives [6].
Table 1 Characteristics of patients with sarcoidosis and chronic back pain by inflammatory and non-inflammatory pain
General characteristics Age, years, mean (SD) Sex (w/m) Disease duration (sarcoidosis), years, mean (SD) Disease duration at CBP onset, years, mean (SD) Geographical origin, n (%) European North African Afro-Caribbean Other Sarcoidosis phenotype, n (%) Multivisceral Sarcoidosis limited to the thorax Sarcoidosis treatment, n (%) Immunosuppressive drugs (prior or current) Corticosteroid treatment (prior or current) Treatment-free (prior or current) Imaging, n (%) MRI sacroiliitis Radiographic sacroiliitis MRI vertebral inflammatory lesions Radiographic syndesmophyte Ultrasound enthesitis Vertebral fracture (symptomatic and asymptomatic) Diagnosis retained, n (%) Spondyloarthritis Sarcoidosis spine bone lesions Degenerative spine Symptomatic vertebral fracture *
Total (n = 64)
Inflammatory back pain (n = 29)
Non-inflammatory back pain (n = 35)
53.0 (10.2) 49/15 12.2 (7.7) 5.6 (9.2)
48.2 (8.5) 21/8 10.4 (7.4) 3.6 (5.6)
57.0 (9.8) 28/7 13.8 (7.8) 6.5 (8.9)
28 (43.7) 19 (29.7) 15 (23.4) 2 (3.1)
14 (48.3) 8 (27.6) 7 (24.1) 0 (0)
14 (40.0) 11 (31.4) 8 (22.9) 2 (5.7)
39 (60.9) 25 (39.1)
15 (51.7) 14 (48.3)
24 (68.6) 11 (31.4)
46 (71.8) 39 (60.1) 7 (10.9)
19 (65.5) 26 (89.6) 0 (0)
27 (77.1) 13 (37.1) 7 (20.0)
NS <0.001 NS
13 (20.3) 7 (10.9) 6 (9.4) 10 (15.6) 5 (7.8) 10 (15.6)
13 (44.8) 7 (24.2) 6 (20.7) 9 (31.0) 4 (13.8) 1 (3.4)
0 (0) 0 (0) 0 (0) 1 (2.9) 1 (2.9) 9 (25.7)
<0.001 <0.05 <0.05 <0.05 NS <0.05
15 (23.4) 12 (18.8) 30 (46.9) 7 (10.9)
14 (48.3) 8 (27.6) 7 (24.1) 0 (0)
1 (2.9) 4 (11.4) 23 (65.7) 7 (20.0)
<0.001 NS <0.001 <0.05
p* <0.001 NS NS NS NS
NS
p: difference between inflammatory and non-inflammatory back pain; CBP: chronic back pain.
J. Sigaux et al. / Seminars in Arthritis and Rheumatism 49 (2019) 246 250
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Table 2 Multivariate analysis of associations of characteristics of CBP patients and prevalent spondyloarthritis Multivariate analysis a
Univariate analysis Characteristics c
Age Male vs. female CRP level >5 Sarcoidosis limited to the thorax Inflammatory back pain
(Model 2b)
(Model 1 )
OR
95% CI
p-value
OR
95% CI
p-value
OR
6.32 4.48 1.61 4.53 31.7
1.57 1.26 0.49 1.32 3.82
0.0093 0.021 0.430 0.013 <0.0001
4.58 4.82 0.76 6.74 28.5
0.57 0.63 0.10 1.08 1.91
0.153 0.130 0.782 0.041 0.015
2.91 6.68 0.82
0.47 18.1 1.08 41.1 0.15 4.53
0.253 0.04 0.82
26.6
2.15 330.8
0.011
25.3 15.9 5.40 15.6 263.8
36.8 37.0 5.43 42.1 425.4
95% CI
p-value
CRP: C-reactive protein. OR: odds ratio. 95% CI: 95% confidence interval. a Model 1: all variables significant on univariate analysis. Predicted probability (area under the receiver operating characteristic curve [AUC]): 89.5% (95% CI: 78.4 96.1). b Model 2: excluding the form of sarcoidosis. Predicted probability (AUC): 85.9% (95% CI: 74.0 93.8). c Age: lower vs. higher than the median age.
