Riding the Omicron BA.5 Wave: Improved Humoral Response after Vaccination with Bivalent Omicron BA.4-5-Adapted mRNA SARS-CoV-2 Vaccine in Chronic Hemodialysis Patients.

Hemodialysis patients faced an excess morbidity and mortality during the COVID-19 pandemic. We evaluated the effect of second-generation mRNA vaccines against Omicron BA.4 and BA.5 variants of SARS-CoV-2 on humoral immunity. The study population comprised 66 adult hemodialysis patients who have encountered four SARS-CoV-2 antigen contacts through vaccination or infection. We assessed their humoral response using an anti-SARS-CoV-2 spike receptor binding domain IgG antibody assay (S-RBD-ab), measuring neutralizing antibodies against ancestral strain of SARS-CoV-2, Delta, and Omicron in a surrogate virus neutralization test (SVNT), and specifically against BA.5 in a plaque reduction neutralization test (PRNT) before and four weeks after vaccination with Comirnaty Original/Omicron BA.4-5. During the following six months, SARS-CoV-2 infections and symptom severity were documented. The bivalent mRNA vaccine led to a 7.6-fold increase in S-RBD-ab levels and an augmented inhibition of the Omicron variant in SVNT by 35% (median). Seroconversion in the Omicron BA.5-specific PRNT was attained by in 78.4% of previously negative patients (29/37). Levels of S-RBD-ab correlated with inhibition in the Omicron-specific SVNT and neutralization titers in the BA.5-PRNT. Eleven SARS-CoV-2 infections occurred in the six-month follow-up, none of which took a life-threatening course. The bivalent mRNA vaccine improved the SARS-CoV-2 virus variant-specific humoral immunity in chronic hemodialysis patients. Measurement of S-RBD-ab can be used in hemodialysis patients to estimate their humoral immunity status against Omicron BA.5.

Renal disease in sarcoidosis patients in a German multicentric retrospective cohort study.

INTRODUCTION: Sarcoidosis is a systemic granulomatous disease potentially affecting every organ system. Renal involvement is reportedly rare, and the evidence consists of case reports and cohort studies. Systematic investigations are scarce and show a varying prevalence ranging from <1% to 30-50%. METHODS: We retrospectively analyzed data from patients with a recent diagnosis of sarcoidosis from five tertiary care centers focusing on renal sarcoidosis. RESULTS: We analyzed data from 327 patients with sarcoidosis between 2001 and 2021. Of 327 patients, 109 (33.3%) had probable or definite renal sarcoidosis. 90 (27.5%) had histopathologic confirmation. 57 (64%) had an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2. The most prominent associated finding was an elevated soluble interleukin-2 receptor. Patients with renal sarcoidosis more frequently received glucocorticoids than other non-renal sarcoidosis patients (92% vs. 78%, p < 0.01). Also, azathioprine (38% vs. 16%, p < 0.001) and mycophenolate mofetil (5% vs. 1%, p < 0.05) were more frequently used in renal sarcoidosis compared to non-renal sarcoidosis, whereas methotrexate was used less frequently (7% vs. 17%, p < 0.05). CONCLUSIONS: Our data of the largest cohort with biopsy-confirmed renal sarcoidosis demonstrate a higher prevalence (27.5% of all patients) than previously published with a relevant disease burden. The urinary findings in most cases were only mildly abnormal, and some patients did not have renal biopsy despite abnormal urinary results. A renal workup should be performed in all patients with a new diagnosis of sarcoidosis.

[Nomenclature for kidney function and kidney diseases - Improving assessment and prognosis through precision and comprehensibility]. / Nomenklatur für Nierenfunktion und Nierenkrankheiten ­ Durch Präzision und Verständlichkeit zu besserer Erfassung und Prognose.

