ARTHRITIS & RHEUMATOLOGY Vol. 67, No. 4, April 2015, pp 1128–1137 DOI 10.1002/art.39013 © 2015, American College of Rheumatology

A Large National Cohort of French Patients With Chronic Recurrent Multifocal Osteitis J. Wipff,1 F. Costantino,2 I. Lemelle,3 C. Pajot,4 A. Duquesne,5 M. Lorrot,6 A. Faye,6 B. Bader-Meunier,7 K. Brochard,4 V. Despert,8 S. Jean,8 M. Grall-Lerosey,9 Y. Marot,10 D. Nouar,10 A. Pagnier,11 P. Quartier,7 and C. Job-Deslandre1 Objective. To document more fully the characteristics of chronic recurrent multifocal osteomyelitis (CRMO) in pediatric patients, to collect data on the outcomes and management of the disease, and to define prognostic factors. Methods. One hundred seventy-eight patients were included (123 female patients and 55 male patients), with a mean ⴞ SD age at diagnosis of 10.9 ⴞ 2.9 years. Inclusion criteria were a diagnosis of CRMO, evidence of at least one lesion of osteitis confirmed by imaging, and development of the syndrome before age 18 years. Results. Longitudinal clinical and imaging studies revealed that only 12 of 178 CRMO patients (7%) had unifocal lesions at the last medical visit. We were able to apply the clinical chronic nonbacterial osteomyelitis score to 110 of 178 patients (62%), which indicated

that bone biopsy could have been avoided in 27 cases (25%). At the last medical visit, disease was in remission in only 73 of 171 patients (43%) (41% receiving therapy) after a mean ⴞ SD of 47.9 ⴞ 38.9 months; 44 of 171 patients (26%) experienced sequelae. Using cluster analysis, the CRMO cohort was separated into 3 homogeneous phenotypes (severe, mild, and intermediate). Patients with the severe phenotype had the worst prognosis. This group was entirely composed of male patients, most of whom had the multifocal form of CRMO and inflammatory syndrome. Patients with the mild phenotype had the best prognosis. This group was primarily composed of female patients with a unifocal form of CRMO and infrequent clavicle involvement and inflammatory syndrome. Patients with the intermediate phenotype had a good prognosis but greater reliance on treatment. This group primarily included female patients with multifocal lesions and inflammatory syndrome. Conclusion. This is the largest CRMO cohort described in the literature to date. Clinical evolution and imaging investigations confirmed the multifocal pattern of the disease. Three distinct subgroups of CRMO patients were distinguished, with very different prognoses.

´ tude des Supported by the Socie´te´ Francophone De´die´e `a l’E Maladies Inflammatoires Pe´diatriques. 1 J. Wipff, MD, PhD, C. Job-Deslandre, MD: Ho ˆpital Cochin, AP-HP, and Universite´ Paris Descartes, Sorbonne Paris Cite´, Paris, 2 France; F. Costantino, MD: Institut Cochin, INSERM U1016, Universite´ Paris Descartes, Sorbonne Paris Cite´, and CNRS UMR 8104, Paris, France; 3I. Lemelle, MD: Centre Hospitalier Universitaire Brabois, Vandoeuvre Le`s Nancy, France; 4C. Pajot, MD, K. Brochard, MD: Ho ˆpital des Enfants, Centre Hospitalier Universitaire de Toulouse, Toulouse, France; 5A. Duquesne, MD: Ho ˆpital Femme Me`re Enfant, Centre Hospitalier Universitaire de Lyon, Lyon, France; 6M. Lorrot, MD, PhD, A. Faye, MD, PhD: Ho ˆpital Robert Debre´, AP-HP, Paris, France; 7B. Bader-Meunier, MD, PhD, P. Quartier, MD: Ho ˆpital Necker-Enfants Malades, AP-HP, Paris, France; 8V. Despert, MD, S. Jean, MD: Centre Hospitalier Universitaire de Rennes, Rennes, France; 9M. Grall-Lerosey, MD: Centre Hospitalier Universitaire de Rouen, Rouen, France; 10Y. Marot, MD, D. Nouar, MD: Centre Hospitalier Universitaire de Tours, Tours, France; 11A. Pagnier, MD: Centre Hospitalier Universitaire de Grenoble, Grenoble, France. Address correspondence to J. Wipff, MD, PhD, Service de Rhumatologie A, Ho ˆpital Cochin, 27 Rue du Faubourg St. Jacques, 75014 Paris, France. E-mail: [email protected]. Submitted for publication July 23, 2014; accepted in revised form December 19, 2014.

