Discovery of Autoantibodies Targeting Nephrin in Minimal Change Disease Supports a Novel Autoimmune Etiology

Background Failure of the glomerular filtration barrier, primarily by loss of slit diaphragm architecture, underlies nephrotic syndrome in minimal change disease. The etiology remains unknown. The efficacy of B cell-targeted therapies in some patients, together with the known proteinuric effect of antinephrin antibodies in rodent models, prompted us to hypothesize that nephrin autoantibodies may be present in patients with minimal change disease. Methods We evaluated sera from patients with minimal change disease enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) cohort and from our own institutions for circulating nephrin autoantibodies by indirect ELISA and by immunoprecipitation of full-length nephrin from human glomerular extract or a recombinant purified extracellular domain of human nephrin. We also evaluated renal biopsies from our institutions for podocyte-associated punctate IgG colocalizing with nephrin by immunofluorescence Results In two independent patient cohorts, we identified in a subset of patients with minimal change disease circulating nephrin autoantibodies during active disease that were significantly reduced or absent during treatment response. We correlated the presence of these autoantibodies with podocyte-associated punctate IgG in renal biopsies from our institutions. We also identified a patient with steroid-dependent childhood minimal change disease that progressed to end-stage kidney disease; she developed a massive posttransplant recurrence of proteinuria that was associated with high pretransplant circulating nephrin autoantibodies. Conclusions Our discovery of nephrin autoantibodies in a subset of adults and children with minimal change disease aligns with published animal studies and provides further support for an autoimmune etiology. We propose a new molecular classification of nephrin autoantibody minimal change disease to serve as framework for instigation of precision therapeutics for these patients.

Distal renal tubular acidosis in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a multisystem disorder of autoimmune etiology. Renal involvement is frequently seen in SLE. Tubular dysfunction is also seen in SLE. Authors report a case of distal renal tubular acidosis in patient with SLE.

Occult Autoimmune Background for Epilepsy—The Preliminary Study on Antibodies Against Neuronal Surface Antigens

Objective: The objective of the study was to determine the incidence of antibodies against neuronal surface antigens (NSA-ab) in patients with different types of epilepsy, in comparison with the subjects diagnosed with immune-mediated disorders.Methods: Forty patients with drug-resistant epilepsy (DRE) of unknown origin, 16 with post-stroke epilepsy, and 23 with systemic autoimmune disorders (SAD) with CNS involvement were included. NSA-ab were sought in serum using indirect immunofluorescence method. Relationships were analyzed between presence of NSA-ab and clinical presentation.Results: NSA-ab was detected in the sera from five patients: anti-DPPX in one patient, anti-AMPAR1/R2 in two, anti-LGI1 in one and, in one case, both anti-CASPR2 and DPPX IgG. Out of these five patients, three represented the SAD subgroup and two the DRE subgroup. None of the patients with post-stroke epilepsy was positive for NSA-ab.Significance: Autoimmune etiology is worth considering in patients with drug-resistant epilepsy of unknown origin. The presence of NSA-ab in patients with systemic autoimmune disorders may be caused by unspecifically enhanced autoimmune reactivity. NSA-ab seem not to be related to epilepsy resulting from ischemic brain injury.

Sex-Specific Limitations in Physical Health in Primary Adrenal Insufficiency

BackgroundPatients with primary adrenal insufficiency (PAI) suffer reduced quality of life (QoL), but comparisons with large-scale normative data are scarce. The clinical characteristics associated with reduced QoL are largely unknown.MethodsCross-sectional data on clinical characteristics and QoL scores from 494 patients were included. QoL was measured using RAND-36 (generic) and AddiQoL (-30 and -8, disease-specific). RAND-36 is reported as subdomain scores as well as physical (PCS) and metal (MCS) summary scores and compared with normative data.ResultsPerception of physical role was consistently decreased across age groups in patients with PAI compared with normative data [75 (0-100) vs. 100 (50-100), p<0.001]. Men with PAI reported significantly lower scores for social functioning [88 (75-100) vs. 100 (75-100), p<0.001], as well as for vitality and physical role. In women, the greatest impairment was seen in physical role [50 (0-100) vs. 100 (50-100), p<0.001], followed by social functioning, vitality, physical function, general health, mental health, and emotional role. Overall, better QoL was associated with male sex (AddiQoL-30: 89 ± 13 vs. 82 ± 13, p<0.002), younger age (e.g. 20-29 vs. 80-89 years: PCS 59 [50-62] vs. 46 [37-53], p<0.001), autoimmune etiology [PCS: 53 (45-59) vs.. 45 (38-54), p<0.001], and absence of autoimmune comorbidity [PCS: 54 (45-59) vs. 50 (43-58), p<0.001]. There were no significant differences in QoL scores between different doses or dosing regimens of glucocorticoid or mineralocorticoid replacement.ConclusionQoL is reduced in patients with PAI, especially perception of physical role in women and social functioning in men. Among patients with PAI, female sex, higher age, non-autoimmune etiology, and autoimmune comorbidity was associated with lower QoL-scores.

