Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination.

Abstract OBJECTIVE: We characterised the clinical course, treatment and outcomes in 59 patients with relapsing myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination. METHODS: We evaluated clinical phenotypes, annualised relapse rates (ARR) prior and on immunotherapy and Expanded Disability Status Scale (EDSS), in 218 demyelinating episodes from 33 paediatric and 26 adult patients. RESULTS: The most common initial presentation in the cohort was optic neuritis (ON) in 54% (bilateral (BON) 32%, unilateral (UON) 22%), followed by acute disseminated encephalomyelitis (ADEM) (20%), which occurred exclusively in children. ON was the dominant phenotype (UON 35%, BON 19%) of all clinical episodes. 109/226 (48%) MRIs had no brain lesions. Patients were steroid responsive, but 70% of episodes treated with oral prednisone relapsed, particularly at doses <10\u2009mg daily or within 2 months of cessation. Immunotherapy, including maintenance prednisone (P=0.0004), intravenous immunoglobulin, rituximab and mycophenolate, all reduced median ARRs on-treatment. Treatment failure rates were lower in patients on maintenance steroids (5%) compared with non-steroidal maintenance immunotherapy (38%) (P=0.016). 58% of patients experienced residual disability (average follow-up 61 months, visual loss in 24%). Patients with ON were less likely to have sustained disability defined by a final EDSS of 652 (OR 0.15, P=0.032), while those who had any myelitis were more likely to have sustained residual deficits (OR 3.56, P=0.077). CONCLUSION: Relapsing MOG antibody-associated demyelination is strongly associated with ON across all age groups and ADEM in children. Patients are highly responsive to steroids, but vulnerable to relapse on steroid reduction and cessation

International multi-centre study of pregnancy outcomes with interleukin-1 inhibitors

Objective: To provide outcome data concerning pregnancies exposed to the Interleukin-1 (IL-1) inhibitors prior to conception in both men and women, during pregnancy and breast feeding. Methods: Retrospective data were collected from members of the International Society for Systemic Autoinflammatory diseases and collated in a single centre. A uniform data collection sheet was used to obtain standardized data including maternal age and diagnosis, type, duration of and response to IL-1 blockade, pregnancy duration, delivery, mode of feeding and neonatal development. Results: There were 31 maternal-exposed pregnancies from seven countries and we report the first data on paternal exposure: six to anakinra and five to canakinumab, with no negative outcomes. We also report the first data on canakinumab-exposed pregnancies: eight pregnancies that resulted in the delivery of seven healthy infants of normal gestational age and birthweight. There were 23 anakinra-exposed pregnancies resulting in the birth of 21 healthy infants, and one baby with unilateral renal agenesis and ectopic neurohypophysis. There were two first trimester miscarriages affecting a mother with active disease. There were no serious neonatal infections. Fourteen infants were breast fed with no complications. There were no reports of developmental delay, with follow-up of up to 10 years (median 18 months). Conclusion: This series substantially increases the published experience of IL-1 blockade and reproduction including the first data on canakinumab and on paternal exposure to these agents. Data are generally reassuring, although the case of renal agenesis is the second reported in an anakinra-exposed pregnancy

B cell–intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans

Engagement of cytokine receptors by specific ligands activate Janus kinase–signal transducer and activator of transcription (STAT) signaling pathways. The exact roles of STATs in human lymphocyte behavior remain incompletely defined. Interleukin (IL)-21 activates STAT1 and STAT3 and has emerged as a potent regulator of B cell differentiation. We have studied patients with inactivating mutations in STAT1 or STAT3 to dissect their contribution to B cell function in vivo and in response to IL-21 in vitro. STAT3 mutations dramatically reduced the number of functional, antigen (Ag)-specific memory B cells and abolished the ability of IL-21 to induce naive B cells to differentiate into plasma cells (PCs). This resulted from impaired activation of the molecular machinery required for PC generation. In contrast, STAT1 deficiency had no effect on memory B cell formation in vivo or IL-21–induced immunoglobulin secretion in vitro. Thus, STAT3 plays a critical role in generating effector B cells from naive precursors in humans. STAT3-activating cytokines such as IL-21 thus underpin Ag-specific humoral immune responses and provide a mechanism for the functional antibody deficit in STAT3-deficient patients

