Value of rare diseases reference centers: impact on diagnosis and access to specialized care in fibrous dysplasia of bone.

INTRODUCTION: Reference Centers and Rare Disease Health Networks aim to improve the management of patients with rare diseases. The French reference center for Fibrous Dysplasia was certified in 2006. OBJECTIVE: The objective of our study was to assess the effectiveness of our reference center since its constitution. METHODS: In a retrospective cohort study, we compared the activity of our center, including the time elapsed between access to the center and the diagnostic delay of patients with Fibrous Dysplasia between two periods, 1994-2006 (before certification) and 2007-2019 (after certification). Data were extracted from patients' records (Easily®). Wilcoxon and Fisher tests were performed, using R®. RESULTS: Our cohort included 527 patients with Fibrous Dysplasia/Mc Cune Albright syndrome. The activity of the Fibrous Dysplasia center increased from 139 patients in the first period (1994-2006) to an additional 388 patients for the second period (2007-2019). Mean time elapsed to diagnosis of Fibrous Dysplasia was 1.5 years before 2007 and 1.9 years after 2007 (p = 0.12). Diagnosis was made before referral in over 80% of patients. There was a non-significant decrease in the number of patients with delayed diagnosis: 37 patients (44%) in the first period had a diagnostic delay and 94 patients (33%) in the second period (p = 0.07). Patients were referred to our center on average 6.8 years (before 2007) and 7.9 years (after 2007) after their diagnosis (p = 0.77). CONCLUSION: Healthcare organization with reference centers significantly impacted the management of patients with Fibrous Dysplasia/Mc Cune Albright syndrome, with a substantial increase in the activity of our center, that roughly tripled since certification. This healthcare organization was also associated with a trend toward decreasing diagnostic delay. However, diagnostic delay affected more than a third of patients and the time to access to the center remained extended (≈7-8 years after diagnosis). The current challenge lies in informing primary care providers and patients about education to rare diseases and existence of reference centers for earlier and more effective specialized management.

Denosumab use in bone fibrous dysplasia refractory to bisphosphonate: A retrospective multicentric study.

INTRODUCTION: Increased RANKL expression is observed in the bone tissue of fibrous dysplasia of bone/McCune-Albright syndrome (FD/MAS). In one animal model of FD/MAS, the inhibition of RANKL reduced tumor volume. A beneficial effect of denosumab on pain in patients refractory to bisphosphonates has been reported, but without systematic quantification of pain improvement. This work describes the clinical experience of our group on the efficacy on pain of denosumab treatment, along with safety, in FD/MAS patients refractory to bisphosphonates. MATERIALS AND METHODS: We have conducted a retrospective multicenter study in 6 academic rheumatology centers in France. We have collected patients and FD/MAS characteristics, duration of prior exposure to bisphosphonates, denosumab treatment modalities (dosage - administration regimen - number of courses); evolution of pain evaluated by Visual Analogic Scale (VAS). RESULTS: 13 patients were included (10 women and 3 men) 45 years on average, 5 MAS, 4 monostotic and 4 polyostotic forms. The average duration post-diagnosis of FD/MAS was 25 years and the mean duration of prior exposure to bisphosphonates was 4.7 years. Pain could be analyzed in 7 patients, showing a significant improvement from a mean VAS of 7.8 to 2.9 (-4.9 points, p = 0.003). In one patient with fronto-orbital FD/MAS, a 30 % decrease in lesional volume, assessed by MRI, was observed within 6 months of treatment, that was sustained over the following 12 months. Treatment regimens were heterogeneous. No hypercalcemia was observed after treatment cessation and the clinical tolerance was good. DISCUSSION: This study suggests that denosumab reduces pain in patients with DF/MAS refractory to bisphosphonates, and quantifies this improvement for the first time in a multicenter study. In our cohort, no patients who discontinued denosumab developed hypercalcemia and clinical tolerance was overall good. This study also provides encouraging data regarding lesion volume control. Further controlled studies are required to determine the place and modalities of the denosumab treatment of FD/MAS. CONCLUSION: Denosumab significantly decreased pain in FD/MAS refractory to bisphosphonate. This study paves the way for a randomized clinical trial to validate and standardize the prescription of denosumab in FD/MAS.

Extent of Extraskeletal Manifestations of Fibrous Dysplasia/McCune-Albright Syndrome in Patients with Mazabraud's Syndrome.

