Erdheim-Chester disease (ECD) is characterized by the infiltration of tissues by foamy CD68+CD1a− histiocytes, with 1500 known cases since 1930. Mutations activating the MAPK pathway are found in ...more than 80% of patients with ECD, mainly the BRAFV600E activating mutation in 57% to 70% of cases, followed by MAP2K1 in close to 20%. The discovery of BRAF mutations and of other MAP kinase pathway alterations, as well as the co-occurrence of ECD with LCH in 15% of patients with ECD, led to the 2016 revision of the classification of histiocytoses in which LCH and ECD belong to the “L” group. Both conditions are considered inflammatory myeloid neoplasms. Ten percent of ECD cases are associated with myeloproliferative neoplasms and/or myelodysplastic syndromes. Some of the most striking signs of ECD are the long bone involvement (80%-95%), as well as the hairy kidney appearance on computed tomography scan (63%), the coated aorta (40%), and the right atrium pseudo-tumoral infiltration (36%). Central nervous system involvement is a strong prognostic factor and independent predictor of death. Interferon-α seems to be the best initial treatment of ECD. Since 2012, more than 200 patients worldwide with multisystem or refractory ECD have benefitted from highly effective therapy with BRAF and MEK inhibitors. Targeted therapies have an overall, robust, and reproducible efficacy in ECD, with no acquired resistance to date, but their use may be best reserved for the most severe manifestations of the disease, as they may be associated with serious adverse effects and as-yet-unknown long-term consequences.
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Capillary leak syndrome (CLS) is a rare, life-threatening disorder characterized by recurrent episodes of fluid leaking from the blood vessels into the surrounding tissues, hypotension, oedema, ...haemoconcentration and hypoalbuminemia.1 CLS can be idiopathic (Clarkson’s disease) or secondary to various conditions and treatments.1 Secondary CLS typically results from, systemic autoimmune disorders, viral infections, malignant haematological diseases and treatments such as chemotherapies and therapeutic growth factors.1 Diagnosis of idiopathic CLS is made by exclusion of secondary diseases, especially as a serum monoclonal immunoglobulin is present, or when there is a relapsing disease, no initial lung involvement or preserved consciousness despite low blood pressure.1 Prophylactic treatment of Clarkson’s disease with intravenous immunoglobulin may reduce the frequency and severity of attacks and may improve survival. Duron L, et al. Syndrome de fuite capillaire idiopathique et formes secondaires : une revue systématique de la littérature Idiopathic and secondary capillary leak syndromes: A systematic review of the literature. Rev Med Interne. 2015 Jun;36(6):386–94. Learning Objectives Describe the clinical presentation of systemic CLS, including symptoms, signs, and complications Discuss the diagnosis of systemic CLS, including diagnostic tests and criteria. Discuss treatment options for systemic CLS, including both acute and chronic management
In adults with active lupus nephritis, the efficacy and safety of intravenous belimumab as compared with placebo, when added to standard therapy (mycophenolate mofetil or ...cyclophosphamide-azathioprine), are unknown.
In a phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled, 104-week trial conducted at 107 sites in 21 countries, we assigned adults with biopsy-proven, active lupus nephritis in a 1:1 ratio to receive intravenous belimumab (at a dose of 10 mg per kilogram of body weight) or matching placebo, in addition to standard therapy. The primary end point at week 104 was a primary efficacy renal response (a ratio of urinary protein to creatinine of ≤0.7, an estimated glomerular filtration rate eGFR that was no worse than 20% below the value before the renal flare (pre-flare value) or ≥60 ml per minute per 1.73 m
of body-surface area, and no use of rescue therapy), and the major secondary end point was a complete renal response (a ratio of urinary protein to creatinine of <0.5, an eGFR that was no worse than 10% below the pre-flare value or ≥90 ml per minute per 1.73 m
, and no use of rescue therapy). The time to a renal-related event or death was assessed.
A total of 448 patients underwent randomization (224 to the belimumab group and 224 to the placebo group). At week 104, significantly more patients in the belimumab group than in the placebo group had a primary efficacy renal response (43% vs. 32%; odds ratio, 1.6; 95% confidence interval CI, 1.0 to 2.3; P = 0.03) and a complete renal response (30% vs. 20%; odds ratio, 1.7; 95% CI, 1.1 to 2.7; P = 0.02). The risk of a renal-related event or death was lower among patients who received belimumab than among those who received placebo (hazard ratio, 0.51; 95% CI, 0.34 to 0.77; P = 0.001). The safety profile of belimumab was consistent with that in previous trials.
In this trial involving patients with active lupus nephritis, more patients who received belimumab plus standard therapy had a primary efficacy renal response than those who received standard therapy alone. (Funded by GlaxoSmithKline; BLISS-LN ClinicalTrials.gov number, NCT01639339.).
