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Reliable and responsive tools for monitoring disease activity and treatment outcomes in patients with neuropathies are lacking. With the emergence of ultrasensitive blood bioassays, proteins released with nerve damage are potentially useful response biomarkers for many neurological disorders, including polyneuropathies. In this review, we provide an overview of the existing literature focusing on potential applications in polyneuropathy clinical care and trials. Whilst several promising candidates have been identified, no studies have investigated if any of these proteins can serve as response biomarkers of longitudinal disease activity, except for neurofilament light (NfL). For NfL, limited evidence exists supporting a role as a response biomarker in Guillain-Barré syndrome, vasculitic neuropathy, and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Most evidence exists for NfL as a response biomarker in hereditary transthyretin-related amyloidosis (hATTR). At the present time, the role of NfL is therefore limited to a supporting clinical tool or exploratory endpoint in trials. Future developments will need to focus on the discovery of additional biomarkers for anatomically specific and other forms of nerve damage using high-throughput technologies and highly sensitive analytical platforms in adequality powered studies of appropriate design. For NfL, a better understanding of cut-off values, the relation to clinical symptoms and long-term disability as well as dynamics in serum on and off treatment is needed to further expand and proceed towards implementation.

Membranous glomerulonephritis (MGN) is a common cause of nephrotic syndrome in adults, mediated by glomerular antibody deposition to an increasing number of newly recognised antigens. Previous case reports have suggested an association between patients with anti-contactin-1 (CNTN1)-mediated neuropathies and MGN. In an observational study we investigated the pathobiology and extent of this potential cause of MGN by examining the association of antibodies against CNTN1 with the clinical features of a cohort of 468 patients with suspected immune-mediated neuropathies, 295 with idiopathic MGN, and 256 controls. Neuronal and glomerular binding of patient IgG, serum CNTN1 antibody and protein levels, as well as immune-complex deposition were determined. We identified 15 patients with immune-mediated neuropathy and concurrent nephrotic syndrome (biopsy proven MGN in 12/12), and 4 patients with isolated MGN from an idiopathic MGN cohort, all seropositive for IgG4 CNTN1 antibodies. CNTN1-containing immune complexes were found in the renal glomeruli of patients with CNTN1 antibodies, but not in control kidneys. CNTN1 peptides were identified in glomeruli by mass spectroscopy. CNTN1 seropositive patients were largely resistant to first-line neuropathy treatments but achieved a good outcome with escalation therapies. Neurological and renal function improved in parallel with suppressed antibody titres. The reason for isolated MGN without clinical neuropathy is unclear. We show that CNTN1, found in peripheral nerves and kidney glomeruli, is a common target for autoantibody-mediated pathology and may account for between 1 and 2% of idiopathic MGN cases. Greater awareness of this cross-system syndrome should facilitate earlier diagnosis and more timely use of effective treatment.

Diagnosing Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) poses numerous challenges. The heterogeneous presentations of CIDP variants, its mimics, and the complexity of interpreting electrodiagnostic criteria are just a few of the many reasons for misdiagnoses. Early recognition and treatment are important to reduce the risk of irreversible axonal damage, which may lead to permanent disability. The diagnosis of CIDP is based on a combination of clinical symptoms, nerve conduction study findings that indicate demyelination, and other supportive criteria. In 2021, the European Academy of Neurology (EAN) and the Peripheral Nerve Society (PNS) published a revision on the most widely adopted guideline on the diagnosis and treatment of CIDP. This updated guideline now includes clinical and electrodiagnostic criteria for CIDP variants (previously termed atypical CIDP), updated supportive criteria, and sensory criteria as an integral part of the electrodiagnostic criteria. Due to its many rules and exceptions, this guideline is complex and misinterpretation of nerve conduction study findings remain common. CIDP is treatable with intravenous immunoglobulins, corticosteroids, and plasma exchange. The choice of therapy should be tailored to the individual patient's situation, taking into account the severity of symptoms, potential side effects, patient autonomy, and past treatments. Treatment responses should be evaluated as objectively as possible using disability and impairment scales. Applying these outcome measures consistently in clinical practice aids in recognizing the effectiveness (or lack thereof) of a treatment and facilitates timely consideration of alternative diagnoses or treatments. This review provides an overview of the current perspectives on the diagnostic process and first-line treatments for managing the disease.

