Glucocorticoid trajectories over 2 years in patients with rheumatoid arthritis in a real-life setting.

OBJECTIVES: To analyse glucocorticoid (GC) use and trajectories in a real-life cohort of rheumatoid arthritis (RA). METHODS: Patients with RA included in the longitudinal RCVRIC cohort for initiating or changing biological disease-modifying antirheumatic drugs, were compared for the use of GCs at baseline. Among the GC users, the GC dose was analysed over 2 years of follow-up by group-based trajectory models. Characteristics and outcomes were compared between the trajectories. RESULTS: Among the 184 patients (RA duration 4.2 years (1.3; 12.6), Disease Activity Scores (DAS)28-C reactive protein (CRP) 4.24±2.14), 81 (44%) were on GCs. The GC users were significantly older, had higher CRP and Health Assessment Questionnaire (HAQ), more hypertension and lower lumbar T-score, but similar activity and erosive scores. Among the GC users, two trajectories were identified: trajectory 1 (n=20, 25%) with GC discontinuation in the first year and trajectory 2 (n=61, 75%) with maintenance of low-dose GCs at 2 years. Trajectory 2 was significantly associated with higher HAQ, a longer GC duration and a less frequent methotrexate association. After adjustment for HAQ, GC duration and MTX use, good EULAR responses were less frequent at 6 months and 1 year in the GC maintenance trajectory (38.3% vs 81.3%, p=0.03; 42.0% vs 82.4%, p=0.02). Diabetes, fractures and increased body mass index were noted in trajectory 2. CONCLUSION: GCs were used in almost half of patients with established RA in real-world practice. For the majority of GC users, a long-term low dose of GCs is maintained over 2 years. These results highlight the difficulties with stopping GCs, the lack of consensus for the efficacy-safety balance of GCs, and the need to individualise the best GC tapering.

Post-traumatic stress disorder prior to diagnosis is as rare in spondyloarthritis as in non-inflammatory rheumatic conditions and rheumatoid arthritis.

OBJECTIVE: Post-traumatic stress disorder (PTSD) may be a risk factor for the development of rheumatoid arthritis (RA). No data are available in spondyloarthritis (SpA). The aim of the present study was to investigate the frequency of traumatic events and PTSD in patients with SpA and its different phenotypes and to compare the results to patients with non inflammatory rheumatic disease and RA patients. METHODS: This was an observational, cross-sectional and bi-centric study. Participants were patients diagnosed with SpA, non-inflammatory rheumatic or autoimmune disease (controls), or RA. Traumatic events were identified by the brief trauma questionnaire (BTQ). PTSD was defined as the presence of a traumatic event and ≥4 symptoms on the short PTSD checklist scale. RESULTS: Among 1389 participants, 510 patients were diagnosed with SpA (167 ankylosing spondylitis, 140 psoriatic arthritis, 130 non-radiographic-axial SpA, and 51 peripheral SpA), 365 with non-inflammatory rheumatic disease and 514 patients with RA. The frequency of trauma in SPA patients was 33.7%, of which 30.5% in AS, 30.7% in PsA, 37.7% in nr-axSpA and 41.2% in peripheral SpA (P=NS). The prevalence of PTSD in SPA patients was 4.9%, (of which 3.6% in AS, 2.9% in PsA, 6.2% in nr-axSpA and 7.8% in peripheral SpA [P=NS]) and was not significantly different from the controls (after IPTW 4.8% vs. 6.7%). The frequency of trauma and PTSD was also comparable between RA and controls and between SPA and RA. CONCLUSION: Traumatic events and PTSD occurring prior to diagnosis is as rare in SpA as in non-inflammatory rheumatic diseases and RA.

Development and Validation of a Predictive Model of Hypovitaminosis D in General Adult Population: SCOPYD Study.