Kidney disease represents an increasing global health problem. Its mitigation requires effective communication between all stakeholders involved in assessment, diagnosis and therapy and individuals affected by kidney disease. However, as of today the nomenclature for kidney function and kidney disease is far from uniform. In 2019, the international non-profit organization Kidney Disease: Improving Global Outcomes (KDIGO) has implemented a consensus process to develop a glossary in English language to standardize the nomenclature for kidney function, kidney structure and kidney disease. Guiding principles for this process were (1) precision, (2) patient-centeredness and (3) consistency with KDIGO guidelines. The current position paper includes a translation of this nomenclature into German that was developed on behalf of the national societies for nephrology in Germany, Austria and Switzerland.

COVID-19 pandemic impairs medical care of vasculitis patients in Germany: Results of a national patient survey.

Objective: To analyze the impact of the COVID-19 pandemic on medical care and vaccination acceptance of vasculitis patients in Germany. Methods: A web-based national survey was developed by rheumatology centers and vasculitis patient advocacy groups. The survey was distributed nationwide by mail and flyers and could be accessed via a QR-code or weblink from December 2021 to April 2022. Descriptive statistics [mean, median, standard derivation (SD), 25%, 75% quantile] were calculated. 95% confidence intervals were presented for responses that were directly related to the impact of COVID-19 on parameters associated with vasculitis patient care. Results: The online survey was completed by 117 patients with small and large vessel vasculitis [granulomatosis with polyangiitis (n = 69), eosinophilic granulomatosis with polyangiitis (n = 16), microscopic polyangiitis (n = 12), giant cell arteritis (n = 17) and Takayasu's arteritis (n = 3)]. Prescheduled rheumatological appointments had been canceled due to the COVID-19 pandemic in 12.6% of the respondents [95% confidence interval (CI), 7.3-20.0%); in 9% (95% CI, 4.5-15.6%)] appointments had been replaced by digital services. Therapeutic regimens were changed (shifted, reduced, or discontinued) due to the pandemic in 15.5% (95% CI 9.5-22.2%). Vaccination coverages were generally high compared to patients with other rheumatic diseases and the general population. Highest vaccination coverage was observed against COVID-19 (98.1% 95% CI 93.9-99.6%). Conclusion: Vasculitis patients experienced changes in medical care during COVID-19 pandemic such as cancelation of prescheduled rheumatology appointments and modifications in therapeutic regimens. The overall acceptance rate for vaccination was comparatively high, particularly for vaccination against COVID-19.

[KDIGO 2021 guideline glomerulonephritis - focus on ANCA-associated vasculitides and anti-glomerular basement membrane glomerulonephritis]. / KDIGO-Leitlinien 2021 zur Glomerulonephritis ­ Focus ANCA-assoziierte Vaskulitiden und antiglomeruläre Basalmembran-Nephritis.

In 2021 new KDIGO (Kidney Disease: Improving Global Outcomes) guidelines for the management of glomerular diseases were published.For ANCA-associated glomerulonephritis the new recommendations comprise a more rapid steroid taper during induction treatment with cyclophosphamide or rituximab, the advice against routine use of plasma exchange, the choice of drug for and duration of maintenance treatment in accordance with predictors of relapse. A kidney transplant should be performed after at least 6 months of remission irrespective of the ANCA titer in ANCA-associated disease, and 6 months after absence of anti-GBM-antibodies in anti-GBM-disease.

The Joint Vasculitis Registry in German-speaking countries (GeVas) - a prospective, multicenter registry for the follow-up of long-term outcomes in vasculitis.