Mazabraud's syndrome (MZB) is a rare condition in which fibrous dysplasia of bone/the McCune-Albright syndrome (FD/MAS) co-exists with intramuscular myxomas. Both FD and the myxomas harbor the GNAS-mutation. Recent studies have shown that extraskeletal, GNAS-related features are associated with a more severe phenotype of FD/MAS. However, patients with MZB are often only seen by orthopedic surgeons. We therefore evaluated MZB patients seen in tertiary referral centers from the Netherlands (LUMC), USA (National Institutes of Health) and France (INSERM UMR 1033 (Lyos), Hôpital Edouard Herriot). All FD/MAS patients known in these centers with an additional diagnosis of a myxoma were included. Demographic information and data on disease extent and extraskeletal manifestations of FD/MAS such as precocious puberty (PP) or café-au-lait patches (CAL) were retrieved from patient's medical records. Thirty MZB patients were included: 20 women (67%) and 10 men (33%). Patients received a diagnosis of MZB (median 42 years, range 16-19) significantly later than the diagnosis of FD/MAS (median 30 years, range 0-60), p < 0.01. Twenty-six patients were diagnosed with polyostotic disease (87%). In 97% the myxoma was located near the skeletal FD lesion. The combination of MZB and MAS was made in 13 patients in whom PP (n = 7), CAL (n = 7), GH-excess (n = 3) and hyperthyroidism (n = 3) were present. Other extraskeletal features were (multinodular) goiter (n = 2) and thyroid cysts (n = 1). Furthermore, in this cohort of patients with MZB several (pre-)malignant tumors were observed; ductal carcinoma in situ of the breast in 3 patients (10%), breast cancer in 1 patient (3.3%), intra pancreatic mucinous neoplasms in 3 patients (10%) and liver adenomas in 2 patients (6.6%). A total of 47% of patients with MZB had an additional extraskeletal feature such as an endocrinopathy. In MZB, 87% of patients suffer from polyostotic FD, 43% of patients have extraskeletal GNAS-features such as an hyperfunctioning endocrinopathy and 30% (pre-)malignant tumors. We therefore advocate that MZB patients should undergo a complete screening and long-term follow-up for extent of bone disease, but also extraskeletal GNAS features of FD/MAS.

Serum periostin levels and severity of fibrous dysplasia of bone.

Fibrous dysplasia of bone (FD) is a rare congenital bone disease, characterized by a fibrous component in the bone marrow. Periostin has been extensively researched because of its implication in various fibrotic or inflammatory diseases. Periostin may be associated with the burden or the severity of FD. The case control PERIOSDYS study aimed at assessing serum periostin levels in FD patients. Sixty four patients with monostotic or polyostotic disease were included, in order to evaluate whether the concentrations were greater in patients than in 128 healthy age, BMI and sex-matched controls and if they were more elevated in patients with the more severe phenotypes. We found that periostin levels were greater in patients with FD compared to controls (mean = 1085 vs 958 pmol/l, p = 0.026), especially in those with a history of fracture (mean = 1475 vs 966 pmol/l, p = 0.0005), polyostotic forms (mean = 1214 vs 955 pmol/l, p = 0.004) or McCune-Albright syndrome (mean = 1585 vs 1023 pmol/l, p = 0.0048). In contrast, high pain levels were not associated with periostin levels (mean = 1137 vs 1036 pmol/l, p = 0.445). Furthermore, patients undergoing bisphosphonate therapy had significantly lower levels than treatment naïve patients (mean = 953 vs 1370 pmol/l, p = 0.002). In conclusion, periostin may be a biochemical marker indicative of the most severe forms of FD and could be used to monitor patients treated with bisphosphonates.

Reduced bone volumetric density and weak correlation between infection and bone markers in cystic fibrosis adult patients.

UNLABELLED: In our current adult CF population, low BMD prevalence was only 20 %, lower than that historically described. We found a mild increase of serum RANK-L levels, independent from the bone resorption level. The increased fracture risk in CF may be explained by a lower tibial cortical thickness and total vBMD. INTRODUCTION: Bone disease is now well described in cystic fibrosis (CF) adult patients. CF bone disease is multifactorial but many studies suggested the crucial role of inflammation. The objectives of this study were, in a current adult CF population, to assess the prevalence of bone disease, to examine its relationship with infections and inflammation, and to characterize the bone microarchitecture using high resolution peripheral scanner (HR-pQCT). METHODS: Fifty-six patients (52 % men, 26 ± 7 years) were assessed in clinically stable period, during a respiratory infection, and finally 14 days after the end of antibiotic therapy. At each time points, we performed a clinical evaluation, lung function tests, and biochemical tests. Absorptiometry and dorso-lumbar radiographs were also performed. A subgroup of 40 CF patients (63 % men, 29 ± 6 years) underwent bone microarchitecture assessment and was age- and gender-matched with 80 healthy controls. RESULTS: Among the 56 CF patients, the prevalence of low areal BMD (T-score < -2 at any site), was 20 % (95 % CI: [10.2 %; 32.4 %]). After infections, serum RANK-L (+24 %, p = 0.08) and OPG (+13 %, p = 0.04) were increased with a stable ratio. Microarchitectural differences were mostly observed at the distal tibia, with lower total and cortical vBMD and trabecular thickness (respectively -9.9, -3.0, and -5 %, p < 0.05) in CF patients compared to controls, after adjustment for age, gender, weight, and height. CONCLUSIONS: In this study, bone disease among adult CF patients was less severe than that previously described with only 20 % of CF patients with low BMD. We found a mild increase of biological marker levels and an impaired volumetric density of the tibia that may explain the increased fracture risk in CF population.

Lupus erythematosus with leflunomide: induction or reactivation?

BACKGROUND: Leflunomide is a new oral disease modifying antirheumatic drug with a good safety profile. CASE REPORT: The first case of lupus erythematosus in a 58 year old white woman after administration of leflunomide for primary Sjögren's syndrome is reported. The relationship between induced lupus and leflunomide was confirmed by the resolution of the skin rash when the drug was stopped and its recurrence when it was reintroduced following a dose-response effect. DISCUSSION: Peripheral blood cells from this patient, from 15 patients with rheumatoid arthritis, and from healthy controls were used in a bioassay, which suggested that leflunomide affected the Th1/Th2 balance. Such a side effect might be related, in part, to the anti-tumour necrosis factor alpha activity of leflunomide.