The worldwide global increase in serum 25-hydroxyvitamin D (25(OH)D) measurements has led some countries to restrict reimbursement for certain clinical situations only. Another approach could consist in providing physicians with screening tools in order to better target blood test prescription. The objective of the SCOPYD study was to identify the best combination of predictors of serum VitD concentration among adults aged 18-70 years. Potential risk factors for VitD deficiency were collected using a comprehensive self-administered questionnaire. A multivariable linear regression was used to build a predictive model of serum 25(OH)D concentration. Among 2488 participants, 1080 (43.4%) had VitD deficiency (<50 nmol/L) and 195 (7.8%) had severe deficiency (<25 nmol/L). The final model included sunlight exposure in the preceding week and during the last holidays, month of blood sampling, age, sex, body mass index, skin phototype, employment, smoking, sport practice, latitude, and VitD supplementation in preceding year. The area under the curve was 0.82 (95% CI (0.78; 0.85)) for severe deficiency. The model predicted severe deficiency with a sensitivity of 77.9% (95% CI (69.1; 85.7)) and a specificity of 68.3% (95% CI (64.8; 71.9)). We identified a set of predictors of severe VitD deficiency that are easy to collect in routine that may help to better target patients for serum 25(OH)D concentration determination.

The Effect of TNF and Non-TNF-Targeted Biologics on Body Composition in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is associated with a decrease in lean mass and stability or even an increase in fat and ectopic adipose tissue. A few data are available on body composition changes under treatment, and data are still controversial. Body composition was assessed before initiation of biologic disease-modifying antirheumatic drug (bDMARD) and after 6 and 12 months of stable treatment. Eighty-three RA patients were included (75% of women, mean age 58.5 ± 10.8 years) of whom 47 patients treated with TNF inhibitor (TNFi), 18 with non-TNF-targeted biologic (Non-TNFi), and 18 with conventional DMARD (cDMARD) alone. In the TNFi group, total lean mass, fat-free mass index, and skeletal muscle mass index significantly increased at 1 year. An increase in subcutaneous adipose tissue (SAT) without change for the visceral or body fat composition was associated. These changes were associated with an improvement in strength and walking test. In non-TNFi or cDMARD groups, no significant changes for body composition or muscle function were observed at 1 year. However, no significant differences for treatment x time interaction were noted between group treatments. In active RA patients starting first bDMARD, treatment with TNFi over 1 year was associated with favorable changes of the body composition and muscle function.

French survey on the crossed needs on sexual health for chronic inflammatory rheumatism patients and healthcare professionals.

Patients with Inflammatory Chronic Rheumatic disease have approximately three times more sexual dysfunction than the healthy population. However, health professionals do not dare to discuss the subject with them, largely because they do not feel educated on the subject. To define the educational needs in the sexual health of health professionals involved in patient education and those of patients with Inflammatory Chronic Rheumatic disease. This French multicenter cross-sectional online study included health professionals involved in patient education and patients with Inflammatory Chronic Rheumatic disease. Two surveys were designed to assess, both of them the specific needs. They were filled out anonymously online with a secured server. The influence of professionals and patients' characteristics on their sexual health needs were tested. 57 health professionals and 239 patients answered. 71,6% of the patients reported sexual difficulties and 79,9% had never discussed them with health professionals. To facilitate discussion, the health professionals most often wanted a colleague specialized in sexual health in their team (59,7%) and access to tools (52,6%). The patients' primary expectations were psychological support (65.7%), information (51.9%), and referral to specialists if needed (43.1%). The topics the health professionals and patients considered most useful were adverse effects of treatment and impact of rheumatism on sexuality and body image. 70,2% of the health professionals felt they needed training. This survey demonstrates the need to offer educational training to health professionals designed to enable them to address and discuss sexual health issues and give their patients appropriate advice.

Prevalence of Migraine and Neuropathic Pain in Rheumatic Diseases.

To investigate the physiopathology of pain in chronic inflammatory rheumatic diseases (CIRDs), we assessed the prevalence of migraine and neuropathic pain in 499 patients with CIRDs. We studied 238 patients with rheumatoid arthritis, 188 with spondyloarthritis (SpA), 72 with psoriatic arthritis (PsA), and 1 unclassified. Migraine was diagnosed according to IHS migraine diagnostic criteria. Neuropathic pain was diagnosed when patients scored at least 3 on the DN4 questionnaire. Participants completed a validated self-assessment questionnaire. Migraine prevalence was 34% (165/484), and it was highest in PsA. Risk factors for migraine were a high level of anxiety, female sex, young age, and TNF-alpha inhibitor treatment (OR = 1.90 (1.13-3.25)). Besides, high disease activity was a risk factor in SpA. Blood CRP level was not significantly associated with migraine. Of 493 patients with CIRDs, 21.5% had chronic pain with neuropathic characteristics. Compared to the French general population, these patients had significantly higher prevalences of migraine (two-fold) and neuropathic pain (three-fold). This study showed that migraine and neuropathic pain frequently occurred in patients with rheumatic diseases. Therefore, upon reporting residual pain, these patients should be checked for the presence of migraine or neuropathic pain, despite adequate clinical control of rheumatic disease.