BACKGROUND: Vasculitides comprise a group of rare diseases which affect less than 5 in 10.000 individuals. Most types of vasculitis can become organ- and life-threatening and are characterized by chronicity, high morbidity and relapses, altogether resulting in significant morbidity and mortality. Previous studies have been either monocentric or mainly retrospective - studies with a prospective design mostly consisted of rather small cohorts of 100 to 200 patients. The aim of the Joint Vasculitis Registry in German-speaking countries (GeVas) is to record all patients who have been recently diagnosed with vasculitis or who have changed their treatment due to a relapse (inception cohort). In GeVas, data are collected prospectively in a multicenter design in Germany, Austria and Switzerland. By this approach, courses of vasculitis and their outcomes can be monitored over an extended period. METHODS: GeVas is a prospective, web-based, multicenter, clinician-driven registry for the documentation of organ manifestations, damage, long-term progress and other outcomes of various types of vasculitis. The registry started recruiting in June 2019. As of October 2020, 14 centers have been initiated and started recruiting patients in Germany. Involvement of sites in Austria and the German-speaking counties of Switzerland is scheduled in the near future. DISCUSSION: In June 2019, we successfully established a prospective multicenter vasculitis registry being the first of its kind in German-speaking countries. The participating centers are currently recruiting, and systematic analysis of long-term vasculitis outcomes is expected in the ensuing period. TRIAL REGISTRATION: German Clinical Trials Register (Deutsches Register Klinischer Studien): DRKS00011866 . Registered 10 May 2019.

[Anti B-cell-antibody treatment for maintenance of remission in granulomatosis with polyangiitis and microscopic polyangiitis]. / Anti-B-Zell-Antikörpertherapie zur Remissionserhaltung bei Granulomatose mit Polyangiitis und mikroskopischer Polyangiitis.

Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are the most frequent primary necrotizing small vessel vasculitides. In these formerly fatal diseases remission can be induced by stage- and activity-adapted immunosuppressive regimens in the majority of patients. This does not lead to drug-free long-term remission or even cure. Consequently, maintenance of remission medication is needed. Recent randomized controlled trials demonstrated that maintenance treatment with the anti-B-cell antibody Rituximab, administered 6-monthly as opposed to azathioprine leads to a significantly lower relapse rate but a similar profile of adverse events. These data enabled the extension of the approval of Rituximab for maintenance of remission treatment of GPA and MPA in Germany in 2018. Guidelines and expert recommendations concerning measures of infection prevention and vaccination of immunosuppressed patients as well as the management of hypogammaglobulinemia and cytopenia on Rituximab are presented in this review.

Higher levels of SDMA and not ADMA are associated with poorer survival of trial patients with systemic ANCA-associated vasculitis.

OBJECTIVE: Endothelial dysfunction, increased cardiovascular events (CVE), and accelerated atherosclerosis have been described in patients with small vessel vasculitis and collagen vascular disease. Identifying predictors of cardiovascular risk will help to optimize short- and long-term care of patients with vasculitis. The present study investigates the predictive role of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) and its stereoisomer symmetric dimethylarginine (SDMA) for cardiovascular risk, all-cause mortality, and renal function in patients with anti-neutrophil-cytoplasmic antibodies-associated small vessel vasculitis (AASV) subjected to standardized treatment regimens in four European Vasculitis Study Group trials representing all stages of renal disease. METHODS: Sera from 89 patients with AASV were available for measuring SDMA, ADMA, and arginine using liquid chromatography/mass spectrometry at the time of active disease and remission. Clinical data on disease activity, remission, relapse rate, and 5-year follow-up data for CVE and renal outcome were collected. RESULTS: Symmetric dimethylarginine and ADMA levels were not predictive of CVE at 5 years of follow-up. The overall CVE rate was low in the present cohort of AASV (8%). However, SDMA, and not ADMA, levels were significantly associated with poorer survival (death/ESRD) independent of entry glomerular filtration rate. CONCLUSION: This novel outcome in a well-defined group of patients with AASV might indicate a different mechanism of endothelial response in AASV as compared with atherosclerosis. This should be further explored in a larger cohort of AASV patients with a higher CVE rate and/or a longer follow-up. Moreover, these findings should be correlated to other markers of vascular damage.

[A rare manifestation of an inflammatory rheumatic systemic disease]. / Eine seltene Manifestation einer entzündlich rheumatischen Systemerkrankung.

Granulomatosis with polyangiitis (GPA) is an ANCA(anti-neutrophil cytoplasmatic antibody)-associated small vessel vasculitis usually affecting the respiratory tract and the kidneys. This article reports on a 46-year-old male patient with a rare organ manifestation pattern of GPA: besides a fulminantly progressive tetraparesis the patient suffered from severe ulcerative colitis. The early diagnosis of GPA with unusual findings and its delineation from a septic event is essential.

