ANCA vasculitis induction management during the COVID-19 pandemic

As the severe acute respiratory syndrome coronavirus 2 pandemic evolved and became a global health threat, the safety of immunosuppression in antineutrophil cytoplasmic antibody-associated vasculitis (AAV) became of utmost important for clinicians and patients. Although timely initiation of immunosuppressive therapy is critical to quell the acute inflammation and prevent AAV-associated mortality and morbidity, concerns for increased susceptibility to Coronavirus Disease 2019 (COVID-19), delayed viral clearance, and decreased humoral response to infection led to speculation about modification in induction therapy practices may be deployed by physicians caring for patients with AAV. This international retrospective cohort study investigated the influence of the COVID-19 pandemic on AAV induction therapy and patient outcomes in different parts of the world by studying differences in treatment regimens in the United States, United Kingdom, and Europe

Chemokine receptor co-expression reveals aberrantly distributed T-H effector memory cells in GPA patients

Linear regression analysis for percentages of CD4 + TEM cells, TEM1, and TEM17 cells between r-GPA patients and HCs. (PDF 208 kb

Mapping of Conformational Epitopes on Human Proteinase 3, the Autoantigen of Wegener's Granulomatosis

Anti-neutrophil cytoplasmic Abs (cANCAs) against conformational epitopes of proteinase 3 (PR3) are regarded as an important pathogenic marker in Wegener's granulomatosis (WG). Although the three-dimensional structure of PR3 is known, binding sites of mAbs and cANCAs have not been mapped to date. Competitive binding and biosensor experiments suggested the existence of four nonoverlapping areas on the PR3 surface. In this paper, we present an approach to identify these discontinuous surface regions that cannot be mimicked by linear peptides. The very few surface substitutions found in closely related PR3 homologs from primates, which were further varied by the construction of functional human-gibbon hybrids, resulted in the differential loss of three Ab binding sites, two of which were mapped to the N-terminal beta-barrel and one to the linker segment connecting the Nand C-terminal barrels of PR3. The sera from WG patients differed in their binding to gibbon PR3 and the gibbon-human PR3 hybrid, and could be divided into two groups with similar or significantly reduced binding to gibbon PR3. Binding of almost all sera to PR3-alpha 1-protease inhibitor (alpha 1-PI) complexes was even more reduced and often absent, indicating that major antigenic determinants overlap with the active site surface on PR3 that associates with alpha 1-PI. Similarly, the mouse mAbs CLB12.8 and 6A6 also did not react with gibbon PR3 and PR3-alpha 1-PI complexes. Our data strongly suggest that cANCAs from WG patients at least in part recognize similar surface structures as do mouse mAbs and compete with the binding of alpha 1-PI to PR3. The Journal of Immunology, 2010, 185: 387-399

Efficacy and safety of the long-acting C5 inhibitor ravulizumab in patients with atypical hemolytic uremic syndrome triggered by pregnancy: a subgroup analysis

Background: Atypical hemolytic uremic syndrome (aHUS) triggered by pregnancy is a rare disease caused by dysregulation of the alternative complement pathway that occurs in approximately 1 in 25,000 pregnancies. The 311 phase 3 trial (NCT02949128) showed that ravulizumab, a long-acting C5 inhibitor obtained through selective modifications to eculizumab, is efficacious in inhibiting complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS. In this analysis, we report outcomes in a subgroup of patients from the 311 study who developed TMA postpartum. Methods: This was a phase 3, multicenter trial evaluating efficacy and safety of ravulizumab in adults ( 6518 years of age) with aHUS na\uefve to complement inhibitor treatment. The primary endpoint was complete TMA response (simultaneous platelet count normalization [ 65150 7 109/L], lactate dehydrogenase normalization [ 64246 U/L] and 25% improvement in serum creatinine) through the 183-day initial evaluation period. Additional efficacy endpoints included time to complete TMA response, hematologic normalization, and dialysis requirement status. Results: Eight patients presenting with TMA postpartum (median age of 37.7 [range; 22.1\u201345.2] years) were diagnosed with aHUS and received 651 dose of ravulizumab. Five patients (63%) were on dialysis at baseline. Complete TMA response was achieved in 7/8 patients (87.5%) in a median time of 31.5 days. Hematologic normalization was observed in all patients. All patients on dialysis at baseline discontinued dialysis within 21 days after treatment with ravulizumab. All patients showed continued improvements in the estimated glomerular filtration rate from baseline to Day 183. Three possible treatment-related adverse events were observed in 2 patients (arthralgia and nasopharyngitis [both non-severe]; urinary tract infection). No deaths or meningococcal infections occurred. Conclusions: Treatment with ravulizumab provided immediate and complete C5 inhibition, resulting in rapid clinical and laboratory improvements and complete TMA response through 183 days in patients with aHUS triggered by pregnancy. The safety profile observed in this subset of patients analysed is consistent with the 311 study investigating ravulizumab in patients with aHUS na\uefve to complement treatment. Trial registration: Clinical trial identifier:NCT02949128

Correction to: Efficacy and safety of the long-acting C5 inhibitor ravulizumab in patients with atypical hemolytic uremic syndrome triggered by pregnancy: a subgroup analysis (BMC Nephrology, (2021), 22, 1, (5), 10.1186/s12882-020-02190-0)

An amendment to this paper has been published and can be accessed via the original article

CD4-Positive effector memory T cells participate in disease expression in ANCA-Associated vasculitis

Although the cause of ANCA-associated vasculitis (AAV) remains undetermined, the presence of lymphocytic infiltrates in inflammatory lesions of patients suggests that vascular damage is immune mediated. Studies over the past decade have implicated a role for T cells in the pathogenesis of AAV as altered T cell phenotype has been observed in this disorder. The distribution of T cell subpopulations has been analyzed most intensely in Wegener's granulomatosis (WG), where an expanded population of circulating CD4(+) effector memory T cells (CD4(+)T(EM)) was demonstrated. CD4(+)T(EM) cells play a major role in the pathogenesis of several autoimmune diseases. Specific suppression of CD4(+)T(EM) cells inhibits delayed-type hypersensitivity (DTH) and has therapeutic potential in autoimmune disease. Thus, CD4(+)T(EM) cells may act as inducers of tissue injury and participate in the development of AAV. Therapies that target CD4(+)T(EM), without impairing the activity of other lymphocyte subsets, may hold therapeutic promise for AAV.</p

Soluble CD26/CD30 levels in visceral leishmaniasis: markers of disease activity

Leishmania infantum is the causative agent of zoonotic visceral leishmaniasis (VL). If untreated the disease could be fatal; however, in some cases the infection can run a subclinical course. In subclinical infections a Th1-response predominates, while Th2-responses and/or probably Treg cells are related to unfavourable outcome of the disease in active VL. In the present study we determined the levels of soluble (s) CD26 and CD30 co-stimulatory molecules in sera from patients with active VL, asymptomatic individuals and healthy volunteers. Results showed a significant difference in both sCD26 and sCD30 between infected cases and normal individuals (P ≤ 0·001). However, there was no significant difference in sCD26 levels between asymptomatic cases and patients, although the difference was not significant. sCD30 levels were significantly higher in VL patients than asymptomatic cases (P ≤ 0·001). These findings suggest a possible association between sCD26 and sCD30 levels and the clinical manifestation of L. infantum infection