While the pathogenesis of anti-neutrophil cytoplasmic autoantibody associated vasculitis (AAV) is still not fully elucidated, there is a mounting evidence that the process is initiated by ...inflammation and activation of innate immunity in the presence of predisposing factors, innate immunity abnormalities, aberrant responses of the adaptive immune system, and complement system activation. Biologics targeting inflammation-related molecules in the immune system have been explored to treat AVV, and these treatments have provided revolutionary advances. When focusing on the pathogenic mechanisms of AVV, this review presents the new findings regarding novel therapeutic approaches for the management of these conditions.
Antibodies to prothrombin are detected by directly coating prothrombin on irradiated ELISA plates (aPT) or by using the phosphatidylserine/prothrombin complex as antigen (aPS/PT). Although these ...antibodies have both been associated with antiphospholipid syndrome (APS) and a correlation between the two assays have been reported, it seems that aPT and aPS/PT belong to different populations of autoantibodies. It was our objective to systematically review the available evidence on aPT and aPS/PT antibodies and the risk of thrombosis in APS. Medline-reports published between 1988 and 2013 investigating aPT and aPS/PT as a risk factor for thrombosis were included. Whenever possible, antibody isotype(s) and site of thrombosis were analysed. This systematic review is based on available data from more than 7,000 patients and controls from 38 studies analysing aPT and 10 aPS/PT. Antibodies to prothrombin (both aPT and aPS/PT) increased the risk of thrombosis (odds ratio OR 2.3; 95% confidence interval CI 1.72–3.5). aPS/PT seemed to represent a stronger risk factor for thrombosis, both arterial and/or venous than aPT (OR 5.11; 95%CI 4.2–6.3 and OR 1.82; 95%CI 1.44–2.75, respectively). In conclusion, routine measurement of aPS/PT (but not aPT) might be useful in establishing the thrombotic risk of patients with previous thrombosis and/or systemic lupus erythematosus. Their inclusion as laboratory criteria for the APS should be indisputably further explored.
The lymphatic kidney system plays a crucial role in managing interstitial fluid removal, regulating fluid balance, and tuning immune response. It also assists in the reabsorption of proteins, ...electrolytes, cytokines, growth factors, and immune cells. Pathological conditions, including tissue damage, excessive interstitial fluid, high blood glucose levels, and inflammation, can initiate lymphangiogenesis-the formation of new lymphatic vessels. This process is associated with various kidney diseases, including polycystic kidney disease, hypertension, ultrafiltration challenges, and complications post-organ transplantation. Although lymphangiogenesis has beneficial effects in removing excess fluid and immune cells, it may also contribute to inflammation and fibrosis within the kidneys. In this review, we aim to discuss the biology of the lymphatic system, from its development and function to its response to disease stimuli, with an emphasis on renal pathophysiology. Furthermore, we explore how innovative treatments targeting the lymphatic system could potentially enhance the management of kidney diseases.
Systemic lupus erythematosus (SLE) is an autoimmune disease with heterogeneous clinical manifestations that can potentially affect every organ and system. SLE is usually identified on the basis of ...clinical or serological manifestations; however, some individuals can present with signs and symptoms that are consistent with SLE but are not sufficient for a definite diagnosis. Disease in these individuals can either progress over time to definite SLE or remain stable, in which case their disease is often described as intermediate, possible or probable SLE. Alternatively, such individuals might have undifferentiated connective tissue disease (UCTD). Being able to differentiate between those with stable UCTD and those with SLE at an early stage is important to avoid irreversible target-organ damage from occurring. This Review provides insight into existing and evolving perceptions of the early stages of SLE, including clinical and mechanistic considerations, as well as potential paths towards early identification and intervention. Further research into the earliest phases of SLE will be important for the development of targeted diagnostic approaches and biomarkers for the identification of individuals with early disease who are likely to progress to definite SLE.
To date, almost 7 billion doses of the different types of vaccine against SARS-CoV-2 have been administered worldwide. Although the severity of new cases of SARS-CoV-2 has progressively decreased, ...and the pressure on national health systems has declined, the development of de novo glomerular injuries has been suggested.
This study aimed to examine the patients who were hospitalized in our Unit between April and November 2021 and underwent renal biopsy for new-onset urinary abnormalities (UA) and/or renal impairment within 3 months of SARS-CoV-2 vaccination.