Treatment of ANCA-associated vasculitis.

Antineutrophil cytoplasmic autoantibody (ANCA)-associated diseases are small-vessel vasculitides, encompassing granulomatosis with polyangiitis (formerly Wegener's granulomatosis), microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis. Once considered life-threatening diseases, the introduction of stage-adapted immunosuppressive therapy and medications with decreased toxicity has improved patients' survival. Treatment is biphasic, consisting of induction of remission (3-6 months) for rapid control of disease activity and maintenance of remission (at least 18 months) to prevent disease relapse using therapeutic alternatives that have reduced toxicity. This Review summarizes current treatment strategies for these diseases, with a special focus on long-term follow-up data from key randomized controlled trials and new developments in remission induction and maintenance therapy. Current treatment strategies have substantial short-term and long-term adverse effects, and relapses are frequent; thus, less-toxic and more-effective approaches are needed. Moreover, the optimal intensity and duration of maintenance therapy remains under debate. Clinical trials have traditionally considered ANCA-associated vasculitides as a single disease entity. However, future studies must stratify participants according to their specific disease, clinical features (different types of organ manifestation, PR3-ANCA or MPO-ANCA positivity) and disease severity.

Renal disease in small-vessel vasculitis.

Glomerulonephritis (GN) is a common manifestation of the antineutrophil cytoplasmic antibody-associated systemic vasculitides (AASV), which include granulomatosis with polyangiitis and microscopic polyangiitis. The level of renal involvement at presentation is highly predictive of survival and should be assessed early so that kidney function can be preserved. AASV patients with urinary sediment but normal function have a twofold greater risk of death than those with no renal involvement. Those with impaired renal function at diagnosis have a fivefold greater risk of death. Renal vasculitis is most prevalent in older patients, who have more severe disease and poorer prognoses. Renal biopsy not only establishes diagnosis but provides information on severity of renal-function impairment and prognosis. Induction of remission with cyclophosphamide is standard treatment. For patients with crescentic, rapidly progressive GN, adjunctive plasma exchange can promote renal recovery. Renal failure occurs in one-fourth of AASV patients after 3 to 4 years; 60% of patients receiving dialysis for acute GN can recover independent renal function. Renal transplant patients with vasculitis fare as well as renal transplant patients without vasculitis. Lastly, renal vasculitis is an independent risk factor for cardiovascular events.

Brief Report: long-term outcome of a randomized clinical trial comparing methotrexate to cyclophosphamide for remission induction in early systemic antineutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVE: The NORAM (Nonrenal Wegener's Granulomatosis Treated Alternatively with Methotrexate [MTX]) trial demonstrated that MTX can replace cyclophosphamide (CYC) as remission-inducing treatment for patients with newly diagnosed early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Duration of relapse-free survival was longer among CYC-treated patients than among MTX-treated patients during short-term followup. The aim of the present study was to describe the long-term outcome in patients enrolled in the randomized clinical trial. METHODS: Outcome questionnaires were sent to investigators who had recruited patients for the NORAM trial. Patients treated with MTX for induction of remission (n = 49) were compared to CYC-treated patients (n = 46) with respect to immunosuppressive therapy during followup, relapse-free survival, mortality, and occurrence of other clinical events. RESULTS: The median duration of followup was 6 years (range 0.1-10.8 years). One patient developed end-stage renal disease, and 11 died. The number of patients affected by serious infection, malignancy, or severe organ failure did not differ between treatment groups, and no difference in survival rate was observed. The duration of corticosteroid therapy was longer in the MTX group during the 18 months of the trial (P = 0.005). During subsequent followup, patients who were in the MTX group in the NORAM trial received corticosteroids, CYC, and other immunosuppressive agents (azathioprine, MTX, and/or mycophenolate mofetil) for longer periods than those who were in the CYC group (P = 0.004, P = 0.037, and P = 0.031, respectively). The cumulative relapse-free survival tended to be lower in the MTX group (P = 0.056). CONCLUSION: In the NORAM cohort, no difference in occurrence of major adverse events was observed between treatment groups during long-term followup. However, first-line treatment with MTX was associated with less effective disease control than CYC-based induction therapy.

