The case for a national breast implant registry in Canada.

SummaryThe House of Commons Standing Committee on Health proposed in 2022 to start a national registry for breast implants. Why, and what requirements are needed, will be outlined. Breast implant products are not always in compliance with international norms and standards, and several scandals have occurred because of industry fraud. To trace which patients have defective breast implants, a good registry is an absolute must. Furthermore, some diseases, such as lymphomas, autoimmune diseases, and so-called breast implant illness, are believed to be associated with breast implants. An accurate estimation of how often these diseases occur in patients with breast implants is lacking. A registry in which not only surgical data but also patient-reported outcome measurements are recorded will result in a better understanding of patient outcomes and device performance. The registry should not be a voluntary ("opt-in") registry but a mandatory ("opt-out") registry, in which only the patient (and not the surgeon) has the choice whether to participate.

Breast implant illness: Is it causally related to breast implants?

Once believed to be completely inert implants, Silicon Breast Implants (SBIs) have been shown to be able to induce a chronic inflammatory response in the body which can lead to a variety of possible manifestations ranging from the most common capsular contraction to rarer conditions such as malignancies and autoimmune diseases. Among the latter, new syndromes have been consistently recognized: Breast Implant Illness (BII) and autoimmunity/autoinflammatory syndrome induced by adjuvants (ASIA syndrome/Shoenfeld's Syndrome). The pathophysiological mechanisms underlying such syndromes are not yet clear and the overlap they show with other common conditions have sparked an important debate in the scientific community regarding their existence and their cause-effect relationship with SBIs. In this article Professor Cohen Tervaert and Professor Bassetto, leading experts in the field, are going to present arguments in favor and against such causal relationship according to the latest scientific evidence. Professor Cohen Tervaert is going to demonstrate how the evidence available is enough to prove a causal relationship as defined by the Bradford Hill's criteria. Professor Bassetto is going to highlight how the many biases that afflict the available evidence prevent us from drawing such conclusions. Professor Shoenfeld is going to moderate the discussion with its insightful conclusions.

Characterization of follicular T helper cells and donor-specific T helper cells in renal transplant patients with de novo donor-specific HLA-antibodies.

T follicular helper (TFH) cells are a heterogeneous subset of immunocompetent T helper (TH) cells capable of augmenting B cell responses in lymphoid tissues. In transplantation, exposure to allogeneic tissue activates TFH cells increasing the risk of the emergence of de novo donor-specific HLA-antibodies (dnDSA). These can cause antibody-mediated rejection (AMR) and allograft loss. Follicular regulatory T (TFR) cells counteract TFH cell activity. Here, we investigated the implications of TFH and TFR cells on dnDSA formation after renal transplantation (RTX). Considering TFH cells to be CXCR5+ and IL-21+, we found by flow cytometry that patients with dnDSA produced IL-21 more abundantly compared to healthy volunteers. In in vitro alloreactivity assays, patients with dnDSA featured an enhanced alloreactive TH cell pool in response to donor-specific HLA antigens. Besides, longitudinal investigations suggested enhanced alloreactivity shortly after transplantation increasing the risk of dnDSA development. Taken together, in spite of continuous immunosuppression we report a strong IL-21 response in TFH cells and an expanded reservoir of donor-specific memory TH cells in patients with dnDSA. This warrants further investigations if aberrant TFH cell activation may precede the formation of dnDSA promoting AMR.

COVID-19, rheumatic diseases and immune dysregulation-a perspective.

The COVID-19 pandemic has resulted in widespread hospitalisations and deaths around the world. As patients with rheumatic diseases generally have increased risk of infections and complications, understandably, there is significant concern of the impact of SARS-CoV-2 on these patients. However, there is a paucity of data in rheumatic patients. We review mechanisms through which SARS-CoV-2 results in infection, including ACE2 receptor, and complications (including immune dysregulation, thrombosis and complement activation). We assess these pathways in patients with rheumatic disease and those on immune modulating therapy. Although data thus far does not appear to show worse outcomes in rheumatic patients as a whole, given alterations in the underlying immune pathways in certain diseases (such as systemic lupus erythematosus), we posit that the risk is not equal in all rheumatic patients. We also discuss the benefit of underlying disease control with respect to COVID-19 risk reduction and potential increased risk of disease flares following viral infection from an immune standpoint.

