Immunoadsorption and plasma exchange-Efficient treatment options for neurological autoimmune diseases.

BACKGROUND: Therapeutic plasma exchange (TPE) and immunoadsorption (IA) are first or second line treatment options in patients with neurological autoimmune diseases, including multiple sclerosis, neuromyelitis optica spectrum disorders (NMSOD), chronic inflammatory demyelinating polyneuropathy, acute inflammatory demyelinating polyradiculoneuropathy (Guillain-Barré syndrome), and autoimmune encephalitis. METHODS: In this prospective randomized controlled monocentric study, we assessed safety and efficacy of therapy with IA or TPE in patients with neurological autoimmune diseases. Treatment response was assessed using various neurological scores as well by measuring immunoglobulin and cytokine concentrations. Clinical outcome was evaluated by application of specific scores for the underlying diseases. RESULTS: A total of 32 patients were analyzed. Among these, 19 patients were treated with TPE and 13 patients with IA. IA and TPE therapy showed a comparable significant treatment response. In patients with MS and NMOSD, mean EDSS before and after treatment showed a significant reduction after treatment with IA. We observed a significant reduction of the pro-inflammatory cytokines IL-12, lL-17, IL-6, INF-γ, and tumor necrosis factor alpha during IA treatment, whereas this reduction was not seen in patients treated with TPE. CONCLUSIONS: In summary, both IA and TPE were effective and safe procedures for treating neurological autoimmune diseases. However, there was a trend towards longer therapy response in patients treated with IA compared to TPE, possibly related to a reduction in plasma levels of pro-inflammatory cytokines seen only in the IA-treated group.

Association of serum neurofilament light chain levels and neuropsychiatric manifestations in systemic lupus erythematosus.

BACKGROUND: The aim was to evaluate the diagnostic potential of serum neurofilament light chain (sNfL) measurements in patients with neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: sNfL levels were determined by single molecule array assay in a retrospective cross-sectional cohort of 144 patients with systemic lupus erythematosus (SLE). After log-transformation of sNfL levels, mean sNfL levels were compared between NPSLE patients and SLE patients without neuropsychiatric disease using Student's t test. Furthermore, the association of different neuropsychiatric manifestations with sNfL levels was assessed using a one-way analysis of variance (ANOVA) with post hoc analysis. Associations of sNfL with clinical and laboratory parameters were assessed by correlation and multiple linear regression analysis. RESULTS: NPSLE patients (n = 69) had significantly higher sNfL levels than SLE patients without neuropsychiatric disease manifestations (n = 75; mean difference: 0.13, 95% CI: 0.04-0.22, p = 0.006). With regard to the category of NPSLE manifestation, mean sNfL levels were only increased in NPSLE patients with focal central nervous system (CNS) involvement (n = 45; mean difference: 0.16, 95% CI: 0.02-0.30, p = 0.019), whereas mean sNfL levels of NPSLE patients with diffuse CNS and peripheral nervous system involvement did not differ from those of SLE patients without neuropsychiatric manifestations. Age and serum creatinine concentrations were identified as relevant contributors to sNfL levels. CONCLUSION: sNfL is a promising, easily accessible biomarker for neuropsychiatric involvement in SLE patients and might therefore complement the diagnostic workup of SLE patients with suspected involvement of the nervous system.

Validating quantitative PCR assays for cfDNA detection without DNA extraction in exercising SLE patients.

Circulating cell-free DNA (cfDNA) has been investigated as a screening tool for many diseases. To avoid expensive and time-consuming DNA isolation, direct quantification PCR assays can be established. However, rigorous validation is required to provide reliable data in the clinical and non-clinical context. Considering the International Organization for Standardization, as well as bioanalytical method validation guidelines, we provide a comprehensive procedure to validate assays for cfDNA quantification from blood plasma without DNA isolation. A 90 and 222 bp assay was validated to study the kinetics of cfDNA after exercise in patients with systemic lupus erythematosus (SLE). The assays showed ultra-low limit of quantification (LOQ) with 0.47 and 0.69 ng/ml, repeatability ≤ 11.6% (95% CI 8.1-20.3), and intermediate precision ≤ 12.1% (95% CI 9.2-17.7). Incurred sample reanalysis confirmed the precision of the procedure. The additional consideration of pre-analytical factors shows that centrifugation speed and temperature do not change cfDNA concentrations. In SLE patients cfDNA increases ~ twofold after a walking exercise, normalizing after 60 min of rest. The established assays allow reliable and cost-efficient quantification of cfDNA in minute amounts of plasma in the clinical setting. Additionally, the assay can be used as a tool to determine the impact of pre-analytical factors and validate cfDNA quantity and quality of isolated samples.

