The MRZ-Reaction and Specific Autoantibody Detection for Differentiation of ANA-Positive Multiple Sclerosis From Rheumatic Diseases With Cerebral Involvement

Abstract

Objective: Rheumatic diseases with involvement of the central nervous system (RDwCNS) may mimic multiple sclerosis (MS). Inversely, up to 60% of MS-patients have antinuclear autoantibodies (ANAs) and may be misdiagnosed as RDwCNS. The detection of antibodies against extractable nuclear antigens (ENA) and oligoclonal bands (OCB) are established valuable diagnostic tools in the differential diagnosis of RDwCNS and MS. The MRZ-reaction (MRZR) is defined by three antibody indices (AIs) against neurotropic viruses and is frequently positive in MS. To investigate the added value of MRZR combined with testing for antibodies against ENAs and OCB detection to distinguish RDwCNS from ANA positive MS.Methods: MRZR was evaluated in RDwCNS (n = 40) and 68 ANA positive MS-patients. Two stringency levels, MRZR-1 and MRZR-2 (at least one respectively two of three AIs positive) were applied. Autoantibody testing included ANA plus ENA and anti-dsDNA antibodies, antiphospholipid antibodies, and anti-neutrophil cytoplasmic antibodies.Results: Most of the RDwCNS patients (n = 32; 80%) suffered from systemic lupus erythematosus. Within the RDwCNS group 20% had a positive MRZR-1 and 8.5% a positive MRZR-2 compared to 80.9 and 60%, respectively within the MS-group (p < 0.0001 for both comparisons). Oligoclonal bands were found in 28.6% of the RDwCNS patients and 94.3% of the MS-patients (p < 0.0001). Conversely, autoantibodies to specific nuclear antigens or phospholipids were found more frequently in RDwCNS. A positive MRZR in conjunction with the absence of ENA autoantibodies distinguished MS from RDwCNS with high specificity (97.5%).Conclusions: We suggest combining MRZR, OCBs, and specific autoantibody diagnostics to differentiate RDwCNS from MS.

Differentiating central nervous system demyelinating disorders: The role of clinical, laboratory, imaging characteristics and peripheral blood type I interferon activity

“…Though lower ANA titers and antiphospholipid antibody positivity have been extensively reported in MS and MS-like populations (Spadaro et al, 1999;Szmyrka-Kaczmarek et al, 2012;Malyavantham et al, 2015;Merashli et al, 2017), in the current report, we emphasize the role of higher ANA titers (more than 1/320) pointing toward an underlying systemic autoimmune process, in support of previous findings (Magro Checa et al, 2013). Moreover, in agreement with previous works, a higher CSF IgG index and the presence of OCBs reinforce the diagnosis of MS without however ruling out a diagnosis of SAD (Magro Checa et al, 2013;Govoni et al, 2016;Venhoff et al, 2019). Of interest, MS spectrum patients displayed lower B12 vitamin levels in comparison to their CNS autoimmune counterparts, possibly due to malabsorption mediated by autoimmune reactivity toward gastrointestinal antigens commonly found in MS populations (Banati et al, 2013).…”

“…While usually helpful, brain MRI (Stosic et al, 2010;Akasbi et al, 2012;Magro Checa et al, 2013;Magro-Checa et al, 2018) and cerebrospinal fluid (CSF) analysis (Govoni et al, 2016;Venhoff et al, 2019) cannot consistently differentiate between MS and CNS involvement in the setting of SADs. Though the detection of serum autoantibodies has a central role in the diagnosis of SAD, they are reported to precede disease onset by many years (Arbuckle et al, 2003).…”

“…Additionally, low-titer antinuclear (ANA) and antiphospholipid antibodies are frequently found in the context of MS at variable frequencies ranging between 3%--63% and 0.9%-8.5%, respectively (Spadaro et al, 1999;Szmyrka-Kaczmarek et al, 2012;Malyavantham et al, 2015;Merashli et al, 2017). Of interest, MRZ reaction [detection of CSF IgG antibody indices to measles (M), rubella (R), and varicella-zoster (Z)] was found to be prevalent in patients with MS and ANA positivity compared to those with rheumatological disease with CNS involvement, providing a potential differentiating tool between the two entities (Venhoff et al, 2019).…”

Diagnosing Organic Causes of Schizophrenia Spectrum Disorders: Findings from a One-Year Cohort of the Freiburg Diagnostic Protocol in Psychosis (FDPP)

“…Anti-glutamate decarboxylase (GAD) 65 antibodies were also tested using radioimmunoassay (RIA). Methods for rheumatic testing and CSF basic analyses are described in earlier papers from our working group [14,17]. CSF analyses were performed in 48 of the 76 patients (63%) in 2018.…”

“…Due to the exploratory approach, no correction for multiple testing was performed. 22 -Tau, p-tau 23 , ß-amyloid quotient 23 , protein 14-3-3 24 , α-synuclein 25 -Cytopathology and cell markers, hypocretin 26 Diseases associated with some specific biomarkers are listed below: 1 neuroacanthocytosis syndromes, 2 antiphospholipid syndrome, 3 Fabry's disease, 4 hyper-/hypoparathyroidism, 5 Wilson disease, 6 metachromatic leukodystrophy, 7 adrenoleukodystrophy, 8 Niemann-Pick disease type C, 9 rheumatoid arthritis, 10 sarcoidosis, 11 minor chorea/Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS), 12 Behcet's syndrome, 13 autoimmune thyroiditis, 14 diabetes mellitus type 1/autoimmune neuropsychiatric syndromes (e.g., Stiff-Person syndrome, limbic encephalitis), 15 celiac disease/cerebellar degeneration, 16 systemic connective tissue disorders, 17 vasculitides, 18 primary biliary cirrhosis, 19 autoimmune hepatitis, 20 autoimmune encephalitis/autoimmune psychosis, 21 multiple sclerosis, 22 acute neuroborreliosis, 23 Alzheimer's disease, 24 Creutzfeldt-Jakob disease, 25 synucleinopathies (Parkinson's disease, dementia with Lewy bodies, multisystem atrophy), 26 narcolepsy, 27 acute intermittent porphyria.…”