Four patients had radiographic sacroiliitis, which resulted in a prevalence of 6.6% (or 12.9% among those with inflammatory back pain). Kobak et al. found radiographic sacroiliitis in 6/42 (14.3%) sarcoidosis patients. Common features were inflammatory back pain, stage 2 radiographic sacroiliitis, and HLA-B27 negativity. The 6 patients with sacroiliitis had a diagnosis of SpA fulfilling both the ASAS and ESSG criteria. The higher prevalence we found could be due to sample fluctuation. However, the systematic use of MRI for all patients with back pain may have increased the sensitivity of our study to detect SpA at an earlier phase. Burgos-Vargas et al. found a prevalence of SpA of the same order magnitude as we found in patients with inflammatory CBP recruited from different rheumatology clinics; among 974 patients with inflammatory CBP, 29.1% met the criteria for non-radiographic SpA and 53.72% met criteria for ankylosing spondylitis [15]. Nevertheless, within our series of 64 patients who already had a diagnosis of sarcoidosis and complained of CBP, almost one in four also had SpA. Prevalence studies of the general population reveal that SpA is infrequent [16] and sarcoidosis is rare [17]. Hence, the frequent finding of patients with both sarcoidosis and SpA, even within a limited sample, questions whether the concomitant occurrence of the two conditions may not be due to just chance. SpA can associate with other granulomatous diseases like Crohn’s disease and a minority of SpA patients (more often those who are HLA-B27 negative) can have granulomatous uveitis. Both diseases can respond to anti-TNF agents, and in the absence of any identified common genetic background, some authors proposed that sarcoidosis and SpA may share a common microbial cause. Nevertheless, in this work we only studied the epidemiological association between sarcoidosis and axial SpA in patients with CBP and our data do not allow to further speculate about potential common pathophysiological pathways between those two diseases, which is beyond the scopes of the study. In this study, patients with sarcoidosis and SpA were younger than other patients with CBP and were more frequently men, which is consistent with the epidemiology of SpA [18]. A high proportion of our SpA patients were HLA-B27 negative, which was also the case for Kobak et al. [7]. In this work, the clinical feature that was more strongly predictive of SpA, on both univariate and multivariate analysis, was the presence of inflammatory back pain. If one considers that almost one in two patients with inflammatory back pain in this series had SpA, the systematic performance of spine and sacroiliac MRI in this subgroup may be warranted when radiographic sacroiliitis is not already present. Compared to conventional radiology, it was necessary to perform 8 MRI to identify one additional patient with SpA, which supports the cost-effectiveness of this approach in patients with inflammatory back pain. Another strong association found was between SpA and the form of sarcoidosis limited to the thorax. To the best of our knowledge, this is the first time this association has been described. Actually, the
relevance of this association is unclear, because it may make sense only assuming that SpA and sarcoidosis share a pathophysiological link. For this reason, we also tested a model that did not involve this clinical feature, which resulted in retaining male sex as predictor of SpA on multivariate analysis. An additional clinical benefit of MRI (besides the diagnosis of SpA) within this population was to identify a differential diagnosis of CBP in sarcoidosis. In our study, the prevalence of sarcoid bone lesions was 18.8%. Sarcoid spine involvement is one of the most frequent diagnoses [19] and may be underestimated, because half of patients are asymptomatic or have mild non-specific symptoms [20]. Moreover, the usual radiographic pattern found in appendicular bone (osteolytic lesions with small focal erosions and coarsened trabeculation) is usually not seen in spine lesions on radiography and only on 5% of CT scans [21]. Nevertheless, since the advent of MRI, detection of these lesions has improved [20]. In sarcoidosis, spine MRI findings typically include multiple intramedullary T1 intermediate intensity and T2 and STIR hyperintensity with gadolinium enhancement lesions. This picture may sometimes evoke osseous metastases but is unlikely to be confused with SpA [22]. The two other differential diagnoses we found were degenerative spine (46.9%) and vertebral fracture, the latter found in 10.9% of sarcoidosis patients with CBP. The main study limitation is the relatively small number of included patients, which limits external validity and resulted in wide confidence intervals for prevalence and associations. External validity may be additionally limited by a potential selection bias of patients, who were all followed in a tertiary center for sarcoidosis. Nevertheless, these limitations are dictated by the rarity of the condition. To the best of our knowledge, no study evaluating SpA in sarcoidosis ever had more than 65 patients. Internal validity may be affected by the cross-sectional design of the study, which limits causal inference. Finally, we may have underestimated the prevalence of SpA, because not all patients underwent systematic sacroiliac MRI. This exam was limited to patients with inflammatory pain and those with noninflammatory pain and clinical features of SpA. However, we estimate that we may have not found a higher prevalence of SpA in this series. In fact, with the current protocol, we could establish alternative diagnoses, consistent with the clinical picture, explaining the chronic back complaints of patients who had not undergone systematic sacroiliac MRI.
Conclusions Sarcoidosis patients with inflammatory back pain are frequently diagnosed with concomitant SpA. This highlights the importance of the recognition of inflammatory back pain, as this clinical feature identifies a subgroup of patients in which the systematic use of spine and sacroiliac MRI is justified.
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Declarations of interest ne, outside the submitted work. JS reports personal fees from Celge LS reports personal fees from Roche, grants and personal fees from Pfizer, outside the submitted work. TN declare no conflicts of interest. HN declare no conflicts of interest. DB declare no conflicts of interest. DV reports personal fees from Boehringer-Ingelheim, personal fees from Roche, personal fees from Astra-Zenecca, outside the submitted work. MCB reports grants from Abbot, grants from Pfizer, grants from MSD, personal fees from Sanofi, personal fees from Lilly, outside the submitted work. NSK declare no conflicts of interest. Acknowledgments We would like to thank the radiologist of Avicenne Hospital Avicenne (Bobigny) for kindly analysing of the X-Ray and the MRI of sarcoidosis patients: Damien BISSERET, Salima LADJEROUD and Boubekeur LANSEUR. We would like to thank Laura SMALES for english editing of the manuscript. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. References [1] Judson MA. The clinical features of sarcoidosis: a comprehensive review. Clin Rev Allergy Immunol 2015;49(1):63–78. [2] Chatham W. Rheumatic manifestations of systemic disease: sarcoidosis. Curr Opin Rheumatol 2010;22(1):85–90. [3] Thelier N, Assous N, Job-Deslandre C, Meyer O, Bardin T, Orcel P, et al. Osteoarticular involvement in a series of 100 patients with sarcoidosis referred to rheumatology departments. J Rheumatol 2008;35(8):1622–8. [4] Sezer I, Melikoglu MA, Cay HF, Kocabas H, Kacar C. A co-occurrence of sarcoidosis and ankylosing spondylitis: a case report. Rheumatol Int 2008;28(6):605–7. [5] Stucki G, von Felten A, Speich R, Michel BA. Ankylosing spondylitis and sarcoidosis coincidence or association? Case report and review of the literature. Clin Rheumatol 1992;11(3):436–9. [6] Erb N, Cushley MJ, Kassimos DG, Shave RM, Kitas GD. An assessment of back pain and the prevalence of sacroiliitis in sarcoidosis. Chest 2005;127(1):192–6. [7] Kobak S, Sever F, Ince O, Orman M. The prevalence of sacroiliitis and spondyloarthritis in patients with sarcoidosis. Int J Rheumatol 2014;2014:289454.
