Induction of cross-reactive, mucosal anti-SARS-CoV-2 antibody responses in rheumatoid arthritis patients after 3rd dose of COVID-19 vaccination.

Systemic vaccination against SARS-CoV-2 elicited high titers of specific antibodies in the blood and in the oral cavity. Preexisting autoimmune diseases, such as rheumatoid arthritis, and biological treatments, like B cell depletion, are known to exhibit higher risk of severe COVID-19 manifestation and increased frequency of breakthrough infections after vaccination. We hypothesized that such increased risk is associated with an aberrant induction of secreted antibodies in the oral cavity. Here we evaluated the levels of secreted antibodies in the oral cavity against the SARS-CoV-2 Spike protein during the course of vaccination in RA patients with or without B cell depletion. We found that total salivary IgG levels were correlated with number of B cells in the blood. Anti-Spike IgG responses 7 days after second vaccination were induced in the oral cavity of all healthy individuals, while only 6 out 23 RA patients exhibited anti-Spike IgG in their saliva regardless of B cell depleting therapy. Importantly, both salivary and serologic anti-Spike IgG and IgA responses towards WT and omicron Spike variants were efficiently induced by third vaccination in RA patients with or without B cell depletion to the levels that were similar to healthy individuals. Altogether, these data advocate for the necessity of three dose vaccination for RA patients to mount anti-Spike antibody responses at the mucosal surfaces and annotate the reduction of secreted salivary IgG by B cell depletion.

[Lupus and thrombophilia : Antiphospholipid syndrome]. / Lupus und Thrombophilie : Antiphospholipidsyndrom.

Even early on thromboembolic events were observed in patients with systemic lupus erythematosus (SLE) until the antiphospholipid syndrome (APS) was described in the 1980s as an independent disorder. The APS is a systemic autoimmune disease often overlapping with SLE in which antiphospholipid autoantibodies, including lupus anticoagulant, can cause a hypercoagulation state, which clinically by definition is manifested as arterial and venous occlusions or pregnancy complications. The pathophysiology has not yet been entirely delineated and the clinical spectrum of associated concomitant manifestations is large. As the mortality is increased with SLE and simultaneous APS, focused diagnostics and risk assessment are indispensable. According to the recently published recommendations of the European League Against Rheumatism the therapeutic strategy comprises individualized secondary prevention of thromboembolic complications by means of anticoagulation (with unaltered importance of vitamin K antagonists) and thrombocyte aggregation inhibition, usually lifelong. Statins and antimalarial drugs are recommended for vascular protection while immunosuppressive treatment has not so far been sufficiently proven for APS but remains the subject of current research.

[Safety and efficacy of off-label use of biologic therapies in patients with inflammatory rheumatic diseases refractory to standard of care therapy : Data from a nationwide German registry (GRAID2)]. / Sicherheit und Wirksamkeitshinweise zum Off-label-Einsatz von Biologikatherapien nach Versagen konventioneller Therapien bei Patienten mit entzündlich rheumatischen Erkrankungen : Ergebnisse eines nationalen Registers (GRAID2).

BACKGROUND: The German Registry of Autoimmune Diseases 2 (GRAID2) is a retrospective, non-interventional, multicenter registry study collecting data from patients with inflammatory, mainly rheumatic diseases refractory to standard of care therapy and treated with an off-label biologic therapy. The retrospective documentation comprised case history, diagnosis, course of disease (including safety and global efficacy). The objective was to evaluate the global clinical outcome and safety of off-label biologic therapy in clinical practice. RESULTS: Data from 311 patients with an overall observation period of 338.5 patient-years were collected. The mean patients age was 47.8 years with 56.9% females. The most frequently documented diagnoses comprised rejection prophylaxis/therapy after renal transplantation (NTX, 18.3%), ANCA-vasculitides (17.4%), systemic lupus erythematosus (SLE, 10.3%), autoinflammatory fever syndromes (8.4%), autoimmune myositis (7.4%) and pemphigus (5.8%). Documented biologic therapies included rituximab (RTX, 70.1%), tocilizumab (TCZ, 9.3%), infliximab (IFX, 7.1%), anakinra (ANK, 5.5%), adalimumab (ADA, 3.5%), etanercept (ETA, 2.3%) and certolizumab (CTZ, 0.6%). After initiation of off-label biologic treatment, tolerability was assessed by the physicians as "very good"/"good" in 95.5%. Altogether, 275 adverse events were documented and of these, 104 were classified as serious adverse events and occurred in 62 patients. In 19 of these patients severe infections (30.6%) were documented, resulting in a rate of 5.6 severe infections per 100 patient years. A total of six deaths were documented, while five of these cases were rated as not related to the biologics treatment. Notably, the use of RTX in patients with small vessel vasculitides and of TCZ in patients with large vessel vasculitides prior to their approval support their relevance in clinical management of patients with severe diseases. CONCLUSION: The results of this registry together with data of GRAID1 provide evidence that use of off-label biologic therapies in patients with inflammatory rheumatic diseases refractory to conventional treatment did not result in any new safety signal already known for these compounds or subsequently shown by clinical trials in certain entities.

