ERN ReCONNET points to consider for treating patients living with autoimmune rheumatic diseases with antiviral therapies and anti-SARS-CoV-2 antibody products.

Recent studies have shown that people who are immunocompromised may inadvertently play a role in spurring the mutations of the virus that create new variants. This is because some immunocompromised individuals remain at risk of getting COVID-19 despite vaccination, experience more severe disease, are susceptible to being chronically infected and remain contagious for longer if they become infected and considering that immunocompromised individuals represent approximately 2% of the overall population, this aspect should be carefully considered. So far, some autoimmune rheumatic disease (ARD) patients with COVID-19 have been treated with antiviral therapies or anti-SARS-CoV-2 antibody products. However, there is no homogeneous approach to these treatment strategies. This issue was addressed within the European Reference Network (ERN) on Rare and Complex Connective Tissue and Musculoskeletal Diseases (ReCONNET) in a discussion among experts and patient's representatives in the context of the rare and complex connective tissue diseases (rCTDs) covered by the Network. ERN ReCONNET is one of the 24 ERNs launched by the European Commission in 2017 with the aim of tackling low prevalence and rare diseases that require highly specialised treatment and promoting concentration of knowledge and resources through virtual networks involving healthcare providers (HCPs) across the European Union (EU). Considering the urgent need to provide guidance not only to the rCTDs community, but also to the whole ARDs community, a multidisciplinary Task Force, including expert clinicians and European Patient Advocacy Group (ePAG) Advocates, was created in the framework of ERN ReCONNET with the aim of developing overarching principles (OP) and points-to-consider (PtC) on a homogenous approach to treat immunocompromised patients with ARDs (with a particular focus on CTDs) affected by COVID-19 using antiviral therapies and anti-SARS-CoV-2 antibody products. The present work reports the final OP and PtC agreed by the Task Force.

Periodontal (formerly type VIII) Ehlers-Danlos syndrome: Description of 13 novel cases and expansion of the clinical phenotype.

Periodontal Ehlers-Danlos syndrome (pEDS) is a rare condition caused by pathogenic variants in the C1R and C1S genes, encoding subunits C1r and C1s of the first component of the classical complement pathway. It is characterized by early-onset periodontitis with premature tooth loss, pretibial hyperpigmentation and skin fragility. Rare arterial complications have been reported, but venous insufficiency is rarely described. Here we report 13 novel patients carrying heterozygous pathogenic variants in C1R and C1S including three novel C1S variants (c.962G > C, c.961 T > G and c.961 T > A). In addition to the pEDS phenotype, three patients and one relative displayed widespread venous insufficiency leading to persistent varicose leg ulcers. One patient suffered an intracranial aneurysm with familial vascular complications including thoracic and abdominal aortic aneurysm and dissection and intracranial aneurysm rupture. This work confirms that vascular complications can occur, although they are not frequent, which leads us to propose to carry out a first complete non-invasive vascular evaluation at the time of the diagnosis in pEDS patients. However, larger case series are needed to improve our understanding of the link between complement pathway activation and connective tissue alterations observed in these patients, and to better assess the frequency, type and consequences of the vascular complications.

Pain in hypermobile Ehlers-Danlos syndrome: New insights using new criteria.

Features of the pain in hypermobile Ehlers-Danlos syndrome (hEDS) are complex and insufficiently known by clinicians. We enrolled 37 hEDS patients. Disease status was ascertained using revised 2017 International Classification criteria, in the EDS French National Reference Center. Patients were evaluated with a clinical examination, quantitative sensory testing, and validated questionnaires. Thirty-seven patients were evaluated. Pain had appeared at 10 ± 5 years old and became chronic at 20 ± 9 years old. hEDS was diagnosed at only 24 ± 10 years old. Ninety-seven percent of them had severe chronic pain, which gradually increased over time in 75% of them. The main location of pain was in joints and predominated in lower limbs. Patients with a generalized presentation of pain had older chronic pain and a higher impact on the affective component. Neuropathic pain was frequent in the most painful joint and associated with heat hypoesthesia. An asymmetric proprioception was found in one third of the patients. A very high rate of attempted suicide was observed. To conclude, pain in hEDS is severe, chronic, and disabling. Sensorial and proprioceptive sensibilities are also affected. Peripheral neuropathic pain is frequent and central sensitization appears to be a key step in the evolution of disease.

Mutation spectrum in the ABCC6 gene and genotype-phenotype correlations in a French cohort with pseudoxanthoma elasticum.