Vasculitis patient journey: a scoping review of patient experiences with vasculitis.

In order to understand the vasculitis journey from the patient's perspective, the existing literature was reviewed regarding patient perceptions of vasculitis' effect on four main domains of health: physical, psychological, social, and financial. A scoping review was performed using CINAHL, Embase, MEDLINE, PsychINFO, and other sources (smaller databases and grey literature). Inclusion criteria included all forms of primary vasculitis, adult patients (≥ 18 years old), and patient perspectives regarding at least one of the four identified health domains. Aggregates of patient experiences with vasculitis were categorized into one of the four health domains: physical, psychological, social, and financial. Nineteen qualitative studies from 2294 total non-duplicated articles were included. Generalized themes emerged for each of the four domains. In relation to physical health, patients were most affected by fatigue. Psychologically, patients were most affected by anxiety. Socially, patients experienced decreased social participation due to lifestyle changes associated with disease and social perceptions of vasculitis. Financially, vasculitis patients had decreased employment due to functional decline. Each of the four domains contributed to a decreased quality of life associated with vasculitis. Decreased quality of life in vasculitis is due to multiple factors across several health domains. Understanding the patient's journey allows physicians to understand patient goals and to better support them in their recovery. Patients may also have an improved understanding of their journey and the most relevant health domains affected.

Long-term efficacy of immunoglobulins in small fiber neuropathy related to Sjögren's syndrome.

The most common peripheral nervous system manifestations in Sjogren's syndrome are small fiber sensory neuropathies (SFPN) and axonal sensorimotor polyneuropathies. Currently, treatment in small fiber neuropathy is mainly symptomatic and based on anti-depressors and anti-epileptics. The benefit of treatment with polyvalent immunoglobulins for SFPN has been reported in small series of patients, although transient in several cases. The medium-to-long-term effects of polyvalent immunoglobulins (Ig) in SFPN in patients with Sjogren's syndrome who are refractory to conventional treatments remain an unmet medical need. We present our experience related to the persistent improvement of Ig in a case series of SFPN in Sjogren's syndrome and relevant data in the literature regarding the benefits of immunoglobulins, for this indication.

Anti-neutrophil Cytoplasmic Antibodies (ANCA) as Disease Activity Biomarkers in a "Personalized Medicine Approach" in ANCA-Associated Vasculitis.

PURPOSE OF REVIEW: ANCA-associated vasculitides (AAV) are a group of rare diseases characterized by blood vessel inflammation and the presence of circulating anti-neutrophil cytoplasmic antibodies recognizing proteinase-3 (PR3) (PR3-ANCA) or myeloperoxidase (MPO), MPO-ANCA. RECENT FINDINGS: Historically, ANCAs have been used as biomarkers for disease associations and increases of ANCA levels as predictors of relapse in patients with AAV. In this review, we will summarize and highlight the most recent developments for using ANCA as predictive biomarkers and review some of the important disease-specific features in patients with AAV.

[Rubber granules on synthetic turf pitches: safe or not safe for children?] / Rubbergranulaat op kunstgrasvelden.

Rubber granules from old car tyres used in synthetic turf pitches contain a significant number of carcinogenic and endocrine-disrupting chemicals. In 2017 the Dutch National Institute for Public Health and the Environment (RIVM) and the European Chemical Agency (ECHA) concluded that the risks for children are negligible. However, their reports contain some scientific inaccuracies and omissions which may have led them to underestimate the risks for children. It is therefore premature to conclude that it is safe for children to play on synthetic turf pitches with rubber granules. It is now primarily up to the parents to decide whether or not playing sports is acceptable in these circumstances. The Dutch government should, in accordance with ECHA recommendations, advise parents that their children ought to avoid hand-and-mouth contact with these granules as much as possible.