Immunologic Long-term Outcomes of Living-Related Kidney Transplantations Depending on the Donor-Recipient Relationship.

BACKGROUND: The aim of this study is to analyze the long-term immunologic outcomes of living-related kidney transplantations depending on the donor-recipient relationship. METHODS: This retrospective single-center study included adult kidney transplant recipients (KTR) transplanted between 2000 and 2014. Among 1117 KTRs, 178 patients (15.9%) received living-related donations. Those patients were further categorized according to the donor-recipient relationship: 65 transplantations between siblings, 39 father-to-child (F-t-C) and 74 mother-to-child (M-t-C) donations. Allograft biopsies were performed for clinically suspected rejections. Data analysis included patient and graft survival, biopsy proven rejections (T-cell mediated [TCMR] or antibody mediated) and development of de novo donor-specific antibody. Outcome data were assessed over a period of a maximum 14 years. RESULTS: There was no significant difference between the groups (F-t-C, M-t-C, and siblings) with regard to HLA-mismatches, prior kidney transplantations, time on dialysis, and cold ischemia time. Among KTRs with related donors, the type of relationship had no significant influence on graft survival. F-t-C and M-t-C pairs showed comparable incidences of TCMR at 7 years post-transplantation, both significantly exceeding the rate in sibling-to-sibling pairs (26.2% and 26.8% vs 10%, respectively; P = .043). A multivariate Cox regression analysis adjusted for recipient age, donor age, and HLA (A, B, DR)-mismatches identified both M-t-C- and F-t-C-donations as important independent risk factors for TCMR (hazard ratio: 8.13; P < .001 and hazard ratio: 8.09; P = .001, respectively). There was no significant difference between the groups concerning the incidence of antibody-mediated rejection and de novo donor-specific antibody. CONCLUSION: Our results indicate that parent-to-child kidney donation is an independent risk factor for TCMR.

Incidence of Infectious Disease and Malignancies After Rituximab Therapy in Kidney Transplant Recipients: Results From a Cohort in Germany.

BACKGROUND: Rituximab is frequently used in solid organ transplantation off-label, especially in patients with renal allografts. Few data are available on the safety aspects of solid organ transplant recipients receiving rituximab. There is a knowledge gap on long-term follow-up data, in particular on infectious complications. PATIENTS AND METHODS: A retrospective observational registry study (German Registry on Autoimmune Diseases) comprising a total of 681 patients was conducted. The data of 63 adult kidney transplant recipients who received rituximab between 2006 and 2013 were used in this analysis. RESULTS: Median follow-up was 42 (1-109) months. At least 1 severe infection occurred in 57% of patients. The median time between the first rituximab infusion and the first infection was 4 (1-48) months. Of the overall 88 infections, 74 were severe bacterial infections, 5 were severe viral infections, 3 were severe fungal infections, 2 were combined severe bacterial and fungal infections, and 4 were combined severe viral, fungal and bacterial infections. Seven patients died during the observational period, 2 of them due to infectious complications. In the observational period, 1 case of squamous cell carcinoma but no other malignancies were observed. CONCLUSION: Consistent with previous data, a high incidence of infections was observed after rituximab treatment in kidney transplant recipients. Most infections occurred within 6 months after rituximab initiation. With more than 3 years of follow-up, we were able to document a low incidence of secondary malignancies after rituximab with only 1 case in our cohort.

Prolonged Low-Dose Prophylaxis With Valganciclovir in Cytomegalovirus-Negative Recipients of Kidney Transplants From Cytomegalovirus-Positive Donors Allows Seroconversion and Prevents Cytomegalovirus Disease.