Chronic recurrent multifocal osteomyelitis (CRMO), also known as nonbacterial osteomyelitis or chronic nonbacterial osteomyelitis (CNO), is an orphan disease (OMIM ID #259680), and its prevalence is probably underestimated. CRMO was first described in 1972 by Giedion et al (1). Recurrent flares of inflammatory bone pain related to aseptic osteomyelitis are the major characteristics of the disease. Some extraarticular manifestations associated with CRMO have been described and include palmoplantar pustulosis (2,4–7), psoriasis (3,4,7), Crohn’s disease (2,5,8–11), acne (12), 1128

PROGNOSTIC FACTORS, OUTCOMES, AND MANAGEMENT OF CRMO

and Sweet syndrome (13,14). Although CRMO is considered a benign disease, it can substantially impair quality of life due to persistent symptoms or sequelae (2,3,15). Recently, there has been interest in the clinical, biologic, and imaging characteristics of CRMO and its natural evolution. Nevertheless, few studies have been published, and those that have been reported have included only relatively small numbers of patients (2– 6,15–17). Results of these studies are consistent regarding the ratio of female patients to male patients (female: male ratio 2:1), mean age at onset (10–11 years), mean age at diagnosis (11 years), and number of initial clinical lesions (n ⫽ 2) (2,3,5). However, results pertaining to outcomes such as sequelae (20–46%) or the activity of disease at the last evaluation (18–59%) were heterogeneous (2,3,5). The pathophysiology of CRMO remains unknown: some authors classify it as the juvenile form of SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis) and others as an autoinflammatory disease. However, recent genetic data (18–23) and the efficacy of anti–interleukin-1 receptor (anti–IL-1R) treatment in Majeed syndrome (24) suggest that CRMO may belong to the large family of autoinflammatory diseases with osseous expression (Majeed syndrome, PAPA syndrome [pyogenic sterile arthritis, pyoderma gangrenosum, and acne], and DIRA syndrome [deficiency of the IL-1R antagonist]). However, anti–IL-1 therapy seems not to yield the same dramatic improvement in CRMO, probably due to its multifactorial pattern (25). Recently, Jansson et al constructed a composite score to improve the management of CRMO. This score was designed to assist in the determination of whether bone biopsy is necessary to confirm the diagnosis in given patients (26). We therefore conducted a retrospective national study to document more fully the characteristics of CRMO in pediatric patients, to collect data on the outcomes and management of this disease, and to define prognostic factors. PATIENTS AND METHODS We retrospectively reviewed medical records of French CRMO patients who were diagnosed in 1995 or later and attended one of 12 French centers (one each in Lyon, Rennes, Brest, Nantes, Nancy, Toulouse, Rouen, Tours, Grenoble, and 3 in Paris). This cohort was not a registry with a goal of collecting all French cases of CRMO, but the medical records of all patients from each center were individually reviewed.

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In the absence of validated international diagnostic criteria, our inclusion criteria were the presence of at least one lesion consistent with osteomyelitis evident via imaging techniques in the absence of detectable infection, onset before 18 years of age, and a diagnosis of CRMO by local physicians. The exclusion criteria were onset after 18 years of age and other differential diagnosis (malignancy, infection, or enthesitisrelated arthritis). Two definitions for unifocal and multifocal patterns of CRMO were used: the first, which we referred to as the clinical definition, was based solely on the presence of clinically painful osseous localization(s) as stated by the patient before diagnosis; and the second, which we referred to as the final definition, was based on clinical and imaging identification of osseous localization(s) during the course of the disease. The characteristics of CRMO patients were recorded during two periods: “revealing” symptoms were recorded at initial presentation during the beginning of the disease, and cumulative symptoms corresponding to those noted over the entire course of the disease were recorded at the last medical visit. Clinical evaluation. Data on the following clinical characteristics were collected: age, sex, age at onset of symptoms, age at diagnosis, the time from symptom onset to diagnosis, and areas of clinically painful localization(s). Other features were recorded, including presence of fever, local inflammatory signs, and personal or family history of associated diseases such as psoriasis, inflammatory bowel disease (IBD), severe acne, palmoplantar pustulosis, spondyloarthritis, and CRMO. Past and current medications were listed. The effectiveness of nonsteroidal antiinflammatory drugs (NSAIDs) was noted when available. NSAIDs were considered effective if the local physicians noted in the medical record that the patient’s symptoms were improved by NSAID treatment. Nevertheless, effectiveness was subjective, and “effective” was not a synonym for “remission” or “completely controlled.” Finally, remission, as judged by the patient’s usual physician at the last medical visit, was defined as the absence of pain and, when available, the absence of biologic inflammatory syndrome and/or osteitis detected by imaging. The presence of sequelae (localized deformation, vertebral fracture, and general growth retardation defined as a body mass index [BMI] more than 2 standard deviations below the third percentile) was noted. Laboratory evaluation. The following laboratory values were recorded, as available, at baseline and at the time of the last medical visit: complete and differential blood cell count, C-reactive protein (CRP) level (analyzed according to local laboratory norms), erythrocyte sedimentation rate (ESR) (abnormal if ⬎10 mm/hour), and the presence of the HLA– B27 antigen. Imaging evaluation. The date, the number, and the localization of lesions evident on standard radiography, isotopic bone scanning, and magnetic resonance imaging (MRI) were recorded. Histologic evaluation. Histologic results of bone biopsies were analyzed, and the presence of neutrophils, lymphocytes, sclerosis, bone remodeling, and the results of bacteriologic cultures (in particular for Propionibacterium acnes and Staphylococcus) were noted.