Evaluation of the Implementation of Guidelines on the Treatment of Osteoporosis in Patients with Rheumatoid Arthritis.

OBJECTIVE: To assess whether the 2003 and 2014 French guidelines on the prevention and treatment of glucocorticoid-induced osteoporosis (GIOP) and the 2012 update of the French guidelines for the treatment of postmenopausal osteoporosis (PMOP) were applied in patients with rheumatoid arthritis (RA). METHODS: We conducted a cross-sectional study of 776 patients with RA (19 centers). We collected the data required for the application of the various recommendations (age, sex, prednisone intake, low-energy fracture, history in the immediate family of hip fractures, and bone densitometry), anti-osteoporotic drugs, and the various factors that may be associated with the application of the recommendations. RESULTS: Of the patients who should have received antiosteoporosis treatment, there were 22.6% actually treated (according to the 2014 guidelines), 27.3% actually treated according to the 2003 guidelines, and of postmenopausal women, 23.6% (according to the 2012 PMOP guidelines). Applying the 2014 GIOP guidelines increased the theoretical number of patients requiring treatment relative to the 2003 GIOP guidelines (77% vs 53%; p < 0.001). In multivariate analysis, being treated was associated with a spinal T score ≤ -2 SD according to the 2014 guidelines; with not taking part in physical activity for more than 30 min a day according to the 2003 guidelines; and with older age, lower body mass index, and a T score ≤ -2.5 SD in at least 1 site according to the PMOP guidelines. CONCLUSION: Patients with RA had inadequate prevention of GIOP and PMOP. The management of osteoporosis needs to be improved in this population.

Retention rates of adalimumab, etanercept, and infliximab as first- or second-line biotherapies for spondyloarthritis patients in daily practice in Auvergne (France).

OBJECTIVE: To compare, in real-life settings, the retention rates of initial anti-tumor-necrosis factor (TNF) treatments (etanercept [ETN], adalimumab [ADA] and infliximab [IFX]) used as first-line biotherapy for axial spondyloarthritis (axSpA), and evaluate treatment switches to another anti-TNF inhibitor in the event of treatment failure. METHODS: We analyzed the medical records of all SpA patients (Assessment in Ankylosing Spondylitis International Working Group axial criteria) treated with ETN, IFX or ADA between 2001 and February 2015. Drug retention rates were calculated using the Kaplan-Meier method and compared by means of the Cox extended model. Sub-analyses were performed according to discontinuation reasons. RESULTS: Of the 249 SpA patients analyzed (135 radiographic cases, 114 non-radiographic), 102 received ETN, 62 ADA, and 85 IFX. In total, 103 discontinued treatment. The retention rates of IFX, ADA and ETN were 67%, 59% and 56% after 3 years; 62%, 42% and 47% after 5 years; 55%, 42% and 24% after 8 years; 53%, 42% and 12% after 10 years, respectively. In multivariate analyses, the predictive factors for retention were: low BASDAI score (hazard ratio [HR]: 1.02 [1.01-1.04]), high C-reactive protein levels (HR: 0.98 [0.97-0.99]), concomitant disease-modifying therapy (HR: 0.4 [0.21-0.75]), and radiographic SpA (HR: 1.5 [1.0-2.52]). In total, 61 patients switched to another anti-TNF therapy. No difference was observed among the three anti-TNF therapies regarding median retention duration, although the retention rate proved higher for treatment switches from one monoclonal antibody to another. CONCLUSION: The retention rate in SpA patients proved high, with retention for IFX superior to that of ETN.

Retention rates of adalimumab, etanercept and infliximab as first-line biotherapy agent for rheumatoid arthritis patients in daily practice - Auvergne experience.