[8] Dougados M, van der Linden S, Juhlin R, Huitfeldt B, Amor B, Calin A, et al. The European spondylarthropathy study group preliminary criteria for the classification of spondylarthropathy. Arthritis Rheum 1991;34(10):1218–27. [9] Pavy S, Dernis E, Lavie F, Maillefert J-F, Mariette X, Schaeverbeke T, et al. Imaging for the diagnosis and follow-up of ankylosing spondylitis: development of recommendations for clinical practice based on published evidence and expert opinion. Jt Bone Spine Rev Rhum 2007;74(4):338–45. [10] Hunninghake GW, Costabel U, Ando M, Baughman R, Cordier JF, du Bois R, et al. ATS/ERS/WASOG statement on sarcoidosis. American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other granulomatous disorders. Sarcoidosis Vasc Diffuse Lung Dis Off J WASOG 1999;16 (2):149–73. R, [11] Hermann K-GA, Baraliakos X, van der Heijde DMFM, Jurik A-G, Landewe Marzo-Ortega H, et al. Descriptions of spinal MRI lesions and definition of a positive MRI of the spine in axial spondyloarthritis: a consensual approach by the ASAS/OMERACT MRI study group. Ann Rheum Dis 2012;71(8):1278–88. R, Brandt J, Burgos-Vagas R, Collantes-Estevez [12] Sieper J, van der Heijde D, Landewe E, et al. New criteria for inflammatory back pain in patients with chronic back pain: a real patient exercise by experts from the Assessment of SpondyloArthritis international Society (ASAS). Ann Rheum Dis 2009;68(6):784–8. R, van der Heijde D, Baraliakos [13] Rudwaleit M, Jurik AG, Hermann K-GA, Landewe X, et al. Defining active sacroiliitis on magnetic resonance imaging (MRI) for classification of axial spondyloarthritis: a consensual approach by the ASAS/OMERACT MRI group. Ann Rheum Dis 2009;68(10):1520–7. R, Listing J, Akkoc N, Brandt J, et al. The [14] Rudwaleit M, van der Heijde D, Landewe development of assessment of spondyloarthritis international society classification criteria for axial spondyloarthritis (part II): validation and final selection. Ann Rheum Dis 2009;68(6):777–83. [15] Burgos-Vargas R, Wei JC-C, Rahman MU, Akkoc N, Haq SA, Hammoudeh M, et al. The prevalence and clinical characteristics of nonradiographic axial spondyloarthritis among patients with inflammatory back pain in rheumatology practices: a multinational, multicenter study. Arthritis Res Ther [Internet] 2016. https://www.ncbi.nlm. nih.gov/pmc/articles/PMC4896040/. [16] Saraux A, Guillemin F, Guggenbuhl P, Roux CH, Fardellone P, Le Bihan E, et al. Prevalence of spondyloarthropathies in France: 2001. Ann Rheum Dis 2005;64 (10):1431–5. € ller-Quernheim J. Sar[17] Valeyre D, Prasse A, Nunes H, Uzunhan Y, Brillet P-Y, Mu coidosis. Lancet Lond Engl 2014;383(9923):1155–67. [18] Montilla C, Del Pino-Montes J, Collantes-Estevez E, Font P, Zarco P, Mulero J, et al. Clinical features of late-onset ankylosing spondylitis: comparison with earlyonset disease. J Rheumatol 2012;39(5):1008–12. [19] Sparks JA, McSparron JI, Shah N, Aliabadi P, Paulson V, Fanta CH, et al. Osseous sarcoidosis: clinical characteristics, treatment, and outcomes experience from a large, academic hospital. Semin Arthritis Rheum 2014;44(3):371–9. [20] Zhou Y, Lower EE, Li H, Farhey Y, Baughman RP. Clinical characteristics of patients with bone sarcoidosis. Semin Arthritis Rheum 2017;47(1):143–8. [21] Mostard RL, Prompers L, Weijers RE, van Kroonenburgh MJ, Wijnen PA, Geusens PP, et al. F-18 FDG PET/CT for detecting bone and bone marrow involvement in sarcoidosis patients. Clin Nucl Med 2012;37(1):21–5. [22] Moore SL, Kransdorf MJ, Schweitzer ME, Murphey MD, Babb JS. Can sarcoidosis and metastatic bone lesions be reliably differentiated on routine MRI? AJR Am J Roentgenol 2012;198(6):1387–93.