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Table 1. Optimal multivariable logistic regression model for calculating the clinical score for a diagnosis of nonbacterial osteitis*

the within-cluster variance and increasing the distance between cluster centers.

Logistic regression coefficient

P

Score coefficient

RESULTS

4.4 3.4 3.29

0.002 0.018 ⬍0.001

13 10 10

3.01

0.011

9

2.63

0.002

8

2.39

0.001

7

1.93

0.005

6 63

Risk factor Normal blood cell count Symmetric lesions Lesions with marginal sclerosis Normal body temperature Vertebral, sternal, or clavicular lesion Radiologically proven lesions ⱖ2 CRP ⱖ1 mg/dl Total clinical score

* Risk factors were included if the regression coefficient was statistically significant (P ⬍ 0.05). Score coefficients are the scaled coefficients of the logistic regression values and represent the score component for each risk factor. If the individual does not have the specific risk factor, his or her contribution to the total clinical score for that characteristic is zero. The total clinical score is the sum of score coefficients not equal to zero, with a range of 0–63. CRP ⫽ C-reactive protein. Adapted from ref. 26.

Clinical CNO score. As noted above, Jansson and colleagues recently developed a score to assist in the diagnosis of CRMO, while reducing the number of unnecessary bone biopsies (26). The clinical score ranges from 0 to 63 (Table 1). We applied this score to evaluate if, retrospectively, CNO score results would facilitate confirmation of a CRMO diagnosis without a bone biopsy. Statistical analysis. All data analyses were performed using MedCalc version 9.2.1.0. Data are reported as the mean ⫾ SD for continuous variables and the number (percent) for categorical variables. Chi-square tests were used to assess differences in frequency, and Student’s t-test was used for comparing pairs of normally distributed continuous variables. P values less than 0.05 were considered significant. When P values were less than 0.05, odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. A multivariate stepwise logistic regression analysis was also performed for all variables identified as having P values less than 0.1 by univariate analysis. For the cluster analysis, we selected 10 variables based on their relevance to the characterization of CRMO features. The variables were sex, BMI, time from symptom onset to diagnosis, unifocal or multifocal pattern, clavicle involvement, presence of extraosseous lesions, family history of associated diseases, CRP level ⬎10 mg/liter, treatment with bisphosphonates and/or anti–tumor necrosis factor ␣ (anti-TNF␣), and whether remission (as defined above) was achieved by the time of the last medical visit. Cluster analysis (based on these significant components and using Ward’s method) was performed with R package (R Development Core Team 2005 [online at http://www.Rproject.org]). This method groups measures of similarity (minimum within the cluster sum of squares). Ward’s method allows for the detection of homogeneous groups by decreasing

“Revealing features.” There were 123 female and 55 male patients with CRMO (female:male ratio 2:1) in the cohort of 178 patients. The mean ⫾ SD age was 16.4 ⫾ 4.7 years (range 4–35 years). The mean ⫾ SD age at onset of symptoms was 9.8 ⫾ 3 years (range 1–17 years), and the time from symptom onset to diagnosis was 17.3 ⫾ 24.8 months (range 1–137 months). Other characteristics of this cohort of CRMO patients are summarized in Table 2. At the time of diagnosis, 124 patients (70%) presented with multifocal clinically painful osseous localizations; the mean ⫾ SD number of clinical lesions per patient was 2.7 ⫾ 1.8 (range 2–9). Among 54 patients (30%) with clinical evidence of a single bone localization, the clavicle was involved in 15 (28%). In all, 456 clinical localizations were described before diagnosis, with the lower limbs (47%), pelvis (16%), and clavicles (10%) being the most frequently involved. Mandibular and vertebral localizations were involved in 2% and 8%,

Table 2. Baseline characteristics of the patients in the French national CRMO cohort (n ⫽178)* Age, mean ⫾ SD years No. female/male Age at onset of symptoms, mean ⫾ SD years Age at diagnosis, mean ⫾ SD years Time from symptom onset to diagnosis, mean ⫾ SD months No. of clinical localizations per patient, mean ⫾ SD Clinical unifocal form of CRMO Local inflammatory aspect† Arthritis Fever Extraosseous involvement Family history Inflammatory syndrome HLA–B27 positive ANA positive No. of radiologic lesions per patient, mean ⫾ SD On radiography On isotopic bone scanning On MRI

16.4 ⫾ 4.7 123/55 9.8 ⫾ 3 10.9 ⫾ 2.9 17.3 ⫾ 24.8 2.7 ⫾ 1.8 54 (30) 77 (43) 20 (11) 36 (20) 21 (12) 51 (32)‡ 119 (67) 6 (7)§ 9 (12)¶ 3.5 ⫾ 2.9 1 ⫾ 0.9 2.5 ⫾ 1.7 3.1 ⫾ 3.3

* Except where indicated otherwise, values are the number (%) of patients. CRMO ⫽ chronic recurrent multifocal osteomyelitis; ANA ⫽ antinuclear antibody; MRI ⫽ magnetic resonance imaging. † Presence of tumefaction and/or heat and/or redness. ‡ n ⫽ 159. § n ⫽ 86. ¶ n ⫽ 74.