PURPOSE: Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder caused by variants in the ABCC6 gene. Ectopic mineralization of connective tissues leads to skin, eye, and cardiovascular manifestations with considerable phenotypic variability of unknown cause. We aimed to identify genotype-phenotype correlations in PXE. METHODS: A molecular analysis was performed on 458 French PXE probands clinically evaluated using the Phenodex score (PS). Variant topographic analysis and genotype-phenotype correlation analysis were performed according to the number and type of identified variants. RESULTS: Complete molecular analysis of 306 cases allowed the identification of 538 mutational events (88% detection rate) with 142 distinct variants, of which 66 were novel. Missense variant distribution was specific to some regions and residues of ABCC6. For the 220 cases with a complete PS, there was a higher prevalence of eye features in Caucasian patients (P = 0.03) and more severe eye and vascular phenotype in patients with loss-of-function variants (P = 0.02 and 0.05, respectively). Nephrolithiases and strokes, absent from the PS, were prevalent features of the disorder (11 and 10%, respectively). CONCLUSION: We propose an updated PS including renal and neurological features and adaptation of follow-up according to the genetic and ethnic status of PXE-affected patients.Genet Med advance online publication 19 January 2017.

Analysis of left ventricular mass in untreated men and in men treated with agalsidase-ß: data from the Fabry Registry.

PURPOSE: The aim of this study was to evaluate the progression of left ventricular hypertrophy in untreated men with Fabry disease and to assess the effects of agalsidase-ß (recombinant human α-galactosidase A) on left ventricular hypertrophy. METHODS: Longitudinal Fabry Registry data were analyzed from 115 men treated with agalsidase-ß (1 mg/kg/2 weeks) and 48 untreated men. Measurements included baseline left-ventricular mass and at least one additional left-ventricular mass assessment over ≥ 2 years. Patients were grouped into quartiles, based on left-ventricular mass slopes. Multivariate logistic regression analyses identified factors associated with left ventricular hypertrophy progression. RESULTS: For men in whom treatment was initiated at the age of 18 to <30 years, mean left ventricular mass slope was -3.6 g/year (n = 31) compared with +9.5 g/year in untreated men of that age (n = 15) (P < 0.0001). Untreated men had a 3.4-fold higher risk of having faster increases in left-ventricular mass compared with treated men (odds ratio: 3.43; 95% confidence interval: 1.05-11.22; P = 0.0415). A baseline age of ≥ 40 years was also associated with left--ventricular hypertrophy progression (odds ratio: 5.03; 95% confidence interval: 1.03-24.49; P = 0.0457) compared with men younger than 30 years. CONCLUSION: Agalsidase-ß treatment for ≥2 years may improve or stabilize left-ventricular mass in men with Fabry disease. Further investigations may determine whether early intervention and stabilization of LVM are correlated with clinical outcomes.

The Effectiveness of Compression Garments for Reducing Pain in Non-Vascular Ehlers-Danlos Syndromes: A Prospective Observational Cohort Study.

Patients with Ehlers-Danlos Syndrome (EDS) frequently suffer from severe chronic pain. We carried out an observational cohort study to assess the effectiveness of compression garments (CGs) for reducing this pain. Patients with non-vascular EDS were given custom-made Cerecare® CGs during a visit to a specialist clinic (visit V0). They were followed up over 2 years with visits every 6 months (V1-V4). At each visit, pain was assessed for the joints treated with CGs using a visual analogue scale (VAS; 0-100 mm). Additional measures were obtained to assess neuropathic pain (painDETECT questionnaire), proprioception/balance (Berg Balance Scale), and functional independence, amongst others. Data were analyzed for 67 patients with EDS (hypermobile: 91%; classical: 6%; kyphoscoliotic: 3%). For the most painful joint, the mean VAS rating was 71.5 ± 22.8 mm at V0; this decreased to 53.5 ± 25.5 mm at V1 and 45.7 ± 29 mm at V4 (t-tests: p < 0.0001). From V0 to V4, improvements were also seen for pain at the other joints, neuropathic pain, functional independence, proprioception/balance, and the incidence of sprains and dislocations/subluxations, although not all comparisons were statistically significant (p < 0.05 level). These results indicate that CGs may effectively reduce the pain and joint instability in non-vascular EDS patients.

Effects of compression garments on balance in hypermobile Ehlers-Danlos syndrome: a randomized controlled trial.