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High prevalence of spondyloarthritis in sarcoidosis patients with chronic back pain Johanna Sigauxa,b,c,*, Luca Semeranoa,b,c, Toufik Nasrallahc, Hilario Nunesb,d,e, Diane Bouvryb,d,e, Dominique Valeyreb,d,e, Marie-Christophe Boissiera,b,c, Nathalie Saidenberg-Kermanac’ha,b,c a
Inserm UMR 1125, 1 rue de Chablis, 93009 Bobigny, France Sorbonne Paris Cite, Universite Paris 13, 1 rue de Chablis, 93009 Bobigny, France ^pitaux de Paris (AP-HP), Service de Rhumatologie, Groupe Hospitalier “Ho ^pitaux Universitaires de Paris-Seine Saint-Denis”, 125, rue de Assistance Publique-Ho Stalingrad, 93009 Bobigny, France d ^pitaux de Paris (AP-HP), Service de Pneumologie, Groupe Hospitalier “Ho ^pitaux Universitaires de Paris-Seine Saint-Denis”, 125, rue de Assistance Publique-Ho Stalingrad, 93009 Bobigny, France e EA2363, 1 rue de Chablis, 93009 Bobigny, France b c
A R T I C L E
I N F O
Keywords: Sarcoidosis Spondyloarthritis Sacroiliitis Magnetic resonance imaging Sarcoid bone lesion
A B S T R A C T
Introduction: Chronic back pain (CBP) is a frequent complaint in patients with sarcoidosis, which challenges the clinician as multiples causes may potentially underlie this symptom. Interestingly, some reports suggest that the coexistence of sarcoidosis and spondyloarthritis (SpA) may be frequent. This study aimed to determine the prevalence of axial radiographic and non-radiographic SpA in patients with sarcoidosis and CBP and assess the association between patient characteristics and SpA. Methods: This cross-sectional study enrolled 64 patients with a diagnosis of sarcoidosis and CBP. Patients describing CBP underwent a full spine MRI and radiography. All patients with inflammatory CBP underwent complementary sacroiliac joint MRI. The diagnosis of axial SpA was based on the Assessment of SpondyloArthritis International Society classification criteria. Results: Among the 64 patients (49 women) with sarcoidosis and CBP, 29 had inflammatory pain; 15/64 had a diagnosis of SpA (23.4% [95% CI: 13.7 35.6], 14/29 (48.3% [95% CI: 29.5 67.5] of those with inflammatory back pain). MRI sacroiliitis was found in 13 patients. On both univariate and multivariate analysis, SpA diagnosis was associated with inflammatory CBP (OR=28.5, 95% CI: 1.91 425.4) and sarcoidosis limited to the thorax (OR=6.74, 95% CI: 1.08 42.1). SpA was associated with young age (p = 0.0093) and male sex (p = 0.021) only on univariate analysis. Besides, 12/64 patients (18.8%, 95% CI: 10.1 30.5) had a diagnosis of sarcoidosis spine bone lesions, 7/64 (10.9%, 95% CI: 4.5 21.2) symptomatic vertebral fracture and 30/64 (46.9%, 95% CI: 34.3 59.8) degenerative spine. Conclusions: The prevalence of SpA is increased in sarcoidosis patients with inflammatory back pain. The systematic use of spine and sacroiliac MRI in this subgroup is justified. The association between other patient features and SpA needs further confirmation. © 2019 Elsevier Inc. All rights reserved.
Introduction Sarcoidosis is a systemic granulomatous disease with a broad spectrum of clinical features and organ involvement. The lung is the most commonly involved organ: at least 90% of sarcoidosis patients have Abbreviations: ASAS, Assessment of SpondyloArthritis International Society classification; CBP, chronic back pain; CI, confidence interval; CRP, C-reactive protein; HLAB27, human leukocyte antigen B27; MRI, magnetic resonance imaging; OR, odds ratio; SD, standard deviation; SpA, spondyloarthritis. ^ pitaux de Paris (AP-HP), Service de *Corresponding author at: Assistance Publique-Ho ^pitaux Universitaires de Paris-Seine SaintRhumatologie, Groupe Hospitalier “Ho Denis”, 125, rue de Stalingrad, 93009 Bobigny cedex, France. E-mail address: [email protected] (J. Sigaux). https://doi.org/10.1016/j.semarthrit.2019.03.006 0049-0172/© 2019 Elsevier Inc. All rights reserved.
pulmonary lesions in most series [1]. Locomotor involvement is usually not the presenting clinical feature, but it affects 40% of the sarcoidosis population, with a reported higher frequency among African Americans and women [2]. Locomotor involvement may be asymptomatic but is usually associated with pain (arthralgia, myalgia, arthritis, dactylitis, chronic back and peripheral pain) and loss of quality of life [3]. The term spondyloarthritis (SpA) is used to indicate a heterogeneous group of chronic inflammatory rheumatic diseases that can affect the axial skeleton (namely the spine and sacroiliac joints), the entheses and peripheral joints. A common genetic background is found in some patients and depends mainly on human leukocyte antigen B27 (HLA-B27), but other genetic determinants of the disease have been identified.