We identified 17 patients who developed UA and/or renal insufficiency within 3 months of vaccination. Minimal change disease was the most common disease in our cohort (5 patients, 29.4%) followed by acute tubulointerstitial nephritis (TIN; 3 patients, 17.6%), membranous nephropathy (3 patients, 17.6%), and rapidly progressive IgA nephropathy (2 patients, 11.8%). The other 4 patients had a diagnosis of membranoproliferative glomerulonephritis (1 patient), systemic lupus erythematosus (1 patient), ANCA-associated vasculitis (1 patient), and tip-variant focal segmental glomerulosclerosis (1 patient), respectively. Eight out of the 17 patients (47.1%) developed acute kidney injury. Two patients with acute TIN had to start hemodialysis that was discontinued after 1 and 2 months, respectively, due to the recovery of renal function. All patients underwent treatment with corticosteroids and/or immunosuppressants.
Although it is not possible to conclusively determine whether there is a causal relationship between SARS-CoV-2 vaccination and new-onset nephropathies, based on the appearance of UA and/or renal insufficiency shortly after vaccination, we hypothesize that the immune response to the COVID-19 vaccine may be a trigger of nephropathies. Therefore, our results highlight the need for pharmacovigilance. However, this report should not lead to vaccine hesitation during this pandemic as the benefits of vaccination strongly outweigh the potential risks.
Physical inactivity is common in patients with chronic kidney disease (CKD) and is an important modifiable risk factor for mortality, morbidity, and reduced quality of life. The present single-centre ...pilot study evaluated the possibility of performing structured physical exercise using a specific walking model, Fitwalking, in a population of patients with CKD and, according to the American College of Rheumatology guidelines, also in a population with immuno-rheumatological disease.INTRODUCTIONPhysical inactivity is common in patients with chronic kidney disease (CKD) and is an important modifiable risk factor for mortality, morbidity, and reduced quality of life. The present single-centre pilot study evaluated the possibility of performing structured physical exercise using a specific walking model, Fitwalking, in a population of patients with CKD and, according to the American College of Rheumatology guidelines, also in a population with immuno-rheumatological disease.Patients were recruited from nephrology, haemodialysis, peritoneal dialysis, transplantation, and immuno-rheumatology outpatient clinics. After general and functional clinical evaluation and exercise prescription at the Department of Sports Medicine, we performed scientifically proven tests on CKD (6-min walk test and sit-to-stand test), before and after the Fitwalking technique training course, and again after 6 and 12 months, evaluated its effectiveness and identify any critical issues.METHODSPatients were recruited from nephrology, haemodialysis, peritoneal dialysis, transplantation, and immuno-rheumatology outpatient clinics. After general and functional clinical evaluation and exercise prescription at the Department of Sports Medicine, we performed scientifically proven tests on CKD (6-min walk test and sit-to-stand test), before and after the Fitwalking technique training course, and again after 6 and 12 months, evaluated its effectiveness and identify any critical issues.We enrolled 80 patients (41 males, 51.2%), with a mean age of 53 ± 12 years; the clinical data showed statistically significant improvements in systolic, average, and differential blood pressure, average speed, and physical strength. Participants also adapted to muscle fatigue, experienced a reduction in BMI with stable lean mass and reduced fat mass, and reported improved perceptions of physical and mental health, and quality of life.RESULTSWe enrolled 80 patients (41 males, 51.2%), with a mean age of 53 ± 12 years; the clinical data showed statistically significant improvements in systolic, average, and differential blood pressure, average speed, and physical strength. Participants also adapted to muscle fatigue, experienced a reduction in BMI with stable lean mass and reduced fat mass, and reported improved perceptions of physical and mental health, and quality of life.All enrolled patients successfully completed the process. A specific prescription was used that provided health education and allowed for the implementation of structured physical activity that could be performed safely and independently even after the training period. The activity was sustainable thanks to the training of in-house medical and nursing staff, demonstrating that it is possible to overcome this type of barrier to physical activity in CKD and in immuno-rheumatological patients.CONCLUSIONAll enrolled patients successfully completed the process. A specific prescription was used that provided health education and allowed for the implementation of structured physical activity that could be performed safely and independently even after the training period. The activity was sustainable thanks to the training of in-house medical and nursing staff, demonstrating that it is possible to overcome this type of barrier to physical activity in CKD and in immuno-rheumatological patients.
