518 - AUTOIMMUNE DEMENTIA – WHEN TO SUSPECT?

Background:Autoimune dementias are underrecognized clinical entities, frequently misdiagnosed as neurodegenerative or prion disorders. However, the prognosis is vastly different since immunotherapy can treat these conditions and restore functionality.Research objective:To reflect on autoimmune dementias, briefly presenting the autoimmune syndromes, how to diagnose them and some clinical cues to be attentive of.Methods:Literature search on Pubmed and Google Scholar.Results:The incidence and prevalence of autoimmune dementias are unknown, but autoimmune and inflammatory causes account for 20% of dementia in patients younger than 45 years of age.Autoimmune dementias are classified according to syndromic presentation, specific serologic markers, or histopathologic findings.Patients with autoimmune dementias usually present with an acute or subacute disorder of memory, thinking, or behaviour. Clinical clues that can help clinicians identify autoimmune dementias include six of the following: (i) rapidly progressive or fluctuating course; (ii) multifocal and diverse clinical presentations; (iii) personal or family history of autoimmunity; (iv) detection of inflammatory markers in the cerebrospinal fluid; (v) presence of a neural-specific autoantibody and (vi) favourable response to a trial of immunotherapy. Also, unsuspected cancer, new or recurrent, may manifest neurologically as autoimmune dementia.In evaluating patients with dementia and autoimmune disease, clinicians should be aware of the possible coexistence of these disorders.Conclusions:Recognition of clinical and serologic clues to autoimmune dementia allows early and sustained treatment. Misdiagnosis of a potentially reversible condition as a progressive neurodegenerative disorder can have devastating consequences for the patient and family.

Autoimmune Hepatitis: Serum Autoantibodies in Clinical Practice

Circulating autoantibodies are a key diagnostic tool in autoimmune hepatitis (AIH), being positive in 95% of the cases if tested according to dedicated guidelines issued by the International Autoimmune Hepatitis Group. They also allow the distinction between type 1 AIH, characterized by positive anti-nuclear and/or anti-smooth muscle antibody, and type 2 AIH, characterized by positive anti-liver kidney microsomal type 1 and/or anti-liver cytosol type 1 antibody. Anti-soluble liver antigen is the only AIH-specific autoantibody, and is found in 20–30% of both type 1 and type 2 AIH. Anti-neutrophil cytoplasmic antibody is frequently positive in type 1 AIH, being associated also with inflammatory bowel disease and with primary/autoimmune sclerosing cholangitis. The reference method for autoantibody testing remains indirect immunofluorescence on triple tissue (rodent liver, kidney and stomach), allowing both the detection of the majority of liver-relevant reactivities, including those autoantibodies whose molecular target antigens are unknown. Of note, the current knowledge of the clinical significance of autoantibodies relies on studies based on this technique. However, immunofluorescence requires trained laboratory personnel, is observer-dependent, and lacks standardization, leading to ongoing attempts at replacing this method with automated assays, the sensitivity, and specificity of which, however, require further studies before they can be used as a reliable alternative to immunofluorescence; currently, they may be used as complementary to immunofluorescence.

Clinical Problem Solving: An Older Woman With Weakness from Head to Toe

A 67-year-old woman was admitted to our hospital for progressive weakness, dysphagia, muscle pain, and weight loss. Here we detail the clinical problem solving involved in diagnosing and treating her immune-mediated necrotizing myopathy caused by anti-HMGCoA reductase autoantibodies. Interestingly, this diagnosis coincided with discovery of a gastrointestinal stromal tumor (GIST) and positivity for anti-nuclear matrix protein (anti-NXP2), another myositis specific autoantibody.