PURPOSE: To evaluate the immediate and 4-week effects of compression garments (CG) on balance using a force platform during 8 different visual, static, and dynamic conditions in hypermobile Ehlers-Danlos Syndrome (hEDS) patients. METHODS: Thirty-six participants were randomly assigned to a group: physiotherapy alone (PT, n = 19) or physiotherapy and daily CG wearing for 4 weeks (PT + CG, n = 17). Both attended 12 physiotherapy sessions (strengthening, proprioception, and balance exercises) for 4 weeks. Primary outcome: sway velocity of the centre of pressure (COP) measured before, immediately with the CG, and at 4 weeks. Secondary outcomes: ellipse area, Romberg quotient, and pain. RESULTS: Sway velocity in dynamic conditions decreased immediately with the CG. After 4 weeks of intervention, sway velocity (95% CI 4.36-39.23, effect size 0.93) and area (95% CI 146-3274, effect size 0.45) on the laterally oscillating platform with eyes-closed improved more in the PT + CG group than the PT group. Romberg quotient on foam cushion improved more in the PT + CG than the PT group. Pain decreased in both groups after 4 weeks with no between-group difference. CONCLUSION: CG combined with physiotherapy improved dynamic balance measured with COP variables significantly more than physiotherapy alone in people with hEDS. TRIAL REGISTRATION: NCT03359135Implications for RehabilitationCompression garments immediately improve balance in people with hypermobile Ehlers-Danlos Syndrome (hEDS)Compression garments combined with regular physiotherapy improve balance in people with hEDS after 4 weeks of treatmentCompression garments could compensate for proprioceptive impairment in hEDS.

A severe case of PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome associated with several arterial and venous complications: A case report.

Kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is a rare genetic disorder combining congenital hypotonia, congenital/early onset and progressive kyphoscoliosis, and generalized joint hypermobility. Vascular fragility is another characteristic of the disease rarely described. We report a severe case of kEDS-PLOD1 with several vascular complications leading to difficulties in disease management.

Classical Ehlers-Danlos syndrome with severe kyphoscoliosis due to a novel pathogenic variant of COL5A2.

We described a novel de novo missense variant of the gene encoding Collagen alpha-2(V) chain, associated with the classical Ehlers-Danlos syndrome (cEDS) (OMIM#130010), in a 14-year-old patient who presented with congenital and severe scoliosis, muscle hypotonia, ocular manifestations, and no atrophic scaring. This case expands the phenotypic spectrum of cEDS.

A novel COL1A1 variant in a family with clinical features of hypermobile Ehlers-Danlos syndrome that proved to be a COL1-related overlap disorder.

COL1-related overlap disorder is a condition, which is not yet considered as part of the 2017 EDS classification. However, it should be investigated as an alternative diagnosis for any patient with hypermobile EDS. This could allow providing appropriate genetic counseling.

Cardiovascular and connective tissue disorder features in FLNA-related PVNH patients: progress towards a refined delineation of this syndrome.

BACKGROUND: FLNA Loss-of-Function (LoF) causes periventricular nodular heterotopia type 1 (PVNH1), an acknowledged cause of seizures of various types. Neurological symptoms are inconstant, and cardiovascular (CV) defects or connective tissue disorders (CTD) have regularly been associated. We aimed at refining the description of CV and CTD features in patients with FLNA LoF and depicting the multisystemic nature of this condition. METHODS: We retrospectively evaluated FLNA variants and clinical presentations in FLNA LoF patient with at least one CV or CTD feature, from three cohorts: ten patients from the French Reference Center for Rare Vascular Diseases, 23 patients from the national reference diagnostic lab for filaminopathies-A, and 59 patients from literature review. RESULTS: Half of patients did not present neurological symptoms. Most patients presented a syndromic association combining CV and CTD features. CV anomalies, mostly aortic aneurysm and/or dilation were present in 75% of patients. CTD features were present in 75%. Variants analysis demonstrated an enrichment of coding variants in the CH1 domain of FLNA protein. CONCLUSION: In FLNA LoF patients, the absence of seizures should not be overlooked. When considering a diagnosis of PVNH1, the assessment for CV and CTD anomalies is of major interest as they represent interlinked features. We recommend systematic study of FLNA within CTD genes panels, regardless of the presence of neurological symptoms.

[Functional renal investigation in Fabry disease]. / Evaluation fonctionnelle rénale de la maladie de Fabry.