Medical Image of the Month: COVID-19-Associated Pulmonary Aspergillosis in a Post-Liver Transplant Patient

No abstract available. Article truncated after first 150 words. A previously healthy, 48-year-old woman, admitted with a working diagnosis of acute-on-chronic liver failure (Grade III) secondary to an autoimmune etiology, was found to be SARS COV-2 RTPCR positive on routine admission screening. She was initially managed with standard medical care for COVID, including steroids. She required invasive ventilation for worsening encephalopathy and when her antigen test was negative 10 days later, she underwent an urgent liver transplantation. Her preoperative infection screen (culture of blood, bronchoalveolar lavage, urine) was negative and computerized tomography (CT) of the chest was normal (Figure 1). She was extubated on day 3 after liver transplantation. Her recovery was uneventful until the 10th postoperative day when she developed cough and desaturation. A repeat CT chest showed multiple multilobular consolidatory nodules with central breakdown involving both lung (Figure 2). Her bronchoalveolar lavage culture grew Aspergillus fumigatus (azole sensitive) which fulfilled criteria for proven COVID-19 Associated pulmonary aspergillosis …

Autoimmune profiling suggests paraneoplastic etiology in pediatric ROHHAD

ROHHAD (Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation and Autonomic Dysregulation) is a rare, yet severe pediatric disorder resulting in hypothalamic dysfunction and frequent sudden death. Genetic and other investigations have failed to identify an etiology or diagnostic test. Frequent co-occurrence of neuroblastic tumors (NTs) and cerebrospinal fluid inflammation point to an autoimmune paraneoplastic neurological syndrome (PNS); however, specific anti-neural autoantibodies, a hallmark of PNS, have not been identified. Here, we screened antibodies from a curated cohort of ROHHAD patients (n=9) and controls (n=150) using a programmable phage display of the human peptidome (PhIP-Seq). Our ROHHAD cohort exhibited frequent association with NTs (8/9) and features consistent with autoimmune etiology. Autoantibodies to Zinc finger and SCAN domain-containing protein 1 (ZSCAN1) were discovered and orthogonally validated in 7 of 9 ROHHAD patients, all of whom had NTs, and shown to be absent in non-ROHHAD pediatric patients with NTs. Notably, human ZSCAN1 expression was confirmed in ROHHAD tumor and healthy human hypothalamus. Our results support the notion that tumor-associated ROHHAD is a pediatric PNS, potentially initiated by an immune response to peripheral NT. ZSCAN1 autoantibodies may aid in an accurate diagnosis of ROHHAD, thus providing a means toward early detection and treatment. Lastly, given the absence of the ZSCAN1 gene in rodents, our study highlights the value of human-based approaches in addition to the classical rodent-based approaches for detecting novel PNS subtypes.

Tubulointerstitial Nephritis and Uveitis Syndrome: Case Series and Literature Review

Tubulointerstitial nephritis and uveitis syndrome (TINU) is a rare oculorenal inflammatory entity with a probable autoimmune etiology. Interstitial nephritis may be asymptomatic and usually has a benign course with spontaneous resolution. Uveitis, instead, is classically anterior, bilateral, and nongranulomatous, but it can be unilateral and presents as posterior uveitis or panuveitis, sometimes with a chronic or recurrent evolution. The frequent time lag of ocular and renal manifestations makes this diagnosis particularly challenging. The authors describe four cases of this rare entity, two with tubulointerstitial nephritis preceding ocular manifestations and the remaining, instead, with uveitis preceding renal involvement. The therapeutic approach included systemic corticosteroids in all cases. The addition of immunosuppressive therapy was required in three patients to achieve uveitis control. TINU is probably an underrecognized entity and should always be considered in the differential diagnosis of a chronic or recurrent idiopathic uveitis, especially in young patients who may have mild and asymptomatic renal disease.

Recurrent Severe Hepatitis of Autoimmune Origin

The autoimmune liver disease constituent conditions include autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis and IgG-4 associated cholangitis. They remain a diagnostic challenge to the practicing physician due to their close resemblance in clinical course, and laboratory and imaging findings to the vast array of other etiologies of liver injury. We report a case of recurrent severe hepatitis of autoimmune origin in a female patient. The disease course was marked by initial onset at age 39, followed by nearly four years of remission, and a second flare with a more exaggerated severity. Systemic lupus erythematosus was initially deemed as the culprit, however formal diagnostic criteria were not fulfilled and the serological findings were not reproduced at a later date. With the aim of ascertaining the underlying process, the patient underwent an extensive array of testing with regards to infectious, genetic, systemic and autoimmune disease. Positive anti-dsDNA (double stranded DNA) and an antinuclear antibody titer of 1:160 provided the strongest support for an autoimmune etiology, specifically autoimmune hepatitis or possibly an overlap syndrome. An excellent outcome was achieved via treatment with corticosteroids, ursodeoxycholic acid and plasmapheresis.

Case Report: Improvement Following Immunotherapy in an Individual With Seronegative Down Syndrome Disintegrative Disorder

Down syndrome disintegrative disorder (DSDD) is a condition of unknown etiology characterized by acute cognitive decline, catatonia, insomnia, and autistic features in individuals with Down syndrome. A prior report of four patients with DSDD suggested a potential autoimmune etiology based on the presence of autoantibodies and on successful treatment with immunotherapy that included intravenous immunoglobulin (IVIG). Herein, we present the case of an 8-year old girl who developed acute cognitive decline to a dementia-like state, insomnia, catatonia, and autistic features. In contrast to the four patients with DSDD above, she had no evidence of autoimmunity and presented at a younger age. Given the gravity of her acute deterioration and the exclusion of other etiologies, she was treated with immunotherapy presumptively. She responded with near complete resolution of symptoms, but demonstrated a pattern of mild decline as she approached each monthly dosing of IVIG and steroids, reversed by treatment. Mycophenolate mofetil (MMF) was therefore added, with stability throughout the month and the ability to taper off IVIG. After stopping IVIG, she had a mild recurrence of symptoms that again resolved with repeat IVIG followed by tapering off. Outcome was assessed at 2.5 years after presentation, at which time she was back to her premorbid condition, except for persistent tics off immunotherapy. This case supports the contention that patients with a rapid onset of severe symptoms consistent with DSDD, who have a thorough evaluation with the exclusion of other etiologies, may warrant a trial of immunotherapy with steroids, IVIG and/or other agents like MMF even in the absence of evidence of autoimmunity on standard evaluation.