Bispecific T cell engager therapy for refractory rheumatoid arthritis.

Bispecific T cell engagers (BiTEs) kill B cells by engaging T cells. BiTEs are highly effective in acute lymphoblastic leukemia. Here we treated six patients with multidrug-resistant rheumatoid arthritis (RA) with the CD19xCD3 BiTE blinatumomab under compassionate use. Low doses of blinatumomab led to B cell depletion and concomitant decrease of T cells, documenting their engager function. Treatment was safe, with brief increase in body temperature and acute phase proteins during first infusion but no signs of clinically relevant cytokine-release syndrome. Blinatumomab led to a rapid decline in RA clinical disease activity in all patients, improved synovitis in ultrasound and FAPI-PET-CT and reduced autoantibodies. High-dimensional flow cytometry analysis of B cells documented an immune reset with depletion of activated memory B cells, which were replaced by nonclass-switched IgD-positive naïve B cells. Together, these data suggest the feasibility and potential for BiTEs to treat RA. This approach warrants further exploration on other B-cell-mediated autoimmune diseases.

Neutralizing monoclonal antibodies against SARS-CoV-2 for COVID-19 pneumonia in a rituximab treated patient with systemic sclerosis-A case report and literature review.

Patients with immune-mediated diseases (IMID) such as systemic sclerosis (SSc), who are treated with B cell depleting treatments, are at risk for developing severe COVID-19 due to inadequate humoral immune response. During B cell depletion, therapeutic substitution of neutralizing monoclonal antibodies against the SARS-CoV-2 spike protein (mAbs) might be helpful to prevent severe COVID-19. It has been shown, that in non-IMID patients mABs reduce SARS-CoV-2 viral load and lower the risk of COVID-19 associated hospitalization or death. However, there are limited data on the effect of mAbs in IMID patients after exposure, especially in patients treated with B cell depleting agents. Herein, we report a case of a rituximab treated SSc patient who developed COVID-19 and was successfully treated with a combination of mAbs (casirivimab/imdevimab). With this case we show that IMID patients may benefit from post-exposure administration of mAbs. In our case treatment with neutralizing autoantibodies was safe and a possible contributor in protecting the patient from mechanical ventilation and eventually death. We frame this case within the current evidence from the literature and provide a perspective on the future potential role of mAbs for treating IMID patients suffering from COVID-19.

Accuracy and usability of a diagnostic decision support system in the diagnosis of three representative rheumatic diseases: a randomized controlled trial among medical students.

BACKGROUND: An increasing number of diagnostic decision support systems (DDSS) exist to support patients and physicians in establishing the correct diagnosis as early as possible. However, little evidence exists that supports the effectiveness of these DDSS. The objectives were to compare the diagnostic accuracy of medical students, with and without the use of a DDSS, and the diagnostic accuracy of the DDSS system itself, regarding the typical rheumatic diseases and to analyze the user experience. METHODS: A total of 102 medical students were openly recruited from a university hospital and randomized (unblinded) to a control group (CG) and an intervention group (IG) that used a DDSS (Ada - Your Health Guide) to create an ordered diagnostic hypotheses list for three rheumatic case vignettes. Diagnostic accuracy, measured as the presence of the correct diagnosis first or at all on the hypothesis list, was the main outcome measure and evaluated for CG, IG, and DDSS. RESULTS: The correct diagnosis was ranked first (or was present at all) in CG, IG, and DDSS in 37% (40%), 47% (55%), and 29% (43%) for the first case; 87% (94%), 84% (100%), and 51% (98%) in the second case; and 35% (59%), 20% (51%), and 4% (51%) in the third case, respectively. No significant benefit of using the DDDS could be observed. In a substantial number of situations, the mean probabilities reported by the DDSS for incorrect diagnoses were actually higher than for correct diagnoses, and students accepted false DDSS diagnostic suggestions. DDSS symptom entry greatly varied and was often incomplete or false. No significant correlation between the number of symptoms extracted and diagnostic accuracy was seen. It took on average 7 min longer to solve a case using the DDSS. In IG, 61% of students compared to 90% in CG stated that they could imagine using the DDSS in their future clinical work life. CONCLUSIONS: The diagnostic accuracy of medical students was superior to the DDSS, and its usage did not significantly improve students' diagnostic accuracy. DDSS usage was time-consuming and may be misleading due to prompting wrong diagnoses and probabilities. TRIAL REGISTRATION: DRKS.de, DRKS00024433 . Retrospectively registered on February 5, 2021.

The value of 18F-FDG-PET/CT in identifying the cause of fever of unknown origin (FUO) and inflammation of unknown origin (IUO): data from a prospective study.