OBJECTIVE: To compare, in real-life conditions, the retention rates of anti-tumor necrosis factor (anti-TNF) treatment (etanercept [ETN], adalimumab [ADA] and infliximab [IFX]) initiated as first-line biotherapy for rheumatoid arthritis (RA) and to evaluate, in case of failure, the switch to another anti-TNF or a non-anti-TNF biological. METHODS: Monocentric retrospective cohort including all patients with RA starting a first anti-TNF between 2001 and 2015. RESULTS: Among the 346 patients analyzed, 201 received ETN, 82 ADA and 63 IFX. The first anti-TNF was interrupted in 151 cases. The retention rates were 82.8%, 67.6%, 46.5%, 28.1% and 22.5% at 1, 2, 5, 10 and 15 years, respectively, with a median retention duration of 52.8 (18.9-136.2) months (ETN: 59.3 [19.1-NA), ADA: 79.9 [19.3-136.2] and IFX: 37.2 [17.5-134.5], P = 0.49). The predictive factors of discontinuation were active RA (Disease Activity Score of 28 joints - C-reactive protein [DAS28-CRP] hazards ratio [HR]: 1.22 [1.03-1.45]), inflammatory syndrome (erythrocyte sedimentation rate HR: 1.01 [1.0-1.02]; CRP HR: 1.00 [1.00-1.01]), absence of methotrexate treatment (HR: 0.60 [0.43-0.83]), and corticosteroid use (HR: 1.91 [1.31-2.78]). The patients who switched to another anti-TNF treatment had an inferior retention than those who switched to a non-anti-TNF treatment (HR: 0.39 [0.17-0.87], P = 0.02). CONCLUSION: In real life, there was no difference in retention among the three anti-TNF agents, and 25% of patients continued them at 15 years. After failure of an anti-TNF, the switch to a non-anti-TNF biotherapy showed better retention.

Prevalence and risk factors of low bone mineral density in spondyloarthritis and prevalence of vertebral fractures.

BACKGROUND: Investigate the prevalence and risk factors of low bone mineral density (BMD) in patients with axial spondyloarthritis as well as investigating the prevalence of vertebral fractures. METHODS: Patients underwent BMD measurements with dual-energy X-ray absorptiometry (DXA) in the anterior-posterior lumbar spine, lateral spine and hip. We screened for vertebral fractures using vertebral fracture assessment, and then checked for syndesmophytes on the VFA images. Sociodemographic and clinical variables were collected. RESULTS: A total of 89 patients (41,6% female) took part in the study with a mean age of 44 ± 14 years and disease duration 10.2 ± 10.6 years. According to World Health Organization (WHO) criteria, 48,3% of patients displayed osteopenia and 6,7% osteoporosis. In the subgroup of women who underwent measurement at all sites including the lateral spine, the prevalence of osteopenia was 39.3% in the anterior-posterior spine, 32.1% in the lateral spine, and 64.3% with all sites together. VFA led to the diagnosis of at least one vertebral fracture in 6.2% of patients. On VFA, syndesmophytes were found in 24.3% of patients. The variables associated in multivariate analyses with low BMD in different measurement sites were low body mass index (BMI), a high physician's global assessment score, a high Bath Ankylosing Spondylitis Functional Index (BASFI) score and female gender. CONCLUSION: Our study found a high prevalence (around 50%) of low BMD in SpA. Conversely, the prevalence of osteoporosis (6.7% according to WHO criteria) and vertebral fractures (6.2%) was lower than generally reported in the literature. While lateral spine BMD measurement did little to improve the detection of osteopenia in women, the sample size was not large enough to enable us to draw definite conclusions.

