[Therapeutic antibodies in rheumatology]. / Therapeutische Antikörper in der Rheumatologie.

Emil von Behring's serum therapy for diphtheria was the first therapeutic use of antibodies. More than 100 years later, a new era in the treatment of rheumatic diseases began in 1998 with the approval of infliximab, an antibody directed against tumor necrosis factor alpha (TNF alpha). The special feature of antibody therapy is the ability to bind and neutralize antigens in a highly specific manner. In addition, target cells can be eliminated by activation of the immune system. These properties of the immune system are exploited in rheumatology to eliminate inflammatory cytokines or antibody-producing B lymphocytes. The tolerability is usually good but potential side effects, such as reactivation of tuberculosis with anti-TNF alpha treatment must be considered. Currently, 20 different antibodies and fusion proteins have been approved in Germany for the treatment of various inflammatory rheumatic diseases. Biosimilars can contribute to a price reduction after the patent protection expires. Many additional target antigens are being investigated and further structural innovations (e.g., bispecific antibodies, nanobodies or coupling with small molecules) are being developed.

Improvement of humoral immunity by repeated dose-intensified COVID-19 vaccinations in primary non- to low-responders and B cell deficient rheumatic disease patients.

OBJECTIVE: To determine whether repeated, dose-intensified mRNA vaccinations against COVID-19 increase humoral immunity in previously low-responding patients with autoimmune rheumatic diseases (AIRD), including rituximab-treated and B cell depleted patients. METHODS: Of 308 AIRD patients receiving basic immunization, 98 had a low serological response against SARS-CoV-2 with a neutralizing capacity of < 70% using surrogate neutralization assay. 38 patients received a third vaccination with 30 µg BNT162b2 16 weeks after second vaccination. If neutralizing serum capacity was below 70% four weeks after the last vaccination, then the fourth vaccination (n = 19) and the fifth (n = 4) vaccination with 100 µg mRNA-1273 took place eight weeks after the last vaccination. RESULTS: Each of the three booster vaccinations resulted in a significant increase of mean serum neutralizing capacity (3rd: Δ = 42%, p < 0.001; 4th: Δ = 19%, p = 0.049 and 5th: Δ = 51%, p = 0.043) and produced a significant proportion of high-responders (3rd: 34%; 4th: 32% and 5th: 75%). Low B cell counts (p = 0.047), lower previous antibody response (p < 0.001) and rituximab therapy (p = 0.021) were negatively associated with successful response to the third but not to the fourth vaccination. Remarkably, substantial increases in neutralization capacity of up to 99% were observed after repeated vaccinations in B cell depleted patients. CONCLUSION: AIRD patients with low humoral response benefited from up to three repeated dose-intensified mRNA booster vaccinations - despite low B cell count and previous rituximab therapy. Each additional vaccination substantially reduced the number of low-responding, vulnerable patients.

Pausing methotrexate improves immunogenicity of COVID-19 vaccination in elderly patients with rheumatic diseases.

OBJECTIVE: To study the effect of methotrexate (MTX) and its discontinuation on the humoral immune response after COVID-19 vaccination in patients with autoimmune rheumatic diseases (AIRD). METHODS: In this retrospective study, neutralising SARS-CoV-2 antibodies were measured after second vaccination in 64 patients with AIRD on MTX therapy, 31 of whom temporarily paused medication without a fixed regimen. The control group consisted of 21 patients with AIRD without immunosuppressive medication. RESULTS: Patients on MTX showed a significantly lower mean antibody response compared with patients with AIRD without immunosuppressive therapy (71.8% vs 92.4%, p<0.001). For patients taking MTX, age correlated negatively with immune response (r=-0.49; p<0.001). All nine patients with antibody levels below the cut-off were older than 60 years. Patients who held MTX during at least one vaccination showed significantly higher mean neutralising antibody levels after second vaccination, compared with patients who continued MTX therapy during both vaccinations (83.1% vs 61.2%, p=0.001). This effect was particularly pronounced in patients older than 60 years (80.8% vs 51.9%, p=0.001). The impact of the time period after vaccination was greater than of the time before vaccination with the critical cut-off being 10 days. CONCLUSION: MTX reduces the immunogenicity of SARS-CoV-2 vaccination in an age-dependent manner. Our data further suggest that holding MTX for at least 10 days after vaccination significantly improves the antibody response in patients over 60 years of age.

Safety, pharmacokinetics and pharmacodynamics of single rising doses of BI 655064, an antagonistic anti-CD40 antibody in healthy subjects: a potential novel treatment for autoimmune diseases.