PROGNOSTIC FACTORS, OUTCOMES, AND MANAGEMENT OF CRMO

Figure 1. Distribution of 456 clinically painful osseous lesions at presentation in patients with chronic recurrent multifocal osteomyelitis.

respectively. The distribution of clinical lesions before diagnosis is detailed in the Figure 1. Forty patients had clinical vertebral lesions during the course of the disease and, of those, 7 (17.5%) had vertebral fractures. Comparison of the patients with and those without clinical vertebral lesions showed a significant difference only for the use of “aggressive treatments” (27.5% versus 9%; P ⫽ 0.003). Of 456 clinical localizations, 9 were mandibular lesions (2%) (one each occurring in 9 of 178 patients [5%], 8 of whom had a clinical multifocal form of CRMO). This occurred more frequently among male patients as compared to female patients (66% versus 29%; P ⫽ 0.02) and among those who had more frequently received aggressive treatment with bisphosphonates (56% versus 11%; P ⫽ 1 ⫻ 10–4). Extraosseous manifestations were initially present in 21 patients (12%) (6 with IBD, 14 with palmoplantar pustulosis, 3 with psoriasis, and 4 with severe acne). For 51 of 159 patients (32%), there was a family history of CRMO (n ⫽ 3) or disease associated with CRMO, e.g., psoriasis (n ⫽ 31), spondyloarthritides (n ⫽ 9), IBD (n ⫽ 6). Laboratory tests revealed a high frequency of inflammatory syndrome (119 patients [67%]), with high CRP concentrations (mean ⫾ SD 23.6 ⫾ 43.5 mg/liter) in 73 of 144 patients (51%) and high ESR (mean ⫾ SD 37.7 ⫾ 25 mm/hour) in 109 of 127 (86%). Blood cell counts were normal in 82 of 106 patients (77%). The HLA–B27 antigen was detected in 6 of 86 patients tested (7%), and antinuclear antibodies were detected in 9 of 74 (12%).

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The mean ⫾ SD number of structural lesions detected by imaging investigation was 3.5 ⫾ 2.9 (range 1–26), with differences between the imaging techniques: on standard radiography, a mean ⫾ SD of 0.9 ⫾ 1, on isotopic bone scanning, 2.4 ⫾ 1.7, and on MRI, 3.1 ⫾ 1.3. Bone biopsies were performed in 119 CRMO patients. Bacteriologic cultures were positive in 11 of 92 cases, with 4 positive for Propionibacterium acnes and 7 positive for Staphylococcus isolates (4 were coagulase negative, 1 was positive for Staphylococcus aureus, and 2 were unspecified). Despite positive cultures, these patients were included in our cohort. Indeed, the lack of improvement during and after antibiotic treatment showed that presence of the bacteria was not the cause of symptoms. Antibiotics were administered to 63 of 178 patients (35%). Histologic investigations showed that lymphocytes were significantly the most frequent inflammatory cells (84%, versus 56% neutrophils; P ⫽ 4.4 ⫻ 10–5). Lymphocytes and neutrophils were simultaneously present in 37 of 83 bone biopsy samples. Patients with only neutrophils demonstrated on biopsy did not exhibit a more severe or autoinflammatory pattern (fever or elevated CRP levels) than patients with lymphocytes demonstrated on biopsy. Bone remodeling was noted in 38 of 84 cases and sclerosis in 45 of 83. For biopsies that revealed the presence of neutrophils, lymphocytes, or sclerosis in infiltrates, bone biopsy was performed a mean ⫾ SD of 8.9 ⫾ 13.4 months (range 1–86), 9.3 ⫾ 15.4 months (range 1–86), and 9.4 ⫾ 15.4 months (range 1–86), respectively, after the onset of symptoms. Comparison between biopsies performed within the first 6 months of symptom onset and those performed ⬎6 months after symptom onset differed only with regard to the presence of lymphocytes, which was demonstrated significantly more frequently when biopsy was performed after the 6 first months (100% versus 80%; P ⫽ 0.006) (Supplementary Table 1, available on the Arthritis & Rheumatology web site at http://onlinelibrary.wiley. com/doi/10.1002/art.39013/abstract). The CNO score was assessed using the “revealing features” at the beginning of the disease, before the diagnosis (i.e., a diagnosis of CRMO made by local physicians) and before bone biopsy. The clinical score for CNO was interpretable for 110 of 178 patients at this particular point in the course of the disease. The CNO score results showed that 27 bone biopsies could have been avoided: 12 patients (score ⬎39) would have been definitively considered to have CRMO even without the result of a bone biopsy, and 15 patients (score between

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Figure 2. Evolution of the percentage of patients diagnosed as having a unifocal form of chronic recurrent multifocal osteomyelitis (CRMO). Among the 54 of 178 CRMO patients initially presenting with a clinically unifocal form of CRMO, a multifocal pattern was eventually detected in 42 based on clinical analysis and imaging studies. Thus, only 12 of 178 patients had a persistent unifocal pattern after ⬃4 years of disease progression.