Changes in body composition and metabolic profile during interleukin 6 inhibition in rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by increased mortality associated with cardiometabolic disorders including dyslipidaemia, insulin resistance, and cachectic obesity. Tumour necrosis factor inhibitors and interleukin 6 receptor blocker licensed for the treatment of RA decrease inflammation and could thus improve cardiovascular risk, but their effects on body composition and metabolic profile need to be clarified. We investigated the effects of tocilizumab (TCZ), a humanized anti-interleukin 6 receptor antibody, on body composition and metabolic profile in patients treated for RA. METHODS: Twenty-one active RA patients treated with TCZ were included in a 1 year open follow-up study. Waist circumference, body mass index, blood pressure, lipid profile, fasting glucose, insulin, serum levels of adipokines and pancreatic/gastrointestinal hormones, and body composition (dual-energy X-ray absorptiometry) were measured at baseline and 6 and 12 months of treatment. At baseline, RA patients were compared with 21 non-RA controls matched for age, sex, body mass index, and metabolic syndrome. RESULTS: Compared with controls, body composition was altered in RA with a decrease in total and appendicular lean mass, whereas fat composition was not modified. Among RA patients, 28.6% had a skeletal muscle mass index below the cut-off point for sarcopaenia (4.8% of controls). After 1 year of treatment with TCZ, there was a significant weight gain without changes for fat mass. In contrast, an increase in lean mass was observed with a significant gain in appendicular lean mass and skeletal muscle mass index between 6 and 12 months. Distribution of the fat was modified with a decrease in trunk/peripheral fat ratio and an increase in subcutaneous adipose tissue. No changes for waist circumference, blood pressure, fasting glucose, and atherogenic index were observed. CONCLUSIONS: Despite weight gain during treatment with TCZ, no increase in fat but a modification in fat distribution was observed. In contrast, muscle gain suggests that blocking IL-6 might be efficient in treating sarcopaenia associated with RA.

Frequency of concomitant fibromyalgia in rheumatic diseases: Monocentric study of 691 patients.

OBJECTIVE: Fibromyalgia (FM) is a confounding factor for diagnosing and assessing rheumatic disease activity. This study sought to assess the extent of this syndrome in rheumatism patients at a French rheumatology department. METHOD: This monocentric epidemiological study enrolled all patients consulting due to rheumatoid arthritis (RA), spondyloarthritis (SpA), or connective tissue disease (CTD). FM diagnosis was confirmed or excluded according to the rheumatologist opinion and the 1990 American College of Rheumatology (ACR) criteria. RESULTS: We enrolled 691 patients, including 451 women (65.3%), with a mean age of 55.8 years (18-93). Of the enrolled patients, 325 presented with RA, 298 SpA [59 psoriatic arthritis (PsA), 137 ankylosing spondylitis (AS), 64 non-radiographic SpA (nr-SpA), and 38 peripheral SpA], and 71 CTD. The rheumatologist established FM diagnosis in 97 patients (14%), while 55 (8%) fulfilled the 1990 ACR criteria. The frequency of FM was lower in RA patients (4.9% by 1990 ACR criteria; 7.7% by expert opinion) compared to SpA (11.1% by 1990 ACR, p < 0.05; 17.5% by expert opinion, p < 0.003) and CTD (11.3% by 1990 ACR, non-significant; 28.2% by expert opinion, p < 0.001). In the SpA subgroups, FM was more common in the nr-SpA than in PsA or AS (23.9%, 9.6%, and 6.4%, by 1990 ACR, p = 0.001; 37.3%, 13.5%, and 7.2%, by expert opinion, p < 0.001). CONCLUSION: FM-like symptoms are commonly associated with rheumatic diseases. The frequency of FM is particularly high in non-radiographic axial SpA, thus raising questions about the specificity of the Assessment of SpondyloArthritis International Society (ASAS) classification criteria.

Psoriatic arthritis treated by anti-TNFs: a monocentric trial of 102 cases in Auvergne, France.

OBJECTIVES: While several registries have already evaluated the retention of anti-TNF therapy in psoriatic arthritis (PsA), they sometimes reach divergent conclusions. Our study therefore sought to assess therapeutic retention rates and predictive factors of response in a patient cohort from Auvergne, France, followed up in routine clinical practice. METHODS: Medical records of all PsA patients treated from 2002 to May 2015 were analysed. PsA diagnosis was established based on the CASPAR criteria. RESULTS: In total, 102 patients were analysed, comprising 62 men (44.6±12.6 years) and 40 women (37.8±13.4). Mean PsA evolution was 2.7 years (0.8-11.2). The most common forms were peripheral (47/102, 45.1%) and mixed (46/102, 46.1%) PsA. The anti-TNF treatment initiated was etanercept in 47 cases (45.2%), adalimumab in 29 (27.9%), infliximab in 20 (19.2%), and golimumab in six [5.8%]. In 28 cases (27.4%), anti-TNF was associated with methotrexate (MTX). Overall, the median duration of anti-TNF retention was 76.5 months. The hazard ratios (HR) for treatment cessation did not significantly differ between the etanercept and monoclonal antibody groups (HR=1.35[0.96-1.93], p=0.08). After 5 years, approximately 30.8% of etanercept patients and 68.8% of monoclonal antibody patients (adalimumab 71.2%; infliximab 67.2%) were still being treated. Combining with MTX did not prolong the overall retention rate (HR=0.85[0.37-1.96], p=0.71). Tobacco use was predictive of discontinuation (p=0.03). CONCLUSIONS: Our study demonstrates good anti-TNF treatment retention in PsA patients, as well as confirming the deleterious effect of smoking while providing no argument in favour of combined treatment with MTX to improve maintenance.