PURPOSE: The CD40-CD40L pathway is a promising treatment target for autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and lupus nephritis. The safety, pharmacokinetics and pharmacodynamics of BI 655064, a novel humanised antagonistic anti-CD40 monoclonal antibody, were investigated in this first-in-human trial. METHODS: Healthy male subjects (n = 72) were randomised 3:1, within each BI 655064 dose group, to single intravenous (IV; 0.2-120 mg) or subcutaneous (SC; 40-120 mg) doses of BI 655064 or placebo. Safety, plasma exposure, CD40 receptor occupancy and CD40L-induced CD54 upregulation were assessed over 12 weeks. RESULTS: Adverse events (AEs) were reported in 43% of subjects (n = 31). Frequency and intensity of AEs were generally similar between BI 655064 and placebo and showed no dose relationship. The most frequent AEs were headache and nasopharyngitis. One mild rash and one local reaction occurred with SC BI 655064; two serious AEs were reported, both judged unrelated to BI 655064. Pharmacokinetic evaluation demonstrated a more than proportional increase in plasma exposure relative to BI 655064 dose, with a terminal half-life between 4 h and 4 days IV and approximately 5 days SC; doses ≥ 20 mg IV and 120 mg SC showed > 90% CD40 receptor occupancy and inhibition of CD54 upregulation, which lasted 7 days in the 120 mg IV and SC groups. CONCLUSIONS: Single doses up to 120 mg BI 655064 IV and SC were well tolerated and showed a high potential to block the CD40-CD40L pathway, supporting further clinical development of BI 655064 in patients with autoimmune disease. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01510782.

Complete early reversal of diffusion-weighted imaging hyperintensities after ischemic stroke is mainly limited to small embolic lesions.

BACKGROUND AND PURPOSE: Case reports have demonstrated complete early reversal of hyperintensities on diffusion-weighted imaging (DWI) after clinically diagnosed stroke. We aimed to investigate systematically the rate and characteristics of reversible diffusion hyperintensities (RDHs) in the first week after stroke. METHODS: Patients with clinical diagnosis of an acute cerebrovascular event and evidence of ischemia on DWI were included. MRI scans were performed on admission, on the following day, and 4 to 7 days after onset of symptoms with DWI and fluid-attenuated inversion recovery. Baseline and follow-up DWIs were coregistered and examined for individual RDHs. Characteristics of patients and of hyperintensities associated with early reversal were identified. RESULTS: We included 153 patients with a median National Institutes of Health Stroke Scale score of 4 (interquartile range, 2-8). In 3 patients (2%), MR images normalized completely. Thirty-seven patients (24%) displayed individual RDHs. Of 611 initial DWI hyperintensities, 97 (16%) reversed. Thirteen percent of the RDHs had corresponding abnormalities on fluid-attenuated inversion recovery images at the third measurement. Median size of the RDHs was 0.029 mL (interquartile range, 0.013-0.055). RDHs were associated with a multiple infarct pattern (odds ratio, 22.1; 95% confidence interval, 4.5-109.7) and symptomatic carotid stenosis (odds ratio, 5.5; 95% confidence interval, 1.4-21.5). Fifty-nine percent of the patients with RDHs had new additional lesions on follow-up DWI. RDHs were not associated with functional improvement on the National Institutes of Health Stroke Scale score. CONCLUSIONS: In this population of mainly minor to moderate stroke patients, complete normalization of MR images was rare. Complete reversal of individual DWI hyperintensities was limited to very small lesions and mostly occurred in embolic stroke patients. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00715533.

Early new diffusion-weighted imaging lesions appear more often in stroke patients with a multiple territory lesion pattern.

BACKGROUND AND PURPOSE: New diffusion-weighted imaging (DWI) lesions are common in patients with acute ischemic stroke. They are associated with an initial nonsingle lesion pattern. Previous studies have not analyzed this association in detail. We differentiated nonsingle lesions in 1 vascular supply territory only (scattered lesion pattern) from nonsingle lesions in ≥2 vascular supply territory (multiple territory lesion -pattern). METHODS: Patients with an acute ischemic stroke underwent 3 MRI (3T) examinations: on admission, on the following day, and 4 to 7 days after symptom onset. First, DWI lesions were delineated manually by raters blinded to clinical details. Second, DWI images were coregistered and analyzed visually for new hyperintensities. The initial lesion pattern was categorized as single, scattered, or multiple territory. RESULTS: Of 340 patients enrolled, 43% had a single lesion pattern, 40% had a scattered lesion pattern, and 17% had a multiple territory lesion pattern. In multivariable analysis, the categorical variable lesion pattern was independently associated with new DWI lesions (odds ratio multiple territory lesion pattern, 3.64 [95% confidence interval, 1.75-7.58]; odds ratio scattered lesion pattern, 1.96 [95% confidence interval, 1.09-3.56]). Patients with multiple territory lesion pattern had significantly more often diabetes mellitus, and their new lesions were more often located remotely from the initial area of hypoperfusion compared with patients with scattered lesion pattern. CONCLUSION: Lesion pattern on initial image is an independent risk factor for new DWI lesions. The risk for new DWI lesions is highest in patients with multiple territory lesion pattern.