The autoimmune/inflammatory syndrome induced by adjuvants (ASIA)/Shoenfeld's syndrome: descriptive analysis of 300 patients from the international ASIA syndrome registry.

The autoimmune/inflammatory syndrome induced by adjuvants (ASIA) is a recently identified condition in which the exposure to an adjuvant leads to an aberrant autoimmune response. We aimed to summarize the results obtained from the ASIA syndrome registry up to December 2016, in a descriptive analysis of 300 cases of ASIA syndrome, with a focus on the adjuvants, the clinical manifestations, and the relationship with other autoimmune diseases. A Web-based registry, based on a multicenter international study, collected clinical and laboratory data in a form of a questionnaire applied to patients with ASIA syndrome. Experts in the disease validated all cases independently. A comparison study regarding type of adjuvants and differences in clinical and laboratory findings was performed. Three hundred patients were analyzed. The mean age at disease onset was 37 years, and the mean duration of time latency between adjuvant stimuli and development of autoimmune conditions was 16.8 months, ranging between 3 days to 5 years. Arthralgia, myalgia, and chronic fatigue were the most frequently reported symptoms. Eighty-nine percent of patients were also diagnosed with another defined rheumatic/autoimmune condition. The most frequent autoimmune disease related to ASIA syndrome was undifferentiated connective tissue disease (UCTD). ASIA syndrome is associated with a high incidence of UCTD and positive anti-nuclear antibodies (ANA) test. Clinical and laboratory features differ from the type of adjuvant used. These findings may contribute to an increased awareness of ASIA syndrome and help physicians to identify patients at a greater risk of autoimmune diseases following the exposure to vaccines and other adjuvants. The ASIA syndrome registry provides a useful tool to systematize this rare condition.

Randomised controlled trial of prolonged treatment in the remission phase of ANCA-associated vasculitis.

OBJECTIVES: A prospective randomised trial to compare two different durations of maintenance immunosuppressive therapy for the prevention of relapse in anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). METHODS: Patients with AAV were recruited 18-24 months after diagnosis if they were in stable remission after cyclophosphamide/prednisolone-based induction followed by azathioprine/prednisolone maintenance therapy. They were randomised (1:1) to receive continued azathioprine/prednisolone to 48 months from diagnosis (continuation group) or to withdraw azathioprine/prednisolone by 24 months (withdrawal group). The primary endpoint was the relapse risk, from randomisation to 48 months from diagnosis. RESULTS: One hundred and seventeen patients were randomised and 110 remained to the trial end. At entry, median serum creatinine was 116 µmol/L (range 58-372), 53% were ANCA positive. The percentage of patients presenting with relapse was higher in the withdrawal than in the continuation treatment group (63% vs 22%, p<0.0001, OR 5.96, 95% CI 2.58 to 13.77). ANCA positivity at randomisation was associated with relapse risk (51% vs 29%, p=0.017, OR 2.57, 95% CI 1.16 to 5.68). Renal function, ANCA specificity, vasculitis type and age were not predictive of relapse. Severe adverse events were more frequent in the continuation than withdrawal groups (nine vs three events), but the continuation group had better renal outcome (0 vs 4 cases of end-stage renal disease), with no difference in patient survival. CONCLUSIONS: Prolonged remission maintenance therapy with azathioprine/prednisolone, beyond 24 months after diagnosis reduces relapse risk out to 48 months and improves renal survival in AAV. TRIAL REGISTRATION NUMBER: ISRCTN13739474.

Chronic nasal Staphylococcus aureus carriage identifies a subset of newly diagnosed granulomatosis with polyangiitis patients with high relapse rate.