29 and 38) could have been monitored instead of undergoing the bone biopsy. Cumulative features at the latest followup. The mean ⫾ SD disease duration between the onset of the first symptoms and the time of the last medical visit was 47.9 ⫾ 38.9 months. The number of clinical and radiologic osseous lesions increased during the course of the disease (mean ⫾ SD 3.6 ⫾ 2.2 and 4.7 ⫾ 3.9, respectively, at the last medical visit). Among the 54 CRMO patients with a clinically unifocal form at the beginning of the disease, longitudinal clinical and imaging studies revealed a multifocal pattern in 42 patients. Thus, only 12 of 178 (7%) had a persistent unifocal pattern after ⬃4 years of disease progression (Figure 2). Unifocal and multifocal forms of CRMO were compared using the two definitions of these patterns (Supplementary Table 2, available on the Arthritis & Rheumatology web site at http:// onlinelibrary.wiley.com/doi/10.1002/art.39013/abstract). By univariate analysis, patients with an initial multifocal form had less frequent clavicle involvement, a higher CRP concentration (mean ⫾ SD 28.1 ⫾ 49.7 mg/liter versus 12.1 ⫾ 16.2 mg/liter; P ⫽ 6 ⫻ 10–3), underwent fewer bone biopsies, and were more frequently treated with anti-TNF␣ and/or bisphosphonates (21 of 124 versus 3 of 54; P ⫽ 0.04). Only high CRP levels and fewer bone biopsies remained associated with multifocal forms in multivariate analysis. Using the final definition, differences between unifocal and multifocal forms were

significant for clavicle involvement (50% versus 9%; P ⫽ 4 ⫻ 10–6) and the mean CRP value (24.9 ⫾ 44.9 mg/liter versus 7.2 ⫾ 7.6 mg/liter; P ⫽ 2 ⫻ 10–4), by univariate analysis only. There was a trend toward a final multifocal pattern being more prevalent among male patients (33% versus 9%; P ⫽ 0.08) and occurring more frequently among patients who were treated with anti-TNF␣ and/or bisphosphonates (14% versus 0%; P ⫽ 0.06). Medical treatment, other than antibiotics, consisted of NSAIDs as first-line therapy in 173 of 178 patients (97%) and was effective in 126 patients. Other treatments included corticosteroids (14 patients), methotrexate (14 patients), sulfasalazine (21 patients), bisphosphonates (17 patients), anti-TNF␣ agents (13 patients), and anti–IL-1R (anakinra) (1 patient). Information on the efficacy of other treatments was recorded when available, with sulfasalazine, methotrexate, bisphosphonates, and anti-TNF␣ found to be efficacious in 41% of treated patients (7 of 17), 37.5% (3 of 8), 75% (6 of 8), and 89% (8 of 9), respectively. At the last visit, disease was considered to be in remission in 74 of 171 patients (43%), of whom 40% (27 of 67) were still receiving therapy (7 patients were lost to followup after the diagnosis). Among patients with active disease at the last visit, 72% (70 of 97) were receiving therapy, but treatment was not specified for some patients (n ⫽ 18), and some patients received therapy only during painful episodes. Sequelae occurred in 44 of 171 (26%). Seventeen patients with localized

PROGNOSTIC FACTORS, OUTCOMES, AND MANAGEMENT OF CRMO

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Table 3. Comparison between the CRMO patients whose disease was in remission and those whose disease was not in remission at the time of the last medical visit*

Age, mean ⫾ SD years No. female/male Age at onset of symptoms, mean ⫾ SD years Age at diagnosis, mean ⫾ SD years Time from symptom onset to diagnosis, mean ⫾ SD months Clinical multifocal form Local inflammatory aspect§ Inflammatory syndrome¶ Extraosseous involvement# No. of radiologic lesions per patient, mean ⫾ SD Underwent biopsy Received bisphosphonates Received anti-TNF␣ No. receiving bisphosphonates and/or anti-TNF␣ Experienced sequelae

No remission (n ⫽ 97)

Remission (n ⫽ 74)

17 ⫾ 4.4 60/37 9.6 ⫾ 3.2 11.3 ⫾ 3.1 22.2 ⫾ 30.6

15.6 ⫾ 4.8 56/18† 9.9 ⫾ 2.6 10.6 ⫾ 2.5 11.7 ⫾ 13.5‡

70 (72) 45 (47) 65 (70) 9 (9) 4.7 ⫾ 3.2 69 (71) 12 (12) 12 (12) 18 (19) 27 (28)

50 (68) 28 (40) 50 (73) 12 (16) 4.8 ⫾ 4.6 46 (62) 5 (7) 1 (1)** 6 (8)†† 17 (23)