COVID-19-Importance for Patients on the Waiting List and after Kidney Transplantation-A Single Center Evaluation in 2020-2021.

(1) Background: Dialysis patients and recipients of a kidney allograft are at high risk for infection with SARS-CoV-2. It has been shown that the development of potent neutralizing humoral immunity against SARS CoV-2 leads to an increased probability of survival. However, the question of whether immunocompromised patients develop antibodies has not yet been sufficiently investigated; (2) Methods: SARS-CoV-2 antibodies were examined in hemodialysis patients on the waiting list for kidney transplantation as well as patients after kidney transplantation. Patients were interviewed about symptoms and comorbidities, BMI, and smoking history; (3) Results: SARS-CoV-2 antibodies were found in 16 out of 259 patients (6%). The trend of infections here reflects the general course of infection in Germany with a peak in November/December of 2020. Remarkably, patients on the waiting list experienced only mild disease. In contrast, transplanted patients had to be hospitalized but recovered rapidly from COVID-19. Most interesting is that all immunosuppressed patients developed antibodies against SARS-CoV-2 after infection; (4) Conclusions: Even with extensive hygiene concepts, an above-average number of patients were infected with SARS-CoV-2 during the second wave of infections in Germany. Because SARS-CoV-2 infection triggered the formation of antibodies even in these immunocompromised patients, we expect vaccination to be effective in this group of patients. Thus, dialysis patients and patients after kidney transplantation should be given high priority in vaccination programs.

Vascular Inflammation and Dysfunction in Lupus-Prone Mice-IL-6 as Mediator of Disease Initiation.

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease and patients are under an increased risk for cardiovascular (CV) events and mortality. The increased CV risk for patients with SLE seems to be caused by a premature and accelerated atherosclerosis, attributable to lupus-specific risk factors (i.e., increased systemic inflammation, altered immune status), apart from traditional CV risk factors. To date, there is no established experimental model to explore the pathogenesis of this increased CV risk in SLE patients. METHODS: Here we investigated whether MRL-Faslpr mice, which develop an SLE-like phenotype, may serve as a model to study lupus-mediated vascular disease. Therefore, MRL-Faslpr, MRL-++, and previously generated Il6-/- MRL-Faslpr mice were used to evaluate vascular changes and possible mechanisms of vascular dysfunction and damage. RESULTS: Contrary to MRL-++ control mice, lupus-prone MRL-Faslpr mice exhibited a pronounced vascular and perivascular leukocytic infiltration in various organs; expression of pro-inflammatory cytokines in the aorta and kidney was augmented; and intima-media thickness of the aorta was increased. IL-6 deficiency reversed these changes and restored aortic relaxation. CONCLUSION: Our findings demonstrate that the MRL-Faslpr mouse model is an excellent tool to investigate vascular damage in SLE mice. Moreover, IL-6 promotes vascular inflammation and damage and could potentially be a therapeutic target for the treatment of accelerated arteriosclerosis in SLE.

Twelve-Week Internet-Based Individualized Exercise Program in Adults With Systemic Lupus Erythematosus: Protocol for a Randomized Controlled Trial.