Objective: The aim of this study was to evaluate whether chronic nasal carriage of Staphylococcus aureus (SA) is related to relapses in patients with newly diagnosed ANCA-associated vasculitis (AAV). Methods: In two clinical trials (n = 200), for early systemic (n = 83) and generalized (n = 117) AAV, nasal swabs were obtained monthly and at the time of a relapse. Chronic nasal SA carriage (CNSAC) was defined as ⩾ 75% of cultures being SA positive, with non-carriers being SA negative in all cultures and remaining patients being intermittent carriers. Fifty-five of 200 (27.5%) patients received prophylactic trimethoprim/sulfamethoxazole (T/S) against Pneumocystis jirovecii . Results: Of the total AAV patients, 24/200 (12%) were chronic, 102/200 (51%) intermittent and 74/200 (37%) non-carriers. Of 65 relapsing patients, 10/24 (41.7%) were chronic, 32/102 (31.4%) intermittent and 23/74 (31.1%) non-carriers (P = 0.59). For all AAV patients, CNSAC was not associated with an increased relapse risk [odds ratio (OR) = 1.57, 95% CI: 0.66, 3.76; P = 0.31]. However, 23/24 chronic carriers had granulomatosis with polyangiitis (GPA). In the 73 patients with generalized GPA (hazard ratio = 4.10, 95% CI: 1.37, 12.25; P = 0.01) and the 78 patients with early systemic GPA during immunosuppression (hazard ratio = 2.73, 95% CI: 0.95, 7.87; P = 0.06), relapse rates were higher for chronic SA carriers. Prophylactic T/S was not associated with a reduced relapse risk (OR = 0.71, 95% CI: 0.36, 1.41; P = 0.33). Nevertheless, prophylactic T/S reduced CNSAC (OR = 0.19, 95% CI: 0.04, 0.91; P = 0.04). Conclusion: The frequency of CNSAC in newly diagnosed GPA paralleled that in the general population. This subset of GPA patients (23/151, 15.2%) has a high relapse rate despite immunosuppression and prophylactic T/S treatment, requiring further investigations on pathogenesis and therapy.

Vitamin D deficiency as a risk factor for the development of autoantibodies in patients with ASIA and silicone breast implants: a cohort study and review of the literature.

The development of autoimmunity and/or autoimmune diseases is multifactorial. Vitamin D is one of the factors that might play a role. We postulated that both the presence of adjuvants and insufficient levels of vitamin D may result in the development of autoimmunity in patients with autoimmune/inflammatory syndrome induced by adjuvants (ASIA) in relation to silicone implant incompatibility. We measured vitamin D levels in 135 patients with ASIA in relation to silicone implant incompatibility and related findings to the presence of autoantibodies that are commonly used to diagnose systemic autoimmune diseases. Furthermore, we systematically reviewed the literature regarding vitamin D deficiency as a risk factor for the development of autoantibodies. Vitamin D measurements were available for analysis in 131 of 135 patients with ASIA in relation to SIIS. Twenty-three patients (18%) tested positive for autoantibodies, from which 18 patients (78%) had either a vitamin D deficiency or insufficiency (median vitamin D level 60.5 mmol/L), whereas five patients (22%) had sufficient vitamin D levels. The risk to develop autoantibodies was significantly increased in vitamin D deficient and/or insufficient patients [RR 3.14; 95% CI, 1.24-7.95; p = 0.009]. Reviewed literature suggested an association between vitamin D levels and the presence and/or titer levels of autoantibodies in different autoimmune diseases. From our current study and from our review of the literature, we conclude that vitamin D deficiency is related to the presence of autoantibodies. Whether vitamin D supplementation results in a decrease of autoimmunity needs to be studied prospectively.

CD4+CD28null T Cells are related to previous cytomegalovirus infection but not to accelerated atherosclerosis in ANCA-associated vasculitis.