* Except where indicated otherwise, values are the number (%) of patients. CRMO ⫽ chronic recurrent multifocal osteomyelitis; anti-TNF␣ ⫽ anti–tumor necrosis factor ␣. † P ⫽ 0.06 versus patients who did not experience remission, odds ratio (OR) 1.9 (95% confidence interval [95% CI] 0.98–3.7). ‡ P ⫽ 0.003 versus patients who did not experience remission; P ⫽ 0.04 by multivariate stepwise logistic regression, OR 0.98 (95% CI 0.97–0.99). § Presence of tumefaction and/or heat and/or redness; n ⫽ 96 patients in whom remission was not achieved and n ⫽ 70 patients in whom remission was achieved. ¶ n ⫽ 93 patients in whom remission was not achieved and n ⫽ 68 patients in whom remission was achieved. # n ⫽ 96 patients in whom remission was not achieved and n ⫽ 73 patients in whom remission was achieved. ** P ⫽ 0.007 versus patients who did not experience remission, OR 10.3 (95% CI 1.3–81.2). †† P ⫽ 0.05 versus patients who did not experience remission, OR 1.3 (95% CI 0.97–6.9); P ⫽ 0.03 by multivariate stepwise logistic regression, OR 0.11 (95% CI 0.01–0.85).

bone deformation at the time of diagnosis were considered to be without deformation at the last medical visit. Sequelae included localized deformation (n ⫽ 26), in particular at the clavicle (n ⫽ 16), vertebral fractures (n ⫽ 7), and growth retardation (n ⫽ 11). Prognostic factors for persistence of symptomatic disease at the last medical visit are reported in Table 3. The risk of not having achieved clinical remission as of the last medical visit was significantly higher among patients in whom the time from symptom onset to diagnosis was longer (mean ⫾ SD 22.2 ⫾ 30.6 months versus 11.7 ⫾ 13.5 months; P ⫽ 0.003), and a tendency was noted among male patients (38% versus 24%; P ⫽ 0.06, OR 1.9 [95% CI 0.98–3.7]). None of the other demographic or disease characteristics, including the clinical unifocal/multifocal pattern of CRMO before diagnosis, were associated with remission. Prognostic factors for the severity of the disease characterized by the use of anti-TNF␣ and/or bisphosphonates were as follows: male sex (50% versus 29%; P ⫽ 0.04, OR 2.4 [95% CI 1–5.75]) and a multifocal pattern before

diagnosis (87% versus 66%; P ⫽ 0.04, OR 3.5 [95% CI 1–12.4]) (Supplementary Table 3, available on the Arthritis & Rheumatology web site at http:// onlinelibrary.wiley.com/doi/10.1002/art.39013/abstract). Cluster analysis of the CRMO cohort. Classification of the 178 CRMO patients by cluster analysis resulted in a dendrogram (Supplementary Figure 1, available on the Arthritis & Rheumatology web site at http:// onlinelibrary.wiley.com/doi/10.1002/art.39013/abstract). The CRMO cohort could be separated into 3 distinct homogeneous phenotypes, which are presented in Table 4. The patients characterized as having a mild phenotype differed dramatically from those characterized as having a severe phenotype, while patients characterized as having an intermediate phenotype fell somewhere in between. The severe phenotype (n ⫽ 36) included male patients (100%), most of whom had the multifocal form of CRMO (97%). Clavicle involvement in these patients was rare (only 11%), and they frequently exhibited evidence of inflammatory syndrome (CRP level ⬎10 mg/liter in 72%). The mild phenotype (n ⫽ 56) was

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Table 4. Cluster analysis of the 3 distinct subgroups of patients with CRMO*

Sex, % female BMI, no. of SD difference from value expected for age Time from symptom onset to diagnosis, months % with multifocal form of CRMO % with clavicle involvement % with extra-rheumatologic manifestations % with family history % with CRP ⬎10 mg/liter % receiving bisphosphonates and/or anti-TNF␣ % in remission

Mild phenotype (n ⫽ 56)

Intermediate phenotype (n ⫽ 86)

Severe phenotype (n ⫽ 36)

P

73 ⫺0.31 14.6 20 43 4 20 26 2 49

95 ⫺0.48 14.6 91 14 20 39 56 13 48

0 ⫺0.10 27.8 97 11 15 35 72 33 22

2 ⫻ 10⫺16 NS NS 2 ⫻ 10⫺16 6 ⫻ 10⫺5 0.02 NS 0.0002 0.0001 0.02

* CRMO ⫽ chronic recurrent multifocal osteomyelitis; BMI ⫽ body mass index; NS ⫽ not significant; CRP ⫽ C-reactive protein; TNF␣ ⫽ tumor necrosis factor ␣.

composed primarily of female patients (73%) with a unifocal form of CRMO (80%). Forty-three percent of these patients exhibited clavicle involvement, 26% exhibited evidence of inflammatory syndrome, and 4% had extraosseous lesions. The intermediate phenotype (n ⫽ 86) was also primarily composed of female subjects (95%) with a multifocal form of CRMO (91%). Fifty-six percent of these patients exhibited evidence of inflammatory syndrome, 39% had a family history of associated disease, and 20% had extraosseous lesions. Patients with the severe phenotype had the worst prognosis, with a remission rate of 22% despite high frequency of the use of bisphosphonates and/or antiTNF␣ (33%). Patients with the mild phenotype had the best prognosis (at the last medical visit, 49% were in remission) despite the infrequent use of bisphosphonates and/or anti-TNF␣ (2%). Patients with the intermediate phenotype had a remission rate of 48%, and 13% used bisphosphonates and/or anti-TNF␣. DISCUSSION Our results, collected from the largest published cohort of CRMO patients, provide detailed clinical, biologic, histologic, and demographic data on CRMO during the course of the disease. Our study identifies, for the first time, 3 homogeneous subgroups of CRMO patients with distinct features and prognosis. Results of the study indicate that the outcome among CRMO patients is not as good as previously reported, show that clinical and imaging followup over a long period confirm, that CRMO is a multifocal disease, and suggest that the clinical CNO score may be helpful in the confirmation of a CRMO diagnosis without the systematic use of bone biopsy.