Rheumatoid arthritis (RA) is one of the most common autoimmune diseases and is characterized by synovitis that causes joint damage. The introduction of biologic agents has made it possible to induce ...remission in many patients and inhibit joint damage. Activated T cells in RA patients proliferate and stimulate the production of pro-inflammatory cytokines including tumor necrosis factor (TNF) and interleukin 6 that play important roles in RA pathogenesis.
The most widely used biologic agents indicated for RA inhibit the activity of TNF. However, newly developed biologic drugs targeting different pathways are now currently part of the therapeutic options to induce remission in patients with RA.
The present review focuses on biologic agents directed at molecular targets different from TNF and addresses the possible advantages of these drugs.
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a cluster of potentially life-threatening disorders often involving the kidney with a necrotizing crescentic ...glomerulonephritis with scanty deposition of immunoglobulins and complement. Historically the role of complement has been considered ancillary. Recently, an anti-myeloperoxidase (MPO) AAV model in complement-deficient mice has shown an involvement for the complement cascade in the development of the renal injuries. Further animal studies showing that in contrast to mice deficient for factor B and C5 animals deficient for C4 were susceptible to AAV development by injection of anti-MPO antibodies emphasized the specific involvement of the alternative pathway. Consonantly, the C5a receptor (Cd88) blockade was found to protect mice from MPO AAV. CCX168, i.e., Avacopan, a powerful inhibitor of C5a receptor that can be administered orally, was shown to reduce the pro-inflammatory effects of C5a and abolish the activation of neutrophils, their migration and adherence to endothelium, and the vascular endothelial cell retraction that increases permeability.
Avacopan was found to be safe in healthy volunteers given a wide range of doses in a Phase 1 clinical trial. The Phase 2 trial CLEAR assessed the possibility to decrease dose or entirely replace glucocorticosteroids in the Standard of Care (SoC) therapy of AAV. Avacopan, added to CYC or RTX either in combination with GCs or not, shortened the time to remission in patients with either newly diagnosed or relapsing AAV. The Phase 3 ADVOCATE study compared the ability of an Avacopan-associated regimen to induce and sustain remission in AAV patients vs a conventional GC-associated scheme. Remission at week 26 was observed in 72.3% of patients given Avacopan and in 70.1% of those given prednisone. Sustained remission at week 52 (second primary endpoint) was obtained in 65.7% of patients given Avacopan and in 54.9% receiving prednisone. The Avacopan-associated regimen was non-inferior at week 26, and superior at week 52 in sustaining remission as compared to the GC-based scheme.
The results of the ADVOCATE trial opened new prospects for the treatment of AAV and also other immune-mediated diseases with renal involvement. The possible position of Avacopan in a routinary clinical setting and its possible indications in specific subsets of patients with AAV are extensively discussed.
Extrahepatic manifestations are a feature of chronic hepatitis C virus (HCV) infection. In the course of chronic HCV infection, about 70% of patients have one or more extrahepatic manifestations. The ...latter are often the first and only clinical sign of infection. Experimental and clinical data support a causal association for many extrahepatic manifestations and HCV infection, which include mixed cryoglobulinemia, non-Hodgkin lymphomas (NHL), cardiovascular disease, insulin resistance, type 2 diabetes, neurological and psychiatric disease and other rheumatic diseases. All these extrahepatic conditions influence the morbidity, quality of life and mortality of HCV-infected patients. Currently, interferon-free therapeutic regimens with direct-acting antiviral agents (DAA) offer the possibility of treatment to almost the entire infected population, irrespective of stage of cirrhosis and associated serious comorbidities, always maintaining a high efficacy and tolerability. Several studies have shown a close association between HCV clearance by DAAs and an improvement or reduction in the risk of extrahepatic manifestations. Patients with HCV after a sustained virologic response (SVR) by DAA treatment have a lower risk than non-responders of developing cryoglobulinemic vasculitis and B-cell non-Hodgkin's lymphomas. Furthermore, the SVR by DAA also reduces the risk of acute coronary syndrome, cardiovascular disease, insulin resistance and type 2 diabetes, and it improves atherosclerosis. HCV clearance by DAA also improves the quality of life and survival of patients with chronic HCV infection with associated extrahepatic diseases. Thus, DAAs should be initiated as early as possible in HCV patients with extrahepatic manifestations.
PDF