BACKGROUND: Cytomegalovirus-negative recipients of kidneys from cytomegalovirus (CMV)-positive donors (D+/R-) are at high risk to develop severe clinical manifestations of CMV disease. Long-term data about incidence and timing of CMV seroconversion, CMV disease, and the influence of prolonged valganciclovir prophylaxis on the clinical course of CMV infection are missing. METHODS: We conducted a retrospective long-term study of 89 consecutive CMV D+/R- kidney transplant recipients transplanted between 2003 and 2012. All recipients received valganciclovir prophylaxis after transplantation (median 187 [126-261] days) with a median dose of 213 (181-338) mg/d. Long-term outcome was assessed over a maximum of 10 years post-transplant. RESULTS: During follow-up (median 62 months) 60 of 89 (67%) patients had CMV seroconversion, and 29 of 89 (33%) developed symptomatic CMV disease. In addition, in 38 of the 60 (63%), seroconversion occurred during prophylaxis (median 154 days post-transplant), and in 22 patients, after the end of prophylaxis (median 320 days after transplantation). Baseline characteristics of the 2 groups did not differ significantly. Seroconversion during prophylaxis vs seroconversion after the end of prophylaxis was associated with significantly lower incidence of CMV disease (34% vs 73%, P = .007), less severe CMV disease (16% vs 64%, P < .001), and fewer organ manifestations (26% vs 64%, P = .006). The risk of CMV disease was limited to the first 475 days after transplantation. Valganciclovir resistance occurred in just 1 case (1%). CONCLUSIONS: Prolonged prophylaxis with low-dose valganciclovir allowed CMV seroconversion during prophylaxis in a high proportion of D+/R- patients. Seroconversion occurred after a median of 154 days and was associated with significantly lower incidence of CMV disease, less severe CMV disease, and fewer CMV complications.

Biomarkers in acute kidney injury - pathophysiological basis and clinical performance.

Various biomarkers of acute kidney injury (AKI) have been discovered and characterized in the recent past. These molecules can be detected in urine or blood and signify structural damage to the kidney. Clinically, they are proposed as adjunct diagnostics to serum creatinine and urinary output to improve the early detection, differential diagnosis and prognostic assessment of AKI. The most obvious requirements for a biomarker include its reflection of the underlying pathophysiology of the disease. Hence, a biomarker of AKI should derive from the injured kidney and reflect a molecular process intimately connected with tissue injury. Here, we provide an overview of the basic pathophysiology, the cellular sources and the clinical performance of the most important currently proposed biomarkers of AKI: neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), liver-type fatty acid-binding protein (L-FABP), interleukin-18 (IL-18), insulin-like growth factor-binding protein 7 (IGFBP7), tissue inhibitor of metalloproteinase 2 (TIMP-2) and calprotectin (S100A8/9). We also acknowledge each biomarker's advantages and disadvantages as well as important knowledge gaps and perspectives for future studies.

Successful Recovery of Acute Renal Transplant Failure in Recurrent Hepatitis C Virus-Associated Membranoproliferative Glomerulonephritis.

Recurrence of hepatitis C virus (HCV)-associated membranoproliferative glomerulonephritis (MPGN) in the kidney transplant may lead to continuous graft deterioration and the need for further renal replacement therapy. The novel direct-acting antiviral agents (DAAs) allow a highly effective and interferon-free treatment option for chronic HCV-infected patients. Data on the therapeutic safety and efficacy in HCV-infected renal transplant patients are sparse, especially for patients with severe renal impairment. We report the case of a 63-year-old female HCV-positive renal transplant patient with biopsy-proven recurrence of MPGN in the renal graft 3 years after transplant. Because of rapid loss of transplant function and consecutive need for hemodialysis, we initiated a combined anti-HCV-directed therapy regimen consisting of daclatasvir and simeprevir over 12 weeks. Viral clearance of HCV was obtained as early as 2 weeks after start of treatment. No adverse therapy-associated side effects were observed, and immunosuppressive dosing remained unchanged. Importantly, graft function fully recovered and hemodialysis was stopped 2 mo after the end of daclatasvir/simeprevir treatment. We report the first case of successful recovery of dialysis-dependent renal transplant failure after treatment of recurrent HCV-associated MPGN in a kidney transplant recipient by curing the underlying HCV infection with a combination of novel DAAs.