Demographic characteristics, such as the ratio of female patients to male patients (2:1) and the mean age at diagnosis (11 years), as well as clinical data from this national French CRMO cohort, are similar to those reported in other published studies (2–6). The delay before diagnosis in our cohort was quite long (mean 17.3 months [range 1–137 months]), and similar to delays described in previous reports (5–23 months) (4,27,28). The difference in time from symptom onset to diagnosis between the periods before 2007 and after 2007 (data not shown) is not significant, suggesting that CRMO remains a poorly identified disease. The distribution of painful osseous lesions before CRMO diagnosis in our cohort is consistent with previous data (4,5), affecting predominantly the lower limbs (47%) followed by the pelvis (16%) and clavicle (10%). Vertebral localizations were less frequent (8%) than previously described (14–30%) (4,5,16). However, the number of patients with vertebral lesions (40 patients [22%]) and, especially, the risk of vertebral fracture (17.5%) when vertebral lesions occurred has to be considered high. According to these results, the presence of inflammatory vertebral lesions should lead to consideration of more aggressive antiinflammatory treatments to prevent complications. In analysis of mandibular involvement (n ⫽ 9 patients), data suggest that this predominantly occurred among male patients (66%) receiving more aggressive treatments (56%). Nevertheless, these data need to be considered with caution, given the small number of patients. The frequency of personal or familial extraosseous manifestations already considered to be autoinflammatory conditions (8–14), such as psoriasis or inflammatory bowel diseases, is consistent with the hypothesis that CRMO belongs to the family of autoinflammatory

PROGNOSTIC FACTORS, OUTCOMES, AND MANAGEMENT OF CRMO

diseases. The alternative hypothesis is that CRMO belongs to the group of spondyloarthritides. The low frequency of HLA–B27 (7%) supports the idea that if CRMO were to be classified as a spondyloarthritis, it would have to be considered a non–HLA–B27 spondyloarthritis like enteropathic or psoriatic arthritis (29). Moreover, psoriasis and IBD are highly associated with CRMO. Another way to address this issue is to consider that spondyloarthritides may be included in the autoinflammatory disease spectrum, as suggested by McGonagle and McDermott in 2006 (30). Elevated levels of inflammatory markers seem to occur frequently in CRMO, as shown in our study and others (2,5,6,17). In these previous studies, CRP and/or ESR levels were elevated in 50–90% of cases. Our findings are in accordance with these results, but they should be interpreted with caution given that the patients in our cohort were all seen at tertiary care hospitals, creating the possibility of selection bias associated with the most severely affected patients being the ones who need hospital medical care. Imaging (isotopic bone scanning and/or MRI) is the cornerstone for confirming the multifocal pattern of CRMO. MRI seems to have a better sensitivity for detecting multiple lesions (20 of 38 [52%]) than isotopic bone scanning (14 of 41 [34%]). This result, consistent with other published data (31), is further strengthened by the fact that only 2 of 38 MRI investigations were whole-body MRI. However, no definitive conclusion can be drawn from this retrospective study, which was not designed to compare these 2 imaging techniques. The unifocal or multifocal forms of CRMO have not been rigorously defined. Because of this, we used 2 definitions, the clinical definition (which was based on the patients’ assertion [before diagnosis] of the presence of clinically painful osseous localizations) and the final definition (which was based on clinical and imaging identification of osseous localizations during the course of the disease). Irrespective of the definition used, comparisons between unifocal and multifocal forms revealed 3 main differences between the 2 forms: CRP values were higher, the clavicle was less frequently involved, and the use of anti-TNF␣ and/or bisphosphonates was more frequent in the multifocal group. Those who had a unifocal form of CRMO according to the final definition were predominantly female patients with clavicle involvement and normal laboratory results. After a mean disease duration of 4 years, the disease was considered to be in clinical remission in only 74 of 171 cases of CRMO in our cohort (43%) (of these patients, 40% were receiving treatment). Among