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The coexistence of sarcoidosis and SpA, notably sacroiliitis, has been reported in case series [4,5] and in two cross-sectional studies [6,7] in which the prevalence of radiographic sacroiliitis varied from 6.6% to 14.2%. The presence of radiographic sacroiliitis was associated with inflammatory back pain, and all patients with these radiological features had a diagnosis of SpA according to both the Assessment of SpondyloArthritis International Society (ASAS) and European Spondyloarthropathy Study Group (ESSG) criteria [8]. At present, imaging tools such as MRI can detect sacroiliitis in patients with no or minimal radiographic sacroiliac abnormalities [9]. Hence, to account for the entire spectrum of axial SpA, the ASAS classification criteria involve both radiographic and non-radiographic forms of the disease. The aim of this cross-sectional study was to determine the prevalence of axial radiographic and non-radiographic SpA in patients with sarcoidosis and chronic back pain (CBP) and assess the association between patient characteristics and SpA. Material and methods Patients This cross-sectional study enrolled 64 patients, collaboratively monitored by rheumatologists and pulmonologists at Avicenne University Hospital, Bobigny, France, with a diagnosis of sarcoidosis and with CBP (for >6 weeks) from January 2016 to May 2018. This sample, which constituted the study population, was selected on the basis of CBP inside a wider sample of 337 patients with sarcoidosis who attended the pulmonology clinic in the same time-period. Subjects were diagnosed with sarcoidosis according to the criteria of the American Thoracic Society/European Respiratory Society/WorldAssociation of Sarcoidosis and Other Granulomatous Dis-orders statement on sarcoidosis [10]. Sarcoidosis was classified as “limited to the thorax” when involvement was limited to thoracic lymph nodes and the lungs or as “multivisceral” with both intra- and extra-thoracic involvement. The diagnosis of sarcoidosis predated the beginning of the study. Patients describing chronic low back pain (i.e., lasting for > 6 weeks) underwent a full spine MRI (if not contraindicated) and radiography. MRI involved the short T1 inversion recovery (STIR) method to identify bone oedema and/or vertebral enthesitis in the cervical, thoracic and lumbar spine region. MRI lesions considered typical for SpA (anterior/ posterior spondylitis, enthesitis of spinal ligaments) were defined as vertebral inflammatory lesions (VILs) according to the definition of the ASAS/OMERACT MRI study group [11]. A complementary sacroiliac joint MRI and enthesis ultrasonography were performed for all patients with inflammatory back pain and patients with noninflammatory pain for whom spinal MRI revealed VILs suggestive of SpA or at least one additional feature of SpA included in ASAS criteria. Patients with at least 4 of the 5 following pain features were considered to have inflammatory back pain: pain onset before age 40 years, insidious onset, improvement with exercise, no improvement with rest, pain at night (with improvement on getting up) [12]. Radiography and MRI images were evaluated separately by at least one radiologist and one rheumatologist experienced in musculoskeletal imaging and, in case of discordance, consensus was reached after discussion between the two readers. Inflammatory sacroiliitis was diagnosed according to 2009 ASAS criteria, in particular the presence of bone oedema in the subchondral or peri-articular compartment of the sacroiliac joint on one slice for bilateral lesions or on two consecutive slices for unilateral localisation [13]. The following laboratory tests were performed for all patients: routine blood biochemistry (including serum calcium) and cytology, acute phase reactants (erythrocyte sedimentation rate, C-reactive protein [CRP]), HLAB27 typing, serum angiotensin converting enzyme (ACE) and 25hydroxyvitamin D3. Complete history of sarcoidosis was assessed in detail (mean disease duration, mean disease duration at CBP onset, organ involvement, current and past systemic treatment).
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The diagnosis of axial SpA was based on the 2009 ASAS classification criteria [14]: presence of sacroiliitis on radiography or MRI plus at least one SpA feature (inflammatory back pain, arthritis, enthesitis, uveitis, dactylitis, psoriasis, Crohn disease/ulcerative colitis, good response to non-steroidal anti-inflammatory drugs, family history of SpA, HLA-B27 positivity, elevated CRP level) or HLA-B27 positivity plus at least two SpA features. Statistical analysis Descriptive statistics are presented as mean (SD) for continuous variables and number (%) for categorical variables. To compare patients with and without SpA, a parametric or non-parametric test (Student t or Mann Whitney test) was used for quantitative variables, depending on the data distribution. Chi-square test was used to compare categorical variables. To explore the association between patient variables and the diagnosis of SpA, a backward logistic multiple regression model was used. All variables associated with the diagnosis of SpA that were significant on univariate analysis at p 0.05 (age, sex, type of sarcoidosis involvement and inflammatory back pain) plus the variables that were considered clinically pertinent (CRP level) were included in the model. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. All statistical analyses were performed with MedCalc (v10.4.0.0). Significance was set at p 0.05. Results We included 64 patients (49 women) with sarcoidosis and CBP (Fig. 1). The main patient characteristics are summarized in Table 1. Among patients with CBP, 29 (45.3%) had inflammatory pain; MRI sacroiliitis was found in 13/64 (20.3%) patients, all with inflammatory pain, and 5 of these had concomitant radiographic sacroiliitis. Hence, in this subgroup of patients, the use of MRI allowed to detect 8 additional SpA. This results in a number need to screen of 8 patients with inflammatory pain to diagnose one patient with SpA. VILs were described in 6/64 (9.4%) patients and radiographic syndesmophytes were found in 7 (10.9%). Only 2 patients with VILs had syndesmophytes on radiography. Vertebral fracture (symptomatic or not) was seen in 10/64 patients (15.6%) on radiography and/or MRI. Among the 28 patients evaluated for HLA-B27 positivity, only 2 were positive; none had sacroiliitis, so for both, the diagnosis of SpA was retained on the basis of concomitant clinical features of SpA. Overall, 15/64 patients had a diagnosis of SpA (23.4% [95% CI: 13.7 35.6]), 14/29 with inflammatory back pain (48.3% [95% CI: 29.5 67.5]) and 1 with non-inflammatory back pain. The latter patient was HLA-B27 positive and had a personal history of psoriasis and clinical peripheral enthesitis associated with enthesal abnormalities suggestive of SpA on ultrasonography. Besides, 12/64 patients (18.8%, 95% CI: 10.1 30.5) had a diagnosis of sarcoidosis spine bone lesions, 7 (10.9%, 95% CI: 4.5 21.2) symptomatic vertebral fracture (bone oedema on spine MRI) and 30 (46.9%, 95% CI: 34.3 59.8) degenerative spine. On univariate analysis, SpA was significantly associated with younger age (OR=6.32, 95% CI: 1.57 25.3), male sex (OR=4.48, 95% CI: 1.26 15.9) and inflammatory back pain (OR=31.7, 95% CI: 3.82 263.8) as well as sarcoidosis limited to the thorax (OR=4.53, 95% CI: =1.32 15.6) (Table 2). Patients with and without SpA did not differ in potentially relevant variables such as CRP, ACE or 25 hydroxyvitamin D3 level (data not shown). On multivariate analysis, SpA was associated with only inflammatory back pain (OR=28.5, 95% CI: 1.9 425.4) and sarcoidosis limited to the thorax (OR=6.74, 95% CI:1.08 42.1) (Table 2). When the form of sarcoidosis was removed from the multivariate model, the association between SpA and male sex was again significant (OR= 6.08, 95% CI: 1.0 41.1).