Case 1: A 38-year-old woman with NPSLEA 38-year-old patient presented for a follow-up consultation for her systemic lupus erythematosus (SLE). She was on 5 mg/day of prednisone and hydroxychloroquine ...400 mg/day. She describes headaches that have been present for a month. On examination her pulse rate was 80 BPM, BP 122/74mmHg and temperature: 37°C. Neurological examination was normal. Respiratory, cardiovascular, joint and skin examinations were normal. Discussion Points: What course of action do you propose? Case 2: A 31-year-old woman with SLE and acute psychosisA 31-year-old woman hospitalised in January 2022. She has had a medical history of SLE diagnosed in December 2018. Malar rash (acute cutaneous lupus), photosensitivity, diffuse alopecia, oral ulcerations, bilateral pleurisy, proteinuria with a kidney biopsy showing Class IV glomerulonephritis according to ISN classification, positive anti-double stranded DNA antibody test (Farr assay 78 UI; N< 9 UI), low C3 fraction, positive lupus anticoagulant, negative anticardiolipin antibody ELISA (IgG and IgM), negative anti-B2GP1 ELISA (IgG and IgM). She had no thrombotic or obstetrical history.She first received three pulses of methylprednisolone (1000 mg each) followed by oral prednisone 0.5 mg/kg/day + mycophenolate mofetil (MMF) 2 g/day + ACE inhibitors. Steroids were tapered to 5 mg/day at 6 months. Daily proteinuria decreased to 1 g at Month 3 and 0.5 g at Month 6. C3 returned to normal level at Month 6. Steroids were stopped at Month 24 and hydrocortisone 20 mg/day was given instead. MMF 2 g/day was decreased to 1 g/day in September 2015.She was hospitalised in January 2022 for altered sleep-wake cycles, hyperactivity, intense anxiety, ideas of persecution and auditory hallucinations. She had no arthritis and no mucocutaneous manifestation. Her physical examination was normal with no neurological abnormalities. Laboratory test showed: normal red and white blood cell and platelet counts; creatinine: 69 µmol/L; proteinuria: 0.2 g/L, Urine tests were sterile with no haematuria, creatininuria: 8.9 mmol/L = ratio 0.02 g/mmol; albuminemia: 43 g/L; C reactive protein: <5 mg/L. Farr assay 18 UI; N< 9 UI, normal C3 fraction. At that time, she was treated with prednisone 5 mg/day + MMF 1 g/day. A diagnosis of acute psychosis given done by the psychiatrist.Learning ObjectivesDescribe how to manage headaches in patients with SLEDescribe how to manage myelitis in patients with SLEDescribe how to manage psychiatric manifestations in patients with SLE
Glucocorticoids (GCs) play a central role in the treatment of active systemic lupus erythematosus (SLE). Long-term GC-related side effects (i.e., infections, diabetes mellitus, cataract, ...osteoporosis, gastrointestinal bleeding and cardiovascular disease), leading to the development of irreversible organ damage, mean that clinicians must develop strategies for minimizing GC exposure in SLE.1 Initiation of oral GC should be avoided, especially when there are effective therapeutic alternatives as for cutaneous and articular manifestations. In patients with lupus nephritis, starting GC with a medium prednisone dose (0.5 mg/kg/day) is as effective as high-dose dose (1 mg/kg/day) prednisone.1 Use of intravenous methylprednisolone (MP) pulses (usually 250–1000 mg/day for 3 days) may allow for a lower starting dose and faster tapering of oral GC.2 3 Early initiation of immunosuppressive drugs can facilitate a more rapid GC tapering and may prevent SLE flares.4 Long-term GC administration with doses of ≤5 mg/day prednisone produces an acceptably low level of harm, with the exception of patients at high cardiovascular risk who may require preventive measures.5 Withdrawal of low dose prednisone is also recommended by EULAR, when possible,1 but recent data suggest that this exposes SLE patients to an increased risk of flare, whereas its long-term maintenance is not associated with increased damage scores.6Learning ObjectivesDescribe strategies for minimizing corticosteroid dose at treatment initiation for lupus nephritis, cutaneous lupus and lupus arthritisDescribe strategies for minimizing corticosteroid exposure when SLE remission has been reachedReferencesFanouriakis A, Kostopoulou M, Alunno A, et al. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis. 2019;78(6):736–45.Ruiz-Arruza I, Lozano J, Cabezas-Rodriguez I, et al. Restrictive Use of Oral Glucocorticoids in Systemic Lupus Erythematosus and Prevention of Damage Without Worsening Long-Term Disease Control: An Observational Study. Arthritis Care Res (Hoboken). 2018;70(4):582–91.Ruiz-Irastorza G, Petri M, Gordon C, Khamashta M. Managing lupus nephritis in pregnant women: comment on the article by Hahn, et al. Arthritis Care Res (Hoboken). 2013;65(8):1391–2.Pego-Reigosa JM, Cobo-Ibanez T, Calvo-Alen J, et al. Efficacy and safety of nonbiologic immunosuppressants in the treatment of nonrenal systemic lupus erythematosus: a systematic review. Arthritis Care Res (Hoboken). 2013;65(11):1775–85.Strehl C, Bijlsma JW, de Wit M, et al. Defining conditions where long-term glucocorticoid treatment has an acceptably low level of harm to facilitate implementation of existing recommendations: viewpoints from an EULAR task force. Ann Rheum Dis. 2016;75(6):952–7.Mathian A, Pha M, Haroche J, et al. Withdrawal of low-dose prednisone in SLE patients with a clinically quiescent disease for more than 1 year: a randomised clinical trial. Ann Rheum Dis. 2020;79(3):339–46.