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CRMO patients with active disease at the last medical visit, 72% were still receiving therapy, although some had discontinued treatment. These results indicate that CRMO may have a poorer prognosis than previously described, with more frequent active disease at followup (2–6); however, data from previous studies are scarce and there is no validated or even agreed-upon definition of remission. This suggests a need to identify homogeneous subtypes of CRMO and prognostic factors facilitating case management in order to improve outcomes. The cluster analysis (Table 4) shows 3 homogeneous subgroups of patients with distinct prognoses and features. The subgroup of patients with a severe phenotype was correlated with the worst prognoses, with remission of disease having been achieved in only 22% of patients at the last medical visit despite the use of anti-TNF␣ and/or bisphosphonates in one-third of patients. The severe phenotype was composed of male CRMO patients, most of whom had a multifocal form of CRMO and inflammatory syndrome at the beginning of the disease. Conversely, the subgroup with a mild phenotype, which was primarily composed of female patients with a unifocal form of CRMO and normal CRP levels, had a better prognosis (nearly 50% in remission). These findings were generally in accordance with results of the study by Jansson et al (5), who based their analysis on 3 subgroups of nonbacterial osteitis characterized by clinical course: 1) acute nonbacterial osteitis (symptoms lasting not longer than 6 months and at least one bone lesion), 2) chronic nonbacterial osteitis (persistent symptoms [without remission] lasting longer than 6 months and at least one bone lesion), and 3) CRMO (multiple bone lesions or one bone lesion plus palmoplantar pustulosis and recurrent flares with remission). The main difference between the 2 studies was the way subgroups were identified. In our study, cluster analysis was performed based on patient characteristics. Our results showed differences for sex, inflammatory syndrome, and treatments. These differences allowed us to distinguish 3 homogeneous subgroups with marked features and prognosis. Another way to identify patients with poor prognosis is to assess patients whose disease did not go into remission or those who needed therapy with anti-TNF␣ and/or bisphosphonates. Results identified male sex, a multifocal pattern at the onset, and a long period of time between onset of symptoms and diagnosis as poor prognostic factors. These observations highlight the importance of increased knowledge and the value of diagnosing patients early in the course of the disease to improve the prognosis. The identification of these prog-

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nostic factors should lead to improved management to prevent sequelae (26% of patients had sequelae in our study regardless of the remission status), which has been found to be associated with psychological consequences and depression (2,3). NSAIDs are the first-line treatment for CRMO and are highly effective, as previously reported (32,33). The wide diversity of second-line treatments used (2– 6,25,34–40) reflects a lack of standardization concerning the treatment of CRMO, a consequence of the absence of controlled and randomized trials. Further studies are needed to evaluate possible treatment strategies. Bone biopsy was performed more frequently in patients with a unifocal pattern versus patients with a multifocal pattern (61% versus 81%; P ⫽ 0.007) in order to rule out differential diagnoses, such as malignancy and infection. Although bone biopsy often remained necessary, some CRMO patients could avoid this invasive investigation. To assess this idea, we applied the clinical score proposed by Jansson et al (26) to our cohort, with interesting results. Among the 110 interpretable cases, bone biopsy could have been avoided for 27 patients. These results suggest that this clinical score may be useful in routine practice for the management of CRMO in order to avoid unnecessary invasive investigations. Our study should be interpreted within its limitations. First, it was a retrospective study, and this implies missing data; however, except for data concerning the presence of HLA–B27 (n ⫽ 86) and antinuclear antibody (n ⫽ 74), the amount of missing data was not excessive, and did not have large consequences for the validity of our results. Our cohort is not an exhaustive registry. Patients recruited into this cohort were CRMO patients followed up in tertiary hospital centers, and more severe cases may therefore have been over represented. However, it is probable that this particular subgroup of patients are at greatest need of adapted management and treatments. Specific strengths of our study include 1) the identification of homogeneous subgroups of CRMO patients with a distinct prognosis identified by cluster analysis, 2) the collection of data at 2 periods (which allowed for the analysis of the characteristics leading to the diagnosis and the prognostic factors in CRMO), 3) the 4-year followup (ensuring that misdiagnoses were eliminated), 4) the large number of CRMO patients (which indicates the validity of our results), and 5) the systematic and longitudinal collection of imaging and clinical findings (which confirmed that CRMO is, in a large majority of cases, a multifocal disease).

WIPFF ET AL

In this large French cohort of patients with CRMO, a severe phenotype and poor prognosis was more often associated with a subgroup of male patients who had an initial multifocal form of CRMO and inflammatory syndrome. Our results also suggest that clinical and imaging investigations, especially MRI, provide essential information to confirm the multifocal pattern of osteitis even in cases that are initially, apparently unifocal. In addition to imaging alone, the clinical CNO score may be useful for avoiding invasive bone biopsy. Although NSAIDs remain the first-line treatment for CRMO, further studies on treatment strategies that take into account the different phenotypes are warranted. AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Wipff had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design. Wipff, Job-Deslandre. Acquisition of data. Wipff, Lemelle, Pajot, Dyquesne, Lorrot, Faye, Bader-Meunier, Brochard, Despert, Jean, Grall-Lerosey, Marot, Nouar, Pagnier, Quartier, Job-Deslandre. Analysis and interpretation of data. Wipff, Costantino, JobDeslandre.

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A large national cohort of French patients with chronic recurrent multifocal osteitis.

To document more fully the characteristics of chronic recurrent multifocal osteomyelitis (CRMO) in pediatric patients, to collect data on the outcomes...
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