Detection and characterization of antigen‐specific T cells are important for studying immune responses upon infection, vaccination, or autoreactivity. The activation‐induced marker (AIM) assay is a robust technique to identify and characterize antigen‐specific CD4 and CD8 T cells. However, there is variability in the AIM assay, particularly in the type and number of activation markers used. In this study, we set out to define which marker combinations are most suited to optimally detect antigen‐specific CD4 and CD8 T cells and if certain marker combinations preferentially detect specific CD4 T helper subsets. A multiparameter flow cytometry panel, including six common activation markers: CD40L, CD137, CD69, OX40, CD25, and PD‐L1, was used for detecting antigen‐specific T cells following infection (SARS‐CoV‐2 and CMV) or vaccination (mRNA‐1273 SARS‐CoV‐2). We demonstrate that combining multiple activation markers increases the detection frequency of antigen‐specific CD4 T cells compared to commonly used dual marker combinations. In addition, marker combinations including PD‐L1 detected a higher frequency of antigen‐specific CD4 T cells in SARS‐CoV‐2 and CMV infected but not in SARS‐CoV‐2–vaccinated individuals. Certain dual marker combinations preferentially detected specific CD4 T helper subsets. The majority of antigen‐specific CD8 T cells were captured by the dual combination of CD69 plus CD25. In conclusion, combining CD137, CD69, OX40, CD25, and PD‐L1 in an AIM assay results in robust and optimal detection of both specific CD4 T helper subsets and CD8 T cells in different antigenic contexts.

The dynamics of cellular immune reactivation upon vaccination of SARS-CoV-2 experienced MS patients treated with the humanized anti-CD20 monoclonal antibody ocrelizumab (OCR) and RA patients treated with methotrexate (MTX) monotherapy were analyzed at great depth via high-dimensional flow cytometry of whole blood samples upon vaccination with the SARS-CoV-2 mRNA-1273 (Moderna) vaccine. Longitudinal B and T cell immune responses were compared to SARS-CoV-2 experienced healthy controls (HCs) before and 7 days after the first and second vaccination. OCR-treated MS patients exhibit a preserved recall response of CD8.sup.+ T central memory cells following first vaccination compared to HCs and a similar CD4.sup.+ circulating T follicular helper 1 and T helper 1 dynamics, whereas humoral and B cell responses were strongly impaired resulting in absence of SARS-CoV-2-specific humoral immunity. MTX treatment significantly delayed antibody levels and B reactivation following the first vaccination, including sustained inhibition of overall reactivation marker dynamics of the responding CD4.sup.+ and CD8.sup.+ T cells. Together, these findings indicate that SARS-CoV-2 experienced MS-OCR patients may still benefit from vaccination by inducing a broad CD8.sup.+ T cell response which has been associated with milder disease outcome. The delayed vaccine-induced IgG kinetics in RA-MTX patients indicate an increased risk after the first vaccination, which might require additional shielding or alternative strategies such as treatment interruptions in vulnerable patients.

To characterize the T cell receptor (TCRβ) repertoire in peripheral blood and muscle tissues of treatment naïve patients with newly diagnosed idiopathic inflammatory myopathies (IIMs). High throughput RNA sequencing of the TCRβ chain was performed in peripheral blood and muscle tissue in twenty newly-diagnosed treatment-naïve IIM patients (9 DM, 5 NM/OM, 5 IMNM and 1 ASyS) and healthy controls. Results thereof were correlated with markers of disease activity. Muscle tissue of IIM patients shows more expansion of TCRβ clones and decreased diversity when compared to peripheral blood of IIM as well as healthy controls (both p=0.0001). Several expanded TCRβ clones in muscle are tissue restricted and cannot be retrieved in peripheral blood. These clones have significantly longer CDR3 regions when compared to clones (also) found in circulation (p=0.0002), while their CDR3 region is more hydrophobic (p<0.01). Network analysis shows that clonal TCRβ signatures are shared between patients. Increased clonal expansion in muscle tissue is significantly correlated with increased CK levels (p=0.03), while it tends to correlate with decreased muscle strength (p=0.08). Network analysis of clones in muscle of IIM patients shows shared clusters of sequences across patients. Muscle-restricted CDR3 TCRβ clones show specific structural features in their T cell receptor. Our results that clonal TCRβ expansion in muscle tissue might be associated with disease activity. Collectively, these findings support a role for specific clonal T cell responses in muscle tissue in the pathogenesis of the IIM subtypes studied.