BACKGROUND: Systemic lupus erythematosus is a systemic autoimmune disease, which is associated with high cardiovascular risk, a predisposition to metabolic disorders, muscle wasting, and fatigue. Exercise therapy has become an important part of the long-term treatment of comorbidities in systemic lupus erythematosus. Exercise can lead to various benefits in patients with systemic lupus erythematosus such as increased aerobic capacity and exercise tolerance, resulting in an increased quality of life, decreased depression, and decreased fatigue. At the moment, no evidence-based treatment guidelines that recommend exercise for patients with systemic lupus erythematosus exist. Also, the efficacy of different training programs requires further investigation. OBJECTIVE: This study focuses on the feasibility, efficacy, and safety of an internet-based exercise program in patients with systemic lupus erythematosus. Furthermore, we investigate the feasibility and efficiency of anaerobic training compared to aerobic training. METHODS: Overall, patients with systemic lupus erythematosus from the Division of Nephrology, Rheumatology, and Immunology outpatient clinic of the University Medical Center Mainz who are clinically stable status are included and randomized in an aerobic exercise group (n=10), anaerobic exercise group (n=10), or treatment as usual group (n=10). After completing initial clinical testing and physical fitness tests, patients undergo supervised 12-week online exercise programs, receiving weekly individualized training plans adapted to their physical performance. The primary outcome is change in physical fitness (VO2 peak) after 12 weeks compared to baseline. Secondary outcomes are disease activity measured via laboratory results (complement, autoantibodies) and questionnaires, as well as changes in muscle mass (anaerobic exercise group), results of the Chair-Stand test, and measurements of circulating cell-free DNA and extracellular vesicles. RESULTS: The study was registered in May 2019. Enrollment began in May 2019. Of 40 patients who were initially screened, 30 patients fulfilled the inclusion criteria and were included in the study; 1 participant withdrew prior to the start of the exercise program. Among the 25 patients who completed the study, no serious adverse events have been reported; 3 participants withdrew during the program (due to frequent colds, n=1; Crohn relapse, n=1; physical strain, n=1), and 1 participant has not yet completed the program. Data analysis is ongoing, and results are expected to be submitted for publication in January 2021. CONCLUSIONS: We expect the online exercise intervention to be a feasible and efficient tool to provide regular individualized exercise for patients with systemic lupus erythematosus. TRIAL REGISTRATION: ClinicalTrials.gov NCT03942718; http://clinicaltrials.gov/ct2/show/NCT03942718. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/18291.

Treatment of Membranous Nephropathy in Patients With THSD7A Antibodies Using Immunoadsorption.

Antibodies against THSD7A (thrombospondin type 1 domain-containing protein 7A) have been proposed to play a causal role in the development of nephrotic syndrome in patients with THSD7A antibody-positive membranous nephropathy. We hypothesized that removal of these antibodies from plasma could lead to a rapid reduction in proteinuria. Using immunoadsorption to reduce THSD7A antibodies led to a rapid reduction in proteinuria in 2 patients with THSD7A antibody-positive membranous nephropathy. Moreover, our findings support and strengthen the pathogenic role of the antibodies in the development of nephrotic syndrome in patients with THSD7A antibody-positive membranous nephropathy. Taken together, these 2 cases suggest that immunoadsorption could be a useful tool in the treatment of patients with THSD7A antibody-positive membranous nephropathy.

Fatigue in SLE: diagnostic and pathogenic impact of anti-N-methyl-D-aspartate receptor (NMDAR) autoantibodies.

OBJECTIVES: We explored the impact of circulating anti-N-methyl-D-aspartate receptor (NMDAR) antibodies on the severity of fatigue in patients with systemic lupus erythematosus (SLE). METHODS: Serum samples of 426 patients with SLE were analysed for the presence of antibodies to the NR2 subunit of the NMDAR. In parallel, the severity of fatigue was determined according to the Fatigue Scale for Motor and Cognitive functions questionnaire. In a subgroup of patients with SLE, the hippocampal volume was correlated with the levels of anti-NR2 antibodies. Isolated immunoglobulin G from patients with anti-NR2 antibodies were used for murine immunohistochemical experiments and functional assays on neuronal cell lines. Treatment effects were studied in 86 patients with lupus under belimumab therapy. RESULTS: We found a close correlation between the titre of anti-NR2 antibodies, the severity of fatigue, the clinical disease activity index (Systemic Lupus Erythematosus Disease Activity Index 2000) and anti-double stranded DNA antibodies-independently of the presence of neuropsychiatric lupus manifestations. Pathogenic effects could be demonstrated by (1) detection of anti-NR2 antibodies in the cerebrospinal fluid, (2) in situ binding of anti-NR2 antibodies to NMDAR of the hippocampus area and (3) distinct functional effects in vitro: downregulating the energy metabolism of neuronal cells without enhanced cytotoxicity. Treatment with belimumab for at least 6 months affected both the severity of fatigue and the levels of anti-NR2 antibodies. CONCLUSION: The presence of anti-NR2 antibodies in patients with SLE with fatigue is a helpful diagnostic tool and may offer a major approach in the therapeutic management of this important disabling symptom in patients with SLE.