BACKGROUND: Fever of unknown origin (FUO) and inflammation of unknown origin (IUO) are diagnostically challenging conditions. Diagnosis of underlying disease may be improved by 18F-fluorodesoxyglucose positron emission tomography (18F-FDG-PET). METHODS: Prospective study to test diagnostic utility of 18F-FDG-PET/CT in a large cohort of patients with FUO or IUO and to define parameters that increase the likelihood of diagnostic 18F-FDG-PET/CT. Patients with FUO or IUO received 18F-FDG-PET/CT scanning in addition to standard diagnostic work-up. 18F-FDG-PET/CT results were classified as helpful or non-helpful in establishing final diagnosis. Binary logistic regression was used to identify clinical parameters associated with a diagnostic 18F-FDG-PET/CT. RESULTS: 240 patients were enrolled, 72 with FUO, 142 with IUO and 26 had FUO or IUO previously (exFUO/IUO). Diagnosis was established in 190 patients (79.2%). The leading diagnoses were adult-onset Still's disease (15.3%) in the FUO group, large vessel vasculitis (21.1%) and polymyalgia rheumatica (18.3%) in the IUO group and IgG4-related disease (15.4%) in the exFUO/IUO group. In 136 patients (56.7% of all patients and 71.6% of patients with a diagnosis), 18F-FDG-PET/CT was positive and helpful in finding the diagnosis. Predictive markers for a diagnostic 18F-FDG-PET/CT were age over 50 years (p=0.019), C-reactive protein (CRP) level over 30 mg/L (p=0.002) and absence of fever (p=0.001). CONCLUSION: 18F-FDG-PET/CT scanning is helpful in ascertaining the correct diagnosis in more than 50% of the cases presenting with FUO and IUO. Absence of intermittent fever, higher age and elevated CRP level increase the likelihood for a diagnostic 18F-FDG-PET/CT.

A Multiplex Kindred with Hennekam Syndrome due to Homozygosity for a CCBE1 Mutation that does not Prevent Protein Expression.

Collagen and calcium-binding EGF domain-containing protein 1 (CCBE1) bi-allelic mutations have been associated with syndromes of widespread congenital lymphatic dysplasia, including Hennekam Syndrome (HS). HS is characterized by lymphedema, lymphangiectasia, and intellectual disability. CCBE1 encodes a putative extracellular matrix protein but the HS-causing mutations have not been studied biochemically. We report two HS siblings, born to consanguineous parents of Turkish ancestry, whose clinical phenotype also includes protein losing enteropathy, painful relapsing chylous ascites, and hypogammaglobulinemia. We identified by whole exome and Sanger sequencing the homozygous CCBE1 C174Y mutation in both siblings. This mutation had been previously reported in another HS kindred from the Netherlands. In over-expression studies, we found increased intracellular expression of all forms (monomers, dimers, trimers) of the CCBE1 C174Y mutant protein, by Western blot, despite mutant mRNA levels similar to wild-type (WT). In addition, we detected increased secretion of the mutant CCBE1 protein by ELISA. We further found the mutant and WT proteins to be evenly distributed in the cytoplasm, by immunofluorescence and confocal microscopy. Finally, we found a strong decrease of lymphatic vessels, with a corresponding diminished expression of CCBE1, by immunohistochemistry of the patients' intestinal biopsies. In contrast, mucosal blood vessels and muscularis mucosae showed normal CCBE1 staining. Our findings show that the mutant CCBE1 C174Y protein is not loss-of-function by loss-of-expression.

In vivo detection of mucosal healing-involved histiocytes by confocal laser endomicroscopy.

Histiocytes have a pivotal role in wound repair and intestinal epithelial recovery - the most important goal to sustain gut functionality. Yet, an in vivo description of colonic histiocytes by confocal laser endomicroscopy (CLE) is missing. Here, we report the case of a 45-years-old male patient who was referred to our clinic with weight loss and a history of two consecutive Clostridium difficile colitis episodes, the latter cured 3 wk before present admission. Stool microbiology was negative. Conventional colonoscopy showed atrophy and a light mucosal oedema in the distal colon. During on-going endoscopy, we performed a fluorescein-aided CLE which revealed large polygonal (histiocytes-like) cells with copious cytoplasm and large nuclei in the lamina propria of the sigmoid colon as well as regenerative epithelial changes. Histopathological assessment of biopsies from the same areas confirmed the endomicroscopical findings: Periodic acid-Schiff- and CD68-positive foamy histiocytes in the colonic lamina propria and an advanced epithelial recovery. Since stool microbiology was repeatedly negative and polymerase chain reaction-analysis from colonic biopsies could not detect any mRNA for Thropheryma whippleii and common pathogens, we interpreted this particular setting as a mucosal healing process after consecutive Clostridium difficile infections. In conclusion, by describing these colonic histiocytes, we highlight the clinical usefulness of CLE in describing the entity of histiocytes in vivo and in real-time during the process of post-infectious mucosal healing in the colon.