Pulsed high-dose dexamethasone induced long-lasting remission in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in a pilot study. The PREDICT study aimed to compare remission rates in patients with CIDP treated with high-dose dexamethasone with rates in patients treated with standard oral prednisolone. In eight neuromuscular centres in the Netherlands and one in the UK, patients aged 18 years or older who had newly diagnosed definite or probable CIDP were randomly assigned to a treatment regimen of either pulsed high-dose dexamethasone or standard oral prednisolone. Randomisation was done with a random number generator. The primary outcome measure was remission at 12 months, defined as improvement of at least three points on the Rivermead mobility index and improvement of at least one point on the inflammatory neuropathy cause and treatment disability scale. Analysis was by intention to treat. This trial is registered with Current Controlled Trials, number ISRCTN07779236. Between December, 2003, and December, 2008, 40 patients were treated: 24 received dexamethasone and 16 received prednisolone. At 12 months, 16 patients were in remission: ten in the dexamethasone group and six in the prednisolone group (odds ratio [OR] 1·2, 95% CI 0·3–4·4). Most adverse events were minor and did not differ substantially between treatment groups; however, sleeplessness and Cushing's face occurred more often in the prednisolone group. Pulsed high-dose dexamethasone treatment did not induce remission more often than prednisolone treatment. A substantial proportion of patients were in remission at 12 months in both treatment groups. High-dose dexamethasone could be considered as induction therapy in CIDP, but comparison with intravenous immunoglobulin treatment is needed. The Prinses Beatrix Fonds (MAR01-0213) and the Department of Neurology, Academic Medical Center.

Background INCbase is an international, multicenter prospective observational study using a customizable web-based modular registry to study the clinical, biological and electrophysiological variation and boundaries of chronic inflammatory demyelinating polyneuropathy (CIDP). The primary objective of INCbase is to develop and validate a clinical prediction model for treatment response. Methods All patients meeting clinical criteria for CIDP can be included in INCbase. Collected data include demographics, clinical history, diagnostics and various domains of clinical outcomes. Data is collected at a minimum of every 6 months for two years, and more frequently at the discretion of the investigational site to allow for assessment of unexpected changes in treatment response or clinical status. Participants can be enrolled in various sub-studies designed to capture data relevant to specific groups of interest. Data is entered directly into the web-based data entry system by local investigators and/or participants. Collection and local storage of biomaterial is optional. To develop a clinical prediction model for treatment response, newly diagnosed patients with active disease warranting start of first-line treatment will be included. The study population will be split into a development and validation cohort. Univariate and multivariate logistic regression analysis will be used to identify and combine predictors at start of treatment for treatment response at six months. Model performance will be assessed through discrimination and calibration in an external validation cohort. The externally validated prediction model will be made available to researchers and clinicians on the INCbase website. Discussion With this study, we aim to create a clinically relevant and implementable prediction model for treatment response to first line treatments in CIDP. INCbase enrollment started in April 2021, with 29 centers across 8 countries and 303 patients participating to date. This collaborative effort between academia, patient advocacy organizations and pharmaceutical industry will deepen our understanding of how to diagnose and treat CIDP.

Upon infection, T cell-driven B cell responses in GC reactions induce memory B cells and antibody-secreting cells that secrete protective antibodies. How formation of specifically long-lived plasma cells is regulated via the interplay between specific B and CD4+ T cells is not well understood. Generally, antibody levels decline over time after clearance of the primary infection. In this study, convalescent individuals with stable RBD antibody levels (n=14, \"sustainers\") were compared with donors (n=13) with the greatest antibody decline from a cohort of 132. To investigate the role of the cellular immune compartment in the maintenance of antibody levels, SARS-CoV-2-specific responses at 4 to 6 weeks post-mild COVID-19 infection were characterized using deep immune profiling. Both groups had similar frequencies of total SARS-CoV-2-specific B and CD4+ T cells. Sustainers had fewer Spike-specific IgG+ memory B cells early after infection and increased neutralizing capacity of RBD antibodies over time, unlike the declining group. However, declining IgG titers correlated with lower frequency of Spike-specific CD4+ T cells. These data suggest that \"sustainers\" have unique dynamics of GC reactions, yield different outputs of terminally differentiating cells, and improve the quality of protective antibodies over time. This study helps identify factors controlling formation of long-lived PC and sustained antibody responses.