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Fig. 1. Flow of participants in the study.
Discussion To our knowledge, this is the first study evaluating the prevalence of SpA in patients with sarcoidosis and inflammatory back pain with systematic spine and sacroiliac MRI. We found a high prevalence of SpA (23.4%) fulfilling the ASAS classification criteria in patients with sarcoidosis and CBP. The prevalence increased to 48.3% for patients
describing inflammatory pain. On both univariate and multivariate analysis, SpA was associated with inflammatory CBP and sarcoidosis limited to the thorax. The epidemiological association between sarcoidosis and SpA and/ or radiographic sacroiliitis has been described. In 2005, Erb et al. investigated the prevalence of sacroiliitis in 61 sarcoidosis patients, 49 of whom had reported back pain at some point in their lives [6].
Table 1 Characteristics of patients with sarcoidosis and chronic back pain by inflammatory and non-inflammatory pain
General characteristics Age, years, mean (SD) Sex (w/m) Disease duration (sarcoidosis), years, mean (SD) Disease duration at CBP onset, years, mean (SD) Geographical origin, n (%) European North African Afro-Caribbean Other Sarcoidosis phenotype, n (%) Multivisceral Sarcoidosis limited to the thorax Sarcoidosis treatment, n (%) Immunosuppressive drugs (prior or current) Corticosteroid treatment (prior or current) Treatment-free (prior or current) Imaging, n (%) MRI sacroiliitis Radiographic sacroiliitis MRI vertebral inflammatory lesions Radiographic syndesmophyte Ultrasound enthesitis Vertebral fracture (symptomatic and asymptomatic) Diagnosis retained, n (%) Spondyloarthritis Sarcoidosis spine bone lesions Degenerative spine Symptomatic vertebral fracture *
Total (n = 64)
Inflammatory back pain (n = 29)
Non-inflammatory back pain (n = 35)
53.0 (10.2) 49/15 12.2 (7.7) 5.6 (9.2)
48.2 (8.5) 21/8 10.4 (7.4) 3.6 (5.6)
57.0 (9.8) 28/7 13.8 (7.8) 6.5 (8.9)
28 (43.7) 19 (29.7) 15 (23.4) 2 (3.1)
14 (48.3) 8 (27.6) 7 (24.1) 0 (0)
14 (40.0) 11 (31.4) 8 (22.9) 2 (5.7)
39 (60.9) 25 (39.1)
15 (51.7) 14 (48.3)
24 (68.6) 11 (31.4)
46 (71.8) 39 (60.1) 7 (10.9)
19 (65.5) 26 (89.6) 0 (0)
27 (77.1) 13 (37.1) 7 (20.0)
NS <0.001 NS
13 (20.3) 7 (10.9) 6 (9.4) 10 (15.6) 5 (7.8) 10 (15.6)
13 (44.8) 7 (24.2) 6 (20.7) 9 (31.0) 4 (13.8) 1 (3.4)
0 (0) 0 (0) 0 (0) 1 (2.9) 1 (2.9) 9 (25.7)
<0.001 <0.05 <0.05 <0.05 NS <0.05
15 (23.4) 12 (18.8) 30 (46.9) 7 (10.9)
14 (48.3) 8 (27.6) 7 (24.1) 0 (0)
1 (2.9) 4 (11.4) 23 (65.7) 7 (20.0)
<0.001 NS <0.001 <0.05
p* <0.001 NS NS NS NS
NS
p: difference between inflammatory and non-inflammatory back pain; CBP: chronic back pain.
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Table 2 Multivariate analysis of associations of characteristics of CBP patients and prevalent spondyloarthritis Multivariate analysis a
Univariate analysis Characteristics c
Age Male vs. female CRP level >5 Sarcoidosis limited to the thorax Inflammatory back pain
(Model 2b)
(Model 1 )
OR
95% CI
p-value
OR
95% CI
p-value
OR
6.32 4.48 1.61 4.53 31.7
1.57 1.26 0.49 1.32 3.82
0.0093 0.021 0.430 0.013 <0.0001
4.58 4.82 0.76 6.74 28.5
0.57 0.63 0.10 1.08 1.91
0.153 0.130 0.782 0.041 0.015
2.91 6.68 0.82
0.47 18.1 1.08 41.1 0.15 4.53
0.253 0.04 0.82
26.6
2.15 330.8
0.011
25.3 15.9 5.40 15.6 263.8
36.8 37.0 5.43 42.1 425.4
95% CI
p-value
CRP: C-reactive protein. OR: odds ratio. 95% CI: 95% confidence interval. a Model 1: all variables significant on univariate analysis. Predicted probability (area under the receiver operating characteristic curve [AUC]): 89.5% (95% CI: 78.4 96.1). b Model 2: excluding the form of sarcoidosis. Predicted probability (AUC): 85.9% (95% CI: 74.0 93.8). c Age: lower vs. higher than the median age.