Molecular Pathogenesis of EBV Susceptibility in XLP as Revealed by Analysis of Female Carriers with Heterozygous Expression of SAP

X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency caused by mutations in SH2D1A which encodes SAP. SAP functions in signalling pathways elicited by the SLAM family of leukocyte receptors. A defining feature of XLP is exquisite sensitivity to infection with EBV, a B-lymphotropic virus, but not other viruses. Although previous studies have identified defects in lymphocytes from XLP patients, the unique role of SAP in controlling EBV infection remains unresolved. We describe a novel approach to this question using female XLP carriers who, due to random X-inactivation, contain both SAP+ and SAP− cells. This represents the human equivalent of a mixed bone marrow chimera in mice. While memory CD8+ T cells specific for CMV and influenza were distributed across SAP+ and SAP− populations, EBV-specific cells were exclusively SAP+. The preferential recruitment of SAP+ cells by EBV reflected the tropism of EBV for B cells, and the requirement for SAP expression in CD8+ T cells for them to respond to Ag-presentation by B cells, but not other cell types. The inability of SAP− clones to respond to Ag-presenting B cells was overcome by blocking the SLAM receptors NTB-A and 2B4, while ectopic expression of NTB-A on fibroblasts inhibited cytotoxicity of SAP− CD8+ T cells, thereby demonstrating that SLAM receptors acquire inhibitory function in the absence of SAP. The innovative XLP carrier model allowed us to unravel the mechanisms underlying the unique susceptibility of XLP patients to EBV infection in the absence of a relevant animal model. We found that this reflected the nature of the Ag-presenting cell, rather than EBV itself. Our data also identified a pathological signalling pathway that could be targeted to treat patients with severe EBV infection. This system may allow the study of other human diseases where heterozygous gene expression from random X-chromosome inactivation can be exploited

Enhanced serum immunoglobulin G clearance in myotonic dystrophy-associated hypogammaglobulinemia: a case series and review of the literature

BACKGROUND: Myotonic dystrophy type 1 is an autosomal dominant disorder characterized by muscle weakness, myotonia, cataracts, and cardiac conduction defects; it is associated with expansions of cytosine-thymine-guanine repeats in the myotonic dystrophy protein kinase. Hypogammaglobulinemia is a lesser known association of myotonic dystrophy type 1 and the underlying pathogenesis of immunoglobulin G depletion remains unclear. CASE PRESENTATION: Here we report a kindred of two members (a 62-year-old white woman and a 30-year-old white man; mother and son) with myotonic dystrophy type 1-associated hypogammaglobulinemia associated with altered intravenous immunoglobulin elimination kinetics and reduced half-life. There was no history of systemic immunosuppression or renal or gastrointestinal protein loss in either patient, and no underlying case for a secondary immunodeficiency could be found. One patient required fortnightly intravenous immunoglobulin to maintain adequate trough immunoglobulin G levels. CONCLUSIONS: Ongoing study of myotonic dystrophy type 1-associated hypogammaglobulinemia using contemporary tools of genomic medicine may help to further delineate the pathogenesis of this entity.</p

Enhanced serum immunoglobulin G clearance in myotonic dystrophy-associated hypogammaglobulinemia: a case series and review of the literature

BACKGROUND: Myotonic dystrophy type 1 is an autosomal dominant disorder characterized by muscle weakness, myotonia, cataracts, and cardiac conduction defects; it is associated with expansions of cytosine-thymine-guanine repeats in the myotonic dystrophy protein kinase. Hypogammaglobulinemia is a lesser known association of myotonic dystrophy type 1 and the underlying pathogenesis of immunoglobulin G depletion remains unclear. CASE PRESENTATION: Here we report a kindred of two members (a 62-year-old white woman and a 30-year-old white man; mother and son) with myotonic dystrophy type 1-associated hypogammaglobulinemia associated with altered intravenous immunoglobulin elimination kinetics and reduced half-life. There was no history of systemic immunosuppression or renal or gastrointestinal protein loss in either patient, and no underlying case for a secondary immunodeficiency could be found. One patient required fortnightly intravenous immunoglobulin to maintain adequate trough immunoglobulin G levels. CONCLUSIONS: Ongoing study of myotonic dystrophy type 1-associated hypogammaglobulinemia using contemporary tools of genomic medicine may help to further delineate the pathogenesis of this entity.</p