Clinical impact of myositis-specific autoantibodies on long-term prognosis of juvenile idiopathic inflammatory myopathies: multicentre study

Objectives This study aimed to investigate the clinical characteristics, treatment and prognosis of juvenile idiopathic inflammatory myopathies (JIIM) in Japan for each myositis-specific autoantibody (MSA) profile. Methods A multicentre, retrospective study was conducted using data of patients with JIIM at nine paediatric rheumatology centres in Japan. Patients with MSA profiles, determined by immunoprecipitation using stored serum from the active stage, were included. Results MSA were detected in 85 of 96 cases eligible for the analyses. Over 90% of the patients in this study had one of the following three MSA types: anti-melanoma differentiation-associated protein 5 (MDA5) (n = 31), anti-transcriptional intermediary factor 1 alpha and/or gamma subunits (TIF1γ) (n = 25) and anti-nuclear matrix protein 2 (NXP2) (n = 25) antibodies. Gottron papules and periungual capillary abnormalities were the most common signs of every MSA group in the initial phase. The presence of interstitial lung disease (ILD) was the highest risk factor for patients with anti-MDA5 antibodies. Most patients were administered multiple drug therapies: glucocorticoids and MTX were administered to patients with anti-TIF1γ or anti-NXP2 antibodies. Half of the patients with anti-MDA5 antibodies received more than three medications including i.v. CYC, especially patients with ILD. Patients with anti-MDA5 antibodies were more likely to achieve drug-free remission (29 vs 21%) and less likely to relapse (26 vs 44%) than others. Conclusion Anti-MDA5 antibodies are the most common MSA type in Japan, and patients with this antibody are characterized by ILD at onset, multiple medications including i.v. CYC, drug-free remission, and a lower frequency of relapse. New therapeutic strategies are required for other MSA types.

Deep Pathological Phenotyping of Dermatomyositis with Different Autoantibodies

Objective Dermatomyositis with different myositis-specific autoantibodies has distinctive clinical presentations. Pathological variation of patients with different antibodies has not been fully understood. Methods A retrospective review of muscle pathological features was performed in dermatomyositis patients with known myositis-specific antibodies. Results A total of 46 dermatomyositis patients with one myositis-specific autoantibody (anti-MDA5 11, anti-Mi-2 10, anti-NXP2 13, anti-TIF1γ 8, anti-SAE 4) were included and the pathological severity score was evaluated. Patients with anti-Mi-2 demonstrated higher pathological severity scores and apparent sarcolemmal complement deposition, which was in consistency of more severe muscle weakness and higher level of muscle enzymes. In contrast, patients with anti-MDA5 generally had minimal pathological changes in muscle with less inflammatory cell infiltration, fewer membrane attack complex deposition, and milder myxovirus resistance protein A upregulation. Patients with anti-SAE had more inflammatory cell infiltration and MAC deposition compared to anti-MDA5 group. Muscle pathological scores varied largely in patients with anti-NXP2 and anti-TIF1γ. Conclusion The muscle pathological features varies among dermatomyositis with different autoantibodies, which further indicates the heterogeneity of dermatomyositis.

CIDP Antibodies Target Junction Proteins and Identify Patient Subgroups

ObjectiveTo discover systemic characteristics in the repertoires of targeted autoantigens in chronic inflammatory demyelinating polyneuropathy (CIDP), we detected the entire autoantigen repertoire of patients and controls and analyzed them systematically.MethodsWe screened 43 human serum samples, of which 22 were from patients with CIDP, 12 from patients with other neuropathies, and 9 from healthy controls via HuProt Human Proteome microarrays testing about 16,000 distinct human bait proteins. Autoantigen repertoires were analyzed via bioinformatical autoantigenomic approaches: principal component analysis, analysis of the repertoire sizes in disease groups and clinical subgroups, and overrepresentation analyses using Gene Ontology and PantherDB.ResultsThe autoantigen repertoires enabled the identification of a subgroup of 10/22 patients with CIDP with a younger age at onset and a higher frequency of mixed motor and sensory CIDP. IV immunoglobulin therapy responders targeted 3 times more autoantigens than nonresponders. No CIDP-specific autoantibody is present in all patients; however, anchoring junction components were significantly targeted by 86.4% of patients with CIDP. There are potential novel CIDP-specific autoantigens such as the myelination- or axo-glial structure–related proteins actin-related protein 2/3 complex subunit 1B, band 4.1-like protein 2, cadherin-15, cytohesin-1, epidermal growth factor receptor, ezrin, and radixin.ConclusionsThe repertoire of targeted autoantigens of patients with CIDP differs in a systematic degree from those of controls. Systematic autoantigenomic approaches can help to understand the disease and to discover novel bioinformatical tools and novel autoantigen panels to improve diagnosis, treatment, prognosis, or patient stratification.