Performance of Fibromyalgia Rapid Screening Tool (FiRST) to detect fibromyalgia syndrome in rheumatic diseases.

OBJECTIVE: To evaluate the performance of the Fibromyalgia Rapid Screening Tool (FiRST) self-questionnaire for the detection of FM associated with inflammatory rheumatic diseases. METHODS: This cross-sectional, French single-centre study was carried out between September 2014 and April 2015 in all patients who consulted for RA, SpA or CTD. Diagnosis of FM was based on ACR 90 criteria and rheumatologist opinion. RESULTS: The self-questionnaire was completed by 605 patients (279 RA, 271 SpA, 57 CTD). It detected 143 concomitant FMs (24.4%). When assessed against ACR 90 criteria, FiRST had a sensitivity of 74.5%, a specificity of 80.4%, a positive predictive value of 26.6% and a negative predictive value (NPV) of 97.1%. Specificity was lower in the CTD group (RA: 84.4%, SpA: 80.2%, CTD: 59.6%) (P = 0.001). When assessed against the rheumatologist's opinion, FiRST had a sensitivity of 75.8%, a specificity of 85.1%, a positive predictive value of 48.3% and an NPV of 95%. Sensitivity was lower in the SpA group than in the CTD group (66% vs 94.4%) (P = 0.004). Performance varied according to self-questionnaire items. CONCLUSION: Although it performs less well in inflammatory rheumatic disease, FiRST's opinion is close to that of the rheumatologist. It can be used by the rheumatologist in clinical practice for patients facing an apparent treatment failure and to rule out a potential FM diagnosis which could interfere with the treatment response.

Parkinson's disease: A risk factor for osteoporosis.

Parkinson's disease is the most common neurodegenerative disease after Alzheimer's disease. On the long term, it may be complicated by various musculoskeletal problems, such as osteoporotic fractures, that have significant socioeconomic consequences. Indeed, patients suffering from Parkinson's disease have a higher fracture risk, particularly hip fracture risk, than other subjects of the same age because of both a higher risk of falls and lower bone mineral density. Bone loss in Parkinson's disease may be associated with the severity and duration of the disease. We review here the different suspected mechanisms of accelerated bone loss in Parkinson's disease, amongst which weight loss and reduced mobility appear to play key roles. Antiparkinsonian drugs, particularly levodopa, may also be associated with decreased bone mineral density as a result of hyperhomocysteinaemia. We discuss the role of other nutritional deficiencies, such as vitamin B12, folate or vitamin K. In conclusion, it seems necessary to screen for and treat osteoporosis in this at-risk population, while actions to prevent falls are still disappointing. A better understanding of the factors explaining bone loss in this population would help implementing preventive actions.

Refractory rheumatic disorder: atypical postpregnancy osteoporosis.

This is a case report on a young patient with severe osteoporosis that was initially revealed when she presented with polyarthralgia during her second pregnancy. Postpartum, the pain increased and her X-ray did not show any abnormalities. A bone scintigraphy was performed. It indicated an inflammatory rheumatic disorder. Six months after partum, an investigation of right coxalgia revealed a spontaneous basicervical fracture. Given the persistent polyarthralgia, the patient underwent a new scintigraphy, which revealed areas of what looked to be old rib and L1 fractures. A subsequent full body magnetic resonance imaging (MRI) scan revealed signal abnormalities that could indicate multiple lower limb bone fractures. Despite exhaustive biological, radiological, and histological testing, no secondary cause for the osteoporosis was found. The patient was started on teriparatide. We finally concluded that, despite the atypical presentation, the patient was suffering from postpregnancy osteoporosis. It is possible that the frequency of occurrence of this still poorly understood disease is underestimated.