Cardiac magnetic resonance imaging-indeterminate/negative cardiac sarcoidosis revealed by 18F-fluorodeoxyglucose-positron emission tomography: two case reports and a review of the literature

Background Sarcoidosis is an inflammatory disorder of immune dysregulation characterized by non-caseating granulomas that can affect any organ. Cardiac sarcoidosis is an under-recognized entity that has a heterogeneous presentation and may occur independently or with any severity of systemic disease. Diagnosing cardiac sarcoidosis remains problematic with endomyocardial biopsies associated with a high risk of complications. Several diagnostic algorithms are currently available that rely on histopathology or clinical and radiological measures. The dominant mode of diagnostic imaging to date for cardiac sarcoidosis has been cardiac magnetic resonance imaging with gadolinium enhancement. Case presentations We report the cases of two adult patients: case 1, a 50-year-old white man who presented with severe congestive cardiac failure; and case 2, a 37-year-old white woman who presented with complete heart block. Both patients had a background of untreated pulmonary sarcoidosis. Cardiac magnetic resonance imaging did not show evidence of sarcoidosis in either patient and both proceeded to 18F-fluorodeoxyglucose-positron emission tomography scans that were highly suggestive of cardiac sarcoidosis. Both patients were systemically immunosuppressed with orally administered prednisone and methotrexate and had subsequent improvement by clinical and nuclear medicine imaging measures. Conclusions Current consensus guidelines recommend all patients with sarcoidosis undergo screening for occult cardiac disease, with thorough history and examination, electrocardiogram, and transthoracic echocardiogram. If any abnormalities are detected, advanced cardiac imaging should follow. While cardiac magnetic resonance imaging identifies the majority of cardiac sarcoidosis, early disease may not be detected. These cases demonstrate 18F-fluorodeoxyglucose-positron emission tomography is warranted following an indeterminate or normal cardiac magnetic resonance imaging if clinical suspicion remains high. Unidentified and untreated cardiac sarcoidosis risks significant morbidity and mortality, but early detection can facilitate disease-modifying immunosuppression and cardiac-specific interventions.</p

Cardiac magnetic resonance imaging-indeterminate/negative cardiac sarcoidosis revealed by 18F-fluorodeoxyglucose-positron emission tomography: two case reports and a review of the literature

Background Sarcoidosis is an inflammatory disorder of immune dysregulation characterized by non-caseating granulomas that can affect any organ. Cardiac sarcoidosis is an under-recognized entity that has a heterogeneous presentation and may occur independently or with any severity of systemic disease. Diagnosing cardiac sarcoidosis remains problematic with endomyocardial biopsies associated with a high risk of complications. Several diagnostic algorithms are currently available that rely on histopathology or clinical and radiological measures. The dominant mode of diagnostic imaging to date for cardiac sarcoidosis has been cardiac magnetic resonance imaging with gadolinium enhancement. Case presentations We report the cases of two adult patients: case 1, a 50-year-old white man who presented with severe congestive cardiac failure; and case 2, a 37-year-old white woman who presented with complete heart block. Both patients had a background of untreated pulmonary sarcoidosis. Cardiac magnetic resonance imaging did not show evidence of sarcoidosis in either patient and both proceeded to 18F-fluorodeoxyglucose-positron emission tomography scans that were highly suggestive of cardiac sarcoidosis. Both patients were systemically immunosuppressed with orally administered prednisone and methotrexate and had subsequent improvement by clinical and nuclear medicine imaging measures. Conclusions Current consensus guidelines recommend all patients with sarcoidosis undergo screening for occult cardiac disease, with thorough history and examination, electrocardiogram, and transthoracic echocardiogram. If any abnormalities are detected, advanced cardiac imaging should follow. While cardiac magnetic resonance imaging identifies the majority of cardiac sarcoidosis, early disease may not be detected. These cases demonstrate 18F-fluorodeoxyglucose-positron emission tomography is warranted following an indeterminate or normal cardiac magnetic resonance imaging if clinical suspicion remains high. Unidentified and untreated cardiac sarcoidosis risks significant morbidity and mortality, but early detection can facilitate disease-modifying immunosuppression and cardiac-specific interventions.</p