Four patients had radiographic sacroiliitis, which resulted in a prevalence of 6.6% (or 12.9% among those with inflammatory back pain). Kobak et al. found radiographic sacroiliitis in 6/42 (14.3%) sarcoidosis patients. Common features were inflammatory back pain, stage 2 radiographic sacroiliitis, and HLA-B27 negativity. The 6 patients with sacroiliitis had a diagnosis of SpA fulfilling both the ASAS and ESSG criteria. The higher prevalence we found could be due to sample fluctuation. However, the systematic use of MRI for all patients with back pain may have increased the sensitivity of our study to detect SpA at an earlier phase. Burgos-Vargas et al. found a prevalence of SpA of the same order magnitude as we found in patients with inflammatory CBP recruited from different rheumatology clinics; among 974 patients with inflammatory CBP, 29.1% met the criteria for non-radiographic SpA and 53.72% met criteria for ankylosing spondylitis [15]. Nevertheless, within our series of 64 patients who already had a diagnosis of sarcoidosis and complained of CBP, almost one in four also had SpA. Prevalence studies of the general population reveal that SpA is infrequent [16] and sarcoidosis is rare [17]. Hence, the frequent finding of patients with both sarcoidosis and SpA, even within a limited sample, questions whether the concomitant occurrence of the two conditions may not be due to just chance. SpA can associate with other granulomatous diseases like Crohn’s disease and a minority of SpA patients (more often those who are HLA-B27 negative) can have granulomatous uveitis. Both diseases can respond to anti-TNF agents, and in the absence of any identified common genetic background, some authors proposed that sarcoidosis and SpA may share a common microbial cause. Nevertheless, in this work we only studied the epidemiological association between sarcoidosis and axial SpA in patients with CBP and our data do not allow to further speculate about potential common pathophysiological pathways between those two diseases, which is beyond the scopes of the study. In this study, patients with sarcoidosis and SpA were younger than other patients with CBP and were more frequently men, which is consistent with the epidemiology of SpA [18]. A high proportion of our SpA patients were HLA-B27 negative, which was also the case for Kobak et al. [7]. In this work, the clinical feature that was more strongly predictive of SpA, on both univariate and multivariate analysis, was the presence of inflammatory back pain. If one considers that almost one in two patients with inflammatory back pain in this series had SpA, the systematic performance of spine and sacroiliac MRI in this subgroup may be warranted when radiographic sacroiliitis is not already present. Compared to conventional radiology, it was necessary to perform 8 MRI to identify one additional patient with SpA, which supports the cost-effectiveness of this approach in patients with inflammatory back pain. Another strong association found was between SpA and the form of sarcoidosis limited to the thorax. To the best of our knowledge, this is the first time this association has been described. Actually, the
relevance of this association is unclear, because it may make sense only assuming that SpA and sarcoidosis share a pathophysiological link. For this reason, we also tested a model that did not involve this clinical feature, which resulted in retaining male sex as predictor of SpA on multivariate analysis. An additional clinical benefit of MRI (besides the diagnosis of SpA) within this population was to identify a differential diagnosis of CBP in sarcoidosis. In our study, the prevalence of sarcoid bone lesions was 18.8%. Sarcoid spine involvement is one of the most frequent diagnoses [19] and may be underestimated, because half of patients are asymptomatic or have mild non-specific symptoms [20]. Moreover, the usual radiographic pattern found in appendicular bone (osteolytic lesions with small focal erosions and coarsened trabeculation) is usually not seen in spine lesions on radiography and only on 5% of CT scans [21]. Nevertheless, since the advent of MRI, detection of these lesions has improved [20]. In sarcoidosis, spine MRI findings typically include multiple intramedullary T1 intermediate intensity and T2 and STIR hyperintensity with gadolinium enhancement lesions. This picture may sometimes evoke osseous metastases but is unlikely to be confused with SpA [22]. The two other differential diagnoses we found were degenerative spine (46.9%) and vertebral fracture, the latter found in 10.9% of sarcoidosis patients with CBP. The main study limitation is the relatively small number of included patients, which limits external validity and resulted in wide confidence intervals for prevalence and associations. External validity may be additionally limited by a potential selection bias of patients, who were all followed in a tertiary center for sarcoidosis. Nevertheless, these limitations are dictated by the rarity of the condition. To the best of our knowledge, no study evaluating SpA in sarcoidosis ever had more than 65 patients. Internal validity may be affected by the cross-sectional design of the study, which limits causal inference. Finally, we may have underestimated the prevalence of SpA, because not all patients underwent systematic sacroiliac MRI. This exam was limited to patients with inflammatory pain and those with noninflammatory pain and clinical features of SpA. However, we estimate that we may have not found a higher prevalence of SpA in this series. In fact, with the current protocol, we could establish alternative diagnoses, consistent with the clinical picture, explaining the chronic back complaints of patients who had not undergone systematic sacroiliac MRI.
Conclusions Sarcoidosis patients with inflammatory back pain are frequently diagnosed with concomitant SpA. This highlights the importance of the recognition of inflammatory back pain, as this clinical feature identifies a subgroup of patients in which the systematic use of spine and sacroiliac MRI is justified.