Maintenance of remission has become central in the management of systemic lupus erythematosus (SLE). However, an active disease-free state is generally maintained only when patients are on ...medication, which often leads to treatment-related complications. Therefore, once remission has been achieved, prolonged maintenance treatment inevitably requires a regimen of drug de-escalation. The recent EULAR recommendations for the treatment of SLE during chronic maintenance treatment advocate that glucocorticoids (GC) should be, when possible, withdrawn.1 However, in routine practice a significant proportion of treating physicians prefers to continue a low dose GC regimen, despite clinical remission, which is most likely due to the fear that withdrawal of low-dose GCs may lead to a severe flare, even after very long intervals of remission.2 In a recent prospective randomised controlled trial, we showed that, in SLE patients in remission and with stable treatment regimen for at least 1 year, withdrawal of 5 mg of prednisone was associated with a fourfold increase (i.e. 27%), in the risk of flare, as defined by the SFI or the BILAG index.3 Other SLE treatments remained unmodified during this study. In particular, at study entry 91% and 27% of the patients were also treated with hydroxychloroquine and an immunosuppressant, respectively. The 27% relapse rate observed in the withdrawal group in our study is in line with the ones recently reported in two recent cohorts.4 5 Tani et al described the longitudinal study of a cohort of 91 SLE Italian patients who attempted stopping GC treatment.4 A total of 77 patients successfully stopped GC. For those patients who were successfully withdrawn from GC, 18 flares (23%) were recorded after a median follow-up period of about 2 years. As in our study, 72% of flares were mild. The time period since the last flare was the sole determinant predictor of disease flare identified. A recent observational study, performed by Goswami et al in India, reported that 21% of patients in remission undergo exacerbation of the disease after GC withdrawal with most of the flares occurring in the first year of follow-up.5 Therefore, until the availability of effective drugs with little or no toxicity, it is recommended to not abandon the option of using very low doses of GCs (i.e. ≤5 mg prednisone) given their potential benefits in SLE patients in remission, especially those at low cardiovascular risk.Learning ObjectivesDefine remission in SLE patientsDiscuss drug de-escalation in SLE patients in remissionReferencesFanouriakis A, Kostopoulou M, Alunno A, et al. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis2019;78(6):736–45.Ngamjanyaporn P, McCarthy EM, Sergeant JC, et al. Clinicians approaches to management of background treatment in patients with SLE in clinical remission: results of an international observational survey. Lupus Sci Med 2017;4(1):e000173.Mathian A, Pha M, Haroche J, et al. Withdrawal of low-dose prednisone in SLE patients with a clinically quiescent disease for more than 1 year: a randomised clinical trial. Ann Rheum Dis 2020;79(3):339–46.Tani C, Elefante E, Signorini V, et al. Glucocorticoid withdrawal in systemic lupus erythematosus: are remission and low disease activity reliable starting points for stopping treatment? A real-life experience. RMD open 2019;5(2):e000916.Goswami RP, Sit H, Ghosh P, et al. Steroid-free remission in lupus: myth or reality; an observational study from a tertiary referral centre. Clin Rheumatol 2019;38(4):1089–97.
Humoral immune responses are typically characterized by primary IgM antibody responses followed by secondary antibody responses associated with immune memory and composed of IgG, IgA, and IgE. Here, ...we measured acute humoral responses to SARS-CoV-2, including the frequency of antibody-secreting cells and the presence of SARS-CoV-2-specific neutralizing antibodies in the serum, saliva, and bronchoalveolar fluid of 159 patients with COVID-19. Early SARS-CoV-2-specific humoral responses were dominated by IgA antibodies. Peripheral expansion of IgA plasmablasts with mucosal homing potential was detected shortly after the onset of symptoms and peaked during the third week of the disease. The virus-specific antibody responses included IgG, IgM, and IgA, but IgA contributed to virus neutralization to a greater extent compared with IgG. Specific IgA serum concentrations decreased notably 1 month after the onset of symptoms, but neutralizing IgA remained detectable in saliva for a longer time (days 49 to 73 post-symptoms). These results represent a critical observation given the emerging information as to the types of antibodies associated with optimal protection against reinfection and whether vaccine regimens should consider targeting a potent but potentially short-lived IgA response.