Progressive decline in kidney function is a cardinal manifestation of Fbry disease. Proteinuria is usually the earliest biological marker of renal involvement. Renoprotection should associate both effective Enzyme Replocement Therapy (ERT) and non-specific anti-proteinuric therapy as recommended for all chronic kidney diseases. ERT has demonstrated high efficiency in the early clearing of globotriaosylceromide deposits, however the functional protecting effect on GFR decrease remains to be validated, especially in patients with CKD stage 3 or higher Estimation of GFR should be very cautious using creatinine based formulas, leading to measure GFR whenever possible in order to characterize the progression of CKD in Fabry patients.

[Development of an orphan drug to treat a genetic disease: the paradigm of agalsidase beta]. / Principe du développement d'un médicament orphelin pour une maladie génétique: l'exemple de l'agalsidase bêta.

Preclinical and phase I/II studies gave the proof of principle of enzyme replacement therapy (ERT) with recombinant alpha-galactosidase A through the demonstration of the clearance of the accumulated subtrate from plasma and tissues. In a multicenter, randomized, placebo-controlled, double-blind phase Ill study, the biological efficacy of recombinant alpha-galactosidose A (agalsidase beta 1 mg/kg/714 days) was demonstrated on the basis of complete clearance of accumulated globotriaosylceramide from the endothelia of the kidney, heart and skin. The phase III extension study data gives additional results: kidney function appears to be stabilized after 54 to 60 months of treatment with agolsidase beta in most patients. Intent-to-treat analysis of a double-blind, randomized, placebo-controlled, phase IV study, showed that, adjusted for on imbalance in baseline proteinuria, agalsidase beta significantly reduces by 53% the risk of a first clinical event (renal, cardiac and cerebrovascular), compared with placebo. Clinical benefits of ERT depend on patients' clinical status at baseline, therefore prompting for onset of ERT before irreversible damage occur and underlying the need to stratify patients' populations to better understand the outcome of ERT.

Chiari type I malformation in four unrelated patients affected with Fabry disease.

Fabry disease (FD) is an X-linked inborn error of metabolism resulting from the deficient activity of alpha-galactosidase A which leads to the widespread deposition of glycosphingolipids in lysosomes, and to ischemic complications involving kidneys, heart and brain. Among neurological symptoms, strokes and transient ischemic attacks (TIA) have been reported. A 30-year-old male patient, with FD, was referred to us for evaluation of a sudden episode of dizziness, with disequilibrium, and diplopia, in agreement with the diagnosis of a TIA. Head magnetic resonance imaging (MRI) showed no cerebrovascular involvement but revealed the presence of Chiari type I malformation (CMI). We subsequently performed head MRI in a cohort of 44 consecutive hemizygous male patients and seven heterozygous females affected with FD, and identified three additional cases (two males and one female) of CMI. Whether the association is coincidental or not will need further studies but our data suggest that CMI should be ruled out in all Fabry patients.

Topical Sodium Thiosulfate: A Treatment for Calcifications in Hyperphosphatemic Familial Tumoral Calcinosis?

CONTEXT: Hyperphosphatemic familial tumoral calcinosis (HFTC) and hyperphosphatemia hyperostosis syndrome (HHS) are rare diseases characterized by hyperphosphatemia and ectopic calcifications or recurrent episodes of diaphysitis. In the setting of metabolic or inflammatory diseases, recent data suggest that systemic administration of sodium thiosulfate (STS) could be effective in the treatment of ectopic calcifications but may also be poorly tolerated (digestive symptoms, metabolic acidosis). Our group developed a topical formulation of STS to treat ectopic calcifications locally, therefore limiting patient exposure to the drug and its adverse effects. OBJECTIVE: We aimed at describing efficacy and tolerance for a topical formulation of STS in treated patients. DESIGN: We performed a retrospective study wherein clinical, radiological, and biological data before and after the application of the topical STS treatment were collected and analyzed. PATIENTS OR OTHER PARTICIPANTS: Three patients admitted to 3 different hospitals with an ectopic calcification secondary to HFTC or HHS were treated with topical STS. INTERVENTION: The topical STS was applied daily by the patients. RESULTS: A significant clinical and radiological decrease of ectopic calcifications was observed after at least 5 months of treatment. The STS treatment was well tolerated and no clinical or biological side effects were observed. CONCLUSION: Topical STS appears to be a promising treatment for ectopic calcifications secondary to HFTC or HHS.