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Declarations of interest ne, outside the submitted work. JS reports personal fees from Celge LS reports personal fees from Roche, grants and personal fees from Pfizer, outside the submitted work. TN declare no conflicts of interest. HN declare no conflicts of interest. DB declare no conflicts of interest. DV reports personal fees from Boehringer-Ingelheim, personal fees from Roche, personal fees from Astra-Zenecca, outside the submitted work. MCB reports grants from Abbot, grants from Pfizer, grants from MSD, personal fees from Sanofi, personal fees from Lilly, outside the submitted work. NSK declare no conflicts of interest. Acknowledgments We would like to thank the radiologist of Avicenne Hospital Avicenne (Bobigny) for kindly analysing of the X-Ray and the MRI of sarcoidosis patients: Damien BISSERET, Salima LADJEROUD and Boubekeur LANSEUR. We would like to thank Laura SMALES for english editing of the manuscript. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. References [1] Judson MA. The clinical features of sarcoidosis: a comprehensive review. Clin Rev Allergy Immunol 2015;49(1):63–78. [2] Chatham W. Rheumatic manifestations of systemic disease: sarcoidosis. Curr Opin Rheumatol 2010;22(1):85–90. [3] Thelier N, Assous N, Job-Deslandre C, Meyer O, Bardin T, Orcel P, et al. Osteoarticular involvement in a series of 100 patients with sarcoidosis referred to rheumatology departments. J Rheumatol 2008;35(8):1622–8. [4] Sezer I, Melikoglu MA, Cay HF, Kocabas H, Kacar C. A co-occurrence of sarcoidosis and ankylosing spondylitis: a case report. Rheumatol Int 2008;28(6):605–7. [5] Stucki G, von Felten A, Speich R, Michel BA. Ankylosing spondylitis and sarcoidosis coincidence or association? Case report and review of the literature. Clin Rheumatol 1992;11(3):436–9. [6] Erb N, Cushley MJ, Kassimos DG, Shave RM, Kitas GD. An assessment of back pain and the prevalence of sacroiliitis in sarcoidosis. Chest 2005;127(1):192–6. [7] Kobak S, Sever F, Ince O, Orman M. The prevalence of sacroiliitis and spondyloarthritis in patients with sarcoidosis. Int J Rheumatol 2014;2014:289454.
[8] Dougados M, van der Linden S, Juhlin R, Huitfeldt B, Amor B, Calin A, et al. The European spondylarthropathy study group preliminary criteria for the classification of spondylarthropathy. Arthritis Rheum 1991;34(10):1218–27. [9] Pavy S, Dernis E, Lavie F, Maillefert J-F, Mariette X, Schaeverbeke T, et al. Imaging for the diagnosis and follow-up of ankylosing spondylitis: development of recommendations for clinical practice based on published evidence and expert opinion. Jt Bone Spine Rev Rhum 2007;74(4):338–45. [10] Hunninghake GW, Costabel U, Ando M, Baughman R, Cordier JF, du Bois R, et al. ATS/ERS/WASOG statement on sarcoidosis. American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other granulomatous disorders. Sarcoidosis Vasc Diffuse Lung Dis Off J WASOG 1999;16 (2):149–73. R, [11] Hermann K-GA, Baraliakos X, van der Heijde DMFM, Jurik A-G, Landewe Marzo-Ortega H, et al. Descriptions of spinal MRI lesions and definition of a positive MRI of the spine in axial spondyloarthritis: a consensual approach by the ASAS/OMERACT MRI study group. Ann Rheum Dis 2012;71(8):1278–88. R, Brandt J, Burgos-Vagas R, Collantes-Estevez [12] Sieper J, van der Heijde D, Landewe E, et al. New criteria for inflammatory back pain in patients with chronic back pain: a real patient exercise by experts from the Assessment of SpondyloArthritis international Society (ASAS). Ann Rheum Dis 2009;68(6):784–8. R, van der Heijde D, Baraliakos [13] Rudwaleit M, Jurik AG, Hermann K-GA, Landewe X, et al. Defining active sacroiliitis on magnetic resonance imaging (MRI) for classification of axial spondyloarthritis: a consensual approach by the ASAS/OMERACT MRI group. Ann Rheum Dis 2009;68(10):1520–7. R, Listing J, Akkoc N, Brandt J, et al. The [14] Rudwaleit M, van der Heijde D, Landewe development of assessment of spondyloarthritis international society classification criteria for axial spondyloarthritis (part II): validation and final selection. Ann Rheum Dis 2009;68(6):777–83. [15] Burgos-Vargas R, Wei JC-C, Rahman MU, Akkoc N, Haq SA, Hammoudeh M, et al. The prevalence and clinical characteristics of nonradiographic axial spondyloarthritis among patients with inflammatory back pain in rheumatology practices: a multinational, multicenter study. Arthritis Res Ther [Internet] 2016. https://www.ncbi.nlm. nih.gov/pmc/articles/PMC4896040/. [16] Saraux A, Guillemin F, Guggenbuhl P, Roux CH, Fardellone P, Le Bihan E, et al. Prevalence of spondyloarthropathies in France: 2001. Ann Rheum Dis 2005;64 (10):1431–5. € ller-Quernheim J. Sar[17] Valeyre D, Prasse A, Nunes H, Uzunhan Y, Brillet P-Y, Mu coidosis. Lancet Lond Engl 2014;383(9923):1155–67. [18] Montilla C, Del Pino-Montes J, Collantes-Estevez E, Font P, Zarco P, Mulero J, et al. Clinical features of late-onset ankylosing spondylitis: comparison with earlyonset disease. J Rheumatol 2012;39(5):1008–12. [19] Sparks JA, McSparron JI, Shah N, Aliabadi P, Paulson V, Fanta CH, et al. Osseous sarcoidosis: clinical characteristics, treatment, and outcomes experience from a large, academic hospital. Semin Arthritis Rheum 2014;44(3):371–9. [20] Zhou Y, Lower EE, Li H, Farhey Y, Baughman RP. Clinical characteristics of patients with bone sarcoidosis. Semin Arthritis Rheum 2017;47(1):143–8. [21] Mostard RL, Prompers L, Weijers RE, van Kroonenburgh MJ, Wijnen PA, Geusens PP, et al. F-18 FDG PET/CT for detecting bone and bone marrow involvement in sarcoidosis patients. Clin Nucl Med 2012;37(1):21–5. [22] Moore SL, Kransdorf MJ, Schweitzer ME, Murphey MD, Babb JS. Can sarcoidosis and metastatic bone lesions be reliably differentiated on routine MRI? AJR Am J Roentgenol 2012;198(6):1387–93.