Abstract While our knowledge of the pathogenesis of Takayasu's arteritis (TA) has considerably improved during the last decade, the exact pathogenic sequence remains to be elucidated. It is now ...hypothesised that an unknown stimulus triggers the expression of the 65 kDa Heat-shock protein in the aortic tissue which, in turn, induces the Major Histocompatibility Class I Chain-Related A (MICA) on vascular cells. The γδ T cells and NK cells expressing NKG2D receptors recognize MICA on vascular smooth muscle cells and release perforin, resulting in acute vascular inflammation. Pro-inflammatory cytokines are released and increase the recruitment of mononuclear cells within the vascular wall. T cells infiltrate and recognize one or a few antigens presented by a shared epitope, which is associated with specific major Histocompatibility Complex alleles on the dendritic cells, these latter being activated through Toll-like receptors. Th1 lymphocytes drive the formation of giant cells through the production of interferon-γ, and activate macrophages with release of VEGF resulting in increased neovascularisation and PDGF, resulting in smooth muscle migration and intimal proliferation. Th17 cells induced by the IL-23 microenvironnement also contribute to vascular lesions through activation of infiltrating neutrophils. Although still controversial, dendritic cells may cooperate with B lymphocytes and trigger the production of anti-endothelial cell auto-antibodies resulting in complement-dependent cytotoxicity against endothelial cells. In a near future, novel drugs specifically designed to target some of the pathogenic mechanisms described above could be expanding the physician's therapeutic arsenal in Takayasu's arteritis.
Histiocytoses are rare disorders of unknown origin with highly heterogeneous prognosis. BRAFV600E gain-of-function mutations have been observed in 57% of cases of Langerhans cell histiocytosis (LCH) ...and 54% of cases of Erdheim-Chester disease (ECD), but not in other types of histiocytoses. Targeted therapy with an inhibitor of mutated BRAF (vemurafenib) improves survival of patients with melanoma. Here, we report vemurafenib treatment of 3 patients with multisystemic and refractory ECD carrying the BRAFV600E mutation; 2 also had skin or lymph node LCH involvement. The patients were assessed clinically, biologically (CRP values), histologically (skin biopsy), and morphologically (positron emission tomography PET, computed tomography and magnetic resonance imaging). For all patients, vemurafenib treatment led to substantial and rapid clinical and biologic improvement, and the tumor response was confirmed by PET, computed tomography, and/or magnetic resonance imaging 1 month after treatment initiation. For the first patient treated, the PET response increased between months 1 and 4 of treatment. The treatment remained effective after 4 months of follow-up although persistent disease activity was still observed. Treatment with vemurafenib, a newly approved BRAF inhibitor, should be considered for patients with severe and refractory BRAFV600E histiocytoses, particularly when the disease is life-threatening.
•Treatment with vemurafenib induced a dramatic response in 3 patients with histiocytosis harboring BRAF V600E mutations.•Tumor response was observed in both Erdheim-Chester disease and Langerhans cell histiocytosis.
Anecdotal evidence rapidly accumulated during March 2020 from sites around the world that sudden hyposmia and hypogeusia are significant symptoms associated with the SARS-CoV-2 pandemic. Our ...objective was to describe the prevalence of hyposmia and hypogeusia and compare it in hospitalized and non-hospitalized COVID-19 patients to evaluate an association of these symptoms with disease severity. We performed a cross-sectional survey during 5 consecutive days in March 2020, within a tertiary referral center, associated outpatient clinic, and two primary care outpatient facilities in Paris. All SARS-CoV-2-positive patients hospitalized during the study period and able to be interviewed (
n
= 198), hospital outpatients seen during the previous month (
n
= 129), and all COVID-19-highly suspect patients in two primary health centers (
n
= 63) were included. Hospitalized patients were significantly more often male (64 vs 40%) and older (66 vs 43 years old in median) and had significantly more comorbidities than outpatients. Hyposmia and hypogeusia were reported by 33% of patients and occurred significantly less frequently in hospitalized patients (12% and 13%, respectively) than in the health centers’ outpatients (33% and 43%, respectively) and in the hospital outpatients (65% and 60%, respectively). Hyposmia and hypogeusia appeared more frequently after other COVID-19 symptoms. Patients with hyposmia and/or hypogeusia were significantly younger and had significantly less respiratory severity criteria than patients without these symptoms. Olfactory and gustatory dysfunction occurs frequently in COVID-19, especially in young, non-severe patients. These symptoms might be a useful tool for initial diagnostic work-up in patients with suspected COVID-19.
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