Myopathy following statin use

Introduction: Myopathies can be caused by various drugs, including statins and corticosteroids, and can be toxic or inflammatory, one example being necrotizing myositis triggered by statins. Objectives: Describe the case of a patient with weakness after statin use. Design and setting: Case report Methods: Analysis of medical record, photographic record of the diagnostic methods and literature review. Case description: 69-year-old female, obese, hypertensive, diabetic, dyslipidemic and hypothyroid, taking atorvastatin since 2017, referred by endocrinology for generalized myalgia in 2019, with increased creatine phosphokinase (CPK). Discontinued statin use since then, maintaining symptoms. Neurological examination showed tetraparesis, with proximal predominance. Electroneuromyography (ENMG) showed signs of myopathy. Corticotherapy with deflazacort was initiated, with improvement of symptoms and reduction of CPK levels. Investigation for paraneoplastic syndrome was performed, with negative results. He started using pioglitazone, prescribed by endocrinology, with reduced corticotherapy, for better glycemic control, presenting worsening weakness, frequent falls, and dyspnea on effort. The patient repeated ENMG in one month, without changes. Performed an anti-HMG-CoA reductase autoantibody test, with a positive result, concluding the diagnosis of immune-mediated necrotizing myositis triggered by statins, with a probable toxic myopathy after use of pioglitazone. Azathioprine was introduced, with gradual weaning from corticosteroids, and physical therapy was started. Conclusion: Several medications can cause myopathy, directly (toxic) or indirectly (immune-mediated), and this patient used 3 potentially myopathy-causing drugs (atorvastatin, deflazacort, and pioglitazone). The nonimprovement upon medication withdrawal suggested an immune-mediated inflammatory cause, confirmed in this case by the determination of a specific autoantibody for statin-induced necrotizing myositis.

TDP-43–specific Autoantibody Decline in Patients With Amyotrophic Lateral Sclerosis

ObjectiveWe hypothesize alterations in the quality and quantity of anti–43-kDa TAR DNA-binding protein (TDP-43) naturally occurring autoantibodies (NAbs) in patients with amyotrophic lateral sclerosis (ALS); therefore, we assessed relative binding properties of anti–TDP-43 NAbs composite in plasma from patients with ALS in comparison with healthy individuals.MethodsELISA competition assay was used to explore the apparent avidity/affinity of anti–TDP-43 NAbs in plasma from 51 normal controls and 30 patients with ALS. Furthermore, the relative levels of anti–TDP-43 NAbs within the immunoglobulin (Ig) classes of IgG (isotype IgG1-4) and IgMs were measured using classical indirect ELISA. The occurring results were hereafter correlated with the measures of disease duration and disease progression.ResultsHigh-avidity/affinity anti–TDP-43 NAbs levels were significantly reduced in plasma samples from patients with ALS. In addition, a significant decrease in relative levels of anti–TDP-43 IgG3 and IgM NAbs and a significant increase in anti–TDP-43 IgG4 NAbs were observed in ALS plasma vs controls. Furthermore, a decrease in global IgM and an increase in IgG4 levels were observed in ALS. These aberrations of humoral immunity correlated with disease duration, but did not correlate with ALS Functional Rating Scale–Revised scores.ConclusionsOur results may suggest TDP-43–specific immune aberrations in patients with ALS. The skewed immune profiles observed in patients with ALS could indicate a deficiency in the clearance capacity and/or blocking of TDP-43 transmission and propagation. The decrease in levels of high affinity/avidity anti-TDP-43 NAbs and IgMs correlates with disease progression and may be disease predictors.