Incidence of new diffusion-weighted imaging lesions outside the area of initial hypoperfusion within 1 week after acute ischemic stroke.

BACKGROUND AND PURPOSE: New diffusion-weighted imaging (DWI) lesions are common in patients with acute ischemic stroke. The pathophysiology of these new lesions is unclear. We differentiated new DWI lesions outside the area of initial hypoperfusion from those confined to the area of initial hypoperfusion. METHODS: Patients with acute stroke underwent 3 MRI examinations: on admission, on the next day, and 4 to 7 days after symptom onset. Patients were included if a perfusion deficit was present on the initial scan. Lesions on DWI images were delineated manually. Coregistered DWI images were analyzed visually for new hyperintensities. In reference to the perfusion maps (mean transit time), patients were classified as having "outside lesions" if new DWI lesions were outside or both outside and inside the area of the initial perfusion deficit or "inside lesions" if new DWI lesions were completely inside. RESULTS: We enrolled 164 patients. Thirty-eight patients (23%) had outside lesions and 34 patients (21%) had inside lesions. In multivariable regression analysis, new outside lesions were significantly associated with symptomatic carotid stenosis, multiple index lesions pattern, and high low-density lipoprotein levels. New inside lesions were significantly associated with (spontaneous or thrombolytic) vessel recanalization, multiple index lesions pattern, and low low-density lipoprotein levels. CONCLUSIONS: Outside and inside lesions represent different pathophysiological entities. More specifically patients with outside lesions may have an increased risk for subsequent cerebrovascular events.

Silent new DWI lesions within the first week after stroke.

BACKGROUND: The rate of cerebral infarct recurrence is determined by clinical examination. Routine neurological examination is less sensitive than cerebral imaging in detecting new cerebral lesions. We aimed to determine the rate of new diffusion-weighted imaging (DWI) lesions at 2 time points after stroke and to identify factors associated with them. METHODS: Patients who were hospitalized with acute ischemic stroke underwent DWI at 3 time points (within 24, 48 and 144 h after stroke onset, respectively). Scans were made anonymous and reviewed in a random order. Lesions on DWI were delineated manually by blinded investigators. Then, coregistered DWI templates were analyzed for new ischemic lesions on the corresponding follow-up DWI. New lesions had to be separate and lesion growth was not considered. Univariate and multivariable logistic regression analyses were performed to define predictors of new DWI lesions. RESULTS: A total of 159 patients were enrolled in the study. Clinical stroke recurrence was detected in 2.5% of patients. A new cerebral lesion was detected in 5.7% of patients between first and second imaging (first interval) and 23.3% between second and third imaging (second interval). In univariate analyses, thrombolysis and multiple lesion pattern were associated with new lesions within the first interval. Ipsilateral carotid stenosis, multiple lesion pattern, vessel recanalization, atrial fibrillation, older age and higher NIHSS were associated with new lesions within the second interval. In multivariable analysis, ipsilateral carotid stenosis, recanalization and multiple lesion pattern remained independently associated with any new lesions. CONCLUSIONS: New DWI lesions occur more often than routine neurological examination suggests. Thrombolysis was associated with very early new DWI lesions within the first interval, ipsilateral carotid stenosis and spontaneous recanalization with new DWI lesions within the second interval.

Type of vaccine and immunosuppressive therapy but not diagnosis critically influence antibody response after COVID-19 vaccination in patients with rheumatic disease.

OBJECTIVE: The development of sufficient COVID-19 vaccines has been a big breakthrough in fighting the global SARS-CoV-2 pandemic. However, vaccination effectiveness can be reduced in patients with autoimmune rheumatic diseases (AIRD). The aim of this study was to identify factors that lead to a diminished humoral vaccination response in patients with AIRD. METHODS: Vaccination response was measured with a surrogate virus neutralisation test and by testing for antibodies directed against the receptor-binding-domain (RBD) of SARS-CoV-2 in 308 fully vaccinated patients with AIRD. In addition, 296 immunocompetent participants were investigated as a control group. Statistical adjusted analysis included covariates with a possible influence on antibody response. RESULTS: Patients with AIRD showed lower antibody responses compared with immunocompetent individuals (median neutralising capacity 90.8% vs 96.5%, p<0.001; median anti-RBD-IgG 5.6 S/CO vs 6.7 S/CO, p<0.001). Lower antibody response was significantly influenced by type of immunosuppressive therapy, but not by rheumatic diagnosis, with patients under rituximab therapy developing the lowest antibody levels. Patients receiving mycophenolate, methotrexate or janus kinase inhibitors also showed reduced vaccination responses. Additional negative influencing factors were vaccination with AZD1222, old age and shorter intervals between the first two vaccinations. CONCLUSION: Certain immunosuppressive therapies are associated with lower antibody responses after vaccination. Additional factors such as vaccine type, age and vaccination interval should be taken into account. We recommend antibody testing in at-risk patients with AIRD and emphasise the importance of booster vaccinations in these patients.