Pulse versus daily oral cyclophosphamide for induction of remission in ANCA-associated vasculitis: long-term follow-up.

INTRODUCTION: The previously reported randomised controlled trial of a consensus regimen of pulse cyclophosphamide suggested that it was as effective as a daily oral (DO) cyclophosphamide for remission induction of antineutrophil cytoplasm autoantibodies-associated systemic vasculitis when both were combined with the same glucocorticoid protocol (CYCLOPS study (Randomised trial of daily oral versus pulse Cyclophosphamide as therapy for ANCA-associated Systemic Vasculitis published de groot K, harper L et al Ann Int Med 2009)). The study had limited power to detect a difference in relapse. This study describes the long-term outcomes of patients in the CYCLOPS study. METHODS: Long-term outcomes were ascertained retrospectively from 148 patients previously recruited to the CYCLOPS Trial. Data on survival, relapse, immunosuppressive treatment, cancer incidence, bone fractures, thromboembolic disease and cardiovascular morbidity were collected from physician records retrospectively. All patients were analysed according to the group to which they were randomised. RESULTS: Median duration of follow-up was 4.3 years (IQR, 2.95-5.44 years). There was no difference in survival between the two limbs (p=0.92). Fifteen (20.8%) DO and 30 (39.5%) pulse patients had at least one relapse. The risk of relapse was significantly lower in the DO limb than the pulse limb (HR=0.50, 95% CI 0.26 to 0.93; p=0.029). Despite the increased risk of relapse in pulse-treated patients, there was no difference in renal function at study end (p=0.82). There were no differences in adverse events between the treatment limbs. DISCUSSION: Pulse cyclophosphamide is associated with a higher relapse risk than DO cyclophosphamide. However, this is not associated with increased mortality or long-term morbidity. Although the study was retrospective, data was returned in 90% of patients from the original trial.

TLR-4+ peripheral blood monocytes and cardiovascular events in patients with chronic kidney disease--a prospective follow-up study.

BACKGROUND: Atherosclerosis is an inflammatory process mediated by circulating immune cells, including monocytes. There is accumulating evidence for the involvement of Toll-like receptor 4 (TLR-4) as a mediator of atherogenesis. METHODS: We evaluated the association between CD14+/TLR-4+ monocytes in peripheral blood (flow cytometry) and future cardiovascular events (CVE), e.g. myocardial infarction, percutaneous transluminal coronary angioplasty (including stenting), aortocoronary bypass, stroke and angiographically verified stenosis of peripheral arteries and cardiovascular (CV) death, in 191 patients with chronic kidney disease Stage V receiving hemodialysis therapy. RESULTS: At baseline, CD14+/TLR-4+ monocytes correlated significantly with age (r = 0.2; P = 0.007), high-sensitivity C-reactive protein (r = 0.2; P = 0.008) and mean arterial pressure (r = -0.2; P = 0.02), but not with gender (P = 0.5), smoking (P = 0.6) and the presence of diabetes (P = 0.5). During a median follow-up period of 36 [1-54] months, 79 (41%) patients experienced a CVE. A total of 55 patients died during the follow-up period, 25 of those due to a confirmed CV cause. Log-rank test did not reveal statistical significance for TLR-4+ monocytes concerning incident CVE (P = 0.3), CV death (P = 0.85) and overall death (P = 0.8). In a multiple Cox-regression analysis, we identified age (P = 0.003) and smoking (P = 0.001) as the only independent variables associated with incident CVE. CONCLUSIONS: Unexpectedly, we could not detect an association between CD14+/TLR-4+ monocytes and incident CVE as well as CV death in stable hemodialysis patients. Further studies have to clarify the potential role of this cell population for CV outcome in this population.