The Possible Role of Interleukin-6 as a Regulator of Insulin Sensitivity in Patients With Neuromyelitis Optica Spectrum Disorder

Background: The aquaporin 4- Immunoglobulin G (AQP4-IgG) is the disease-specific autoantibody that has a significant role in the pathogenesis of Neuromyelitis optica spectrum disorder (NMOSD). Circulating AQP4-IgG induces pro-inflammatory cytokines and may also trigger downstream signaling pathways leading to metabolic dysregulation.Methods: We aimed to determine the risk association of hyperinsulinemia in NMOSD patients with seropositive AQP4-IgG and the serum levels of interleukin (IL)-6 and IL-17 compared with the control group.Serum levels of metabolic (Insulin, Fasting Blood Sugar (FBS), lipid profile) and inflammatory (IL-6 and IL-17) markers were assessed in 56 NMOSD patients and 100 controls.Results: Hyperinsulinemia was more prevalent in NMOSD patients independent of age, gender and body mass index (BMI) (48.2% vs. 26%, p=0.005). After adjusting age, sex and BMI, there was significant association between lower insulin sensitivity (IS) and NMOSD risk (95% CI: Beta=0.73, 0.62 to 0.86, p=0.0001).The correlation between the duration of disease and circulating levels of insulin and FBS in NMOSD patients was not significant (P>0.05). Circulating levels of IL-6 and IL-17 were higher in NMOSD patients, and only IL-6 had an effect modifier for the association between lower insulin sensitivity and NMOSD risk. Conclusions: Our data suggests that inflammatory pathogenesis of NMOSD leads to hyperinsulinemia and increases the risk of insulin resistance.

Anti-MDA5 autoantibodies associated with juvenile dermatomyositis constitute a distinct phenotype in North America

Objective Myositis-specific autoantibodies have defined distinct phenotypes of patients with juvenile myositis (JIIM). We assessed the frequency and clinical significance of anti-melanoma differentiation-associated gene 5 (MDA5) autoantibody-associated JIIM in a North American registry. Methods Retrospective examination of the characteristics of 35 JIIM patients with anti-MDA5 autoantibodies was performed, and differences from other myositis-specific autoantibody groups were evaluated. Results Anti-MDA5 autoantibodies were present in 35/453 (7.7%) of JIIM patients and associated with older age at diagnosis, and lower serum creatine kinase and aldolase levels. Patients with anti-MDA5 autoantibodies had more frequent weight loss, adenopathy, arthritis, interstitial lung disease (ILD), and less frequent falling compared with anti-transcriptional intermediary factor 1 (TIF1), anti-nuclear matrix protein 2 (NXP2) and myositis-specific autoantibody/myositis-associated autoantibody-negative patients. They had a different season of diagnosis and less frequent mechanic’s hands and ILD compared with those with anti-synthetase autoantibodies. Anti-MDA5 patients received fewer medications compared with anti-TIF1, and corticosteroid treatment was shorter compared with anti-TIF1 and anti-nuclear matrix protein 2 autoantibody groups. The frequency of remission was higher in anti-MDA5 than anti-synthetase autoantibody-positive JIIM. In multivariable analyses, weight loss, arthritis and arthralgia were most strongly associated with anti-MDA5 autoantibody-positive JIIM. Conclusion Anti-MDA5 JIIM is a distinct subset, with frequent arthritis, weight loss, adenopathy and less severe myositis, and is also associated with ILD. Anti-MDA5 is distinguished from anti-synthetase autoantibody-positive JIIM by less frequent ILD, lower creatine kinase levels and differing seasons of diagnosis. Anti-MDA5 has comparable outcomes, but with the ability to discontinue steroids more rapidly and less frequent flares compared with anti-TIF1 autoantibodies, and more frequent remission compared with anti-synthetase JIIM patients.