Previous studies have suggested an increased risk for cardiovascular events in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). We analyzed the presence of atherosclerotic damage in patients with AAV in relation to the presence of CD4+CD28null T cells and antibodies against cytomegalovirus (CMV) and human Heat-Shock Protein 60 (hHSP60). In this cross-sectional study, patients with inactive AAV were compared with healthy controls (HC). Carotid intima-media thickness (IMT) and aortic pulse-wave velocity (PWV) were measured. In addition, CD4+CD28null T cells, anti-CMV, and anti-hHSP60 levels were determined. Forty patients with AAV were included. Patients' spouses were recruited as HC (N = 38). CD4+CD28null T cells are present in patients with AAV in a higher percentage (median 3.1, range 0.01-85) than in HC (0.28, 0-36, P < 0.0001). No significant difference in IMT (mm) between patients and controls was detected (mean 0.77 ± standard deviation 0.15 and 0.73 ± 0.11, respectively, P = 0.20). PWV standardized for MAP was increased in AAV patients (9.80 ± 2.50 m/s, compared to 8.72 ± 1.68 in HC, P = 0.04). There was a strong association between a previous CMV infection and the presence and percentage of CD4+CD28null T cells (0.33 vs 13.8, P < 0.001). There was no relationship between CD4+CD28null T cells and/or a previous CMV infection and IMT or PWV. There was no relation between anti-hHSP60 and CD4+CD28null T cells. Increased PWV values suggest atherosclerotic damage in patients with AAV. Plaque size, as determined by IMT, did not differ. CD4+CD28null T cells are increased in AAV and related to the previous CMV infection.

Extended versus standard azathioprine maintenance therapy in newly diagnosed proteinase-3 anti-neutrophil cytoplasmic antibody-associated vasculitis patients who remain cytoplasmic anti-neutrophil cytoplasmic antibody-positive after induction of remission: a randomized clinical trial.

BACKGROUND: Cytoplasmic anti-neutrophil cytoplasmic antibody (C-ANCA) positivity at remission has been associated with an increased relapse rate in patients with proteinase 3 anti-neutrophil cytoplasmic antibody-associated vasculitis (PR3-AAV) after a switch to azathioprine maintenance therapy. We therefore hypothesized that extended azathioprine maintenance therapy could reduce the incidence of relapse in this setting. METHODS: Patients newly diagnosed with PR3-AAV at 12 centres in The Netherlands during 2003-11 who received a standardized induction regimen consisting of oral cyclophosphamide and corticosteroids were enrolled (n = 131). Patients were randomized to standard or extended azathioprine maintenance therapy when C-ANCA was positive at the time of stable remission. Standard maintenance treatment consisted of azathioprine (1.5-2.0 mg/kg) until 1 year after diagnosis and subsequent tapering to 25 mg every 3 months. Extended azathioprine maintenance therapy (1.5-2.0 mg/kg) was continued until 4 years after diagnosis and tapered thereafter. The primary endpoint was relapse-free survival at 4 years after diagnosis. RESULTS: In patients with PR3-AAV who were C-ANCA positive at the time of stable remission, relapse-free survival at 4 years after diagnosis did not differ significantly between standard azathioprine (n = 24) and extended azathioprine (n = 21) maintenance therapy (P = 0.40). There was also no significant difference in relapse-free survival between patients receiving standard azathioprine (n = 106) versus extended azathioprine maintenance therapy (n = 21; P = 0.94). In addition, there was no difference in the relapse rate between patients with PR3-AAV who were C-ANCA positive (n = 45) at the time of remission versus patients who became C-ANCA negative at the time of remission (n = 82; P = 0.62). CONCLUSIONS: This randomized trial suggests that extended azathioprine maintenance therapy has only a limited effect on the prevention of relapse in patients with PR3-AAV at 4 years after diagnosis. Moreover, positive C-ANCA status at stable remission was not associated with an increased rate of relapse. TRIAL REGISTRATION: ClinicalTrials.gov NCT 00128895.

Viral RNA in the influenza vaccine may have contributed to the development of ANCA-associated vasculitis in a patient following immunisation.

A number of large studies have demonstrated influenza vaccinations to be safe and effective. However, there have been some sporadic case reports, describing a temporal association of influenza vaccination with onset or relapse of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. The nature of this association, beyond time of occurrence, remains unknown. The presentation of a previously healthy patient who developed ANCA-associated vasculitis (AAV) shortly after influenza vaccination provided us with the rare opportunity to study the possible mechanisms behind this observation. We tested the ability of different types and batches of influenza vaccines to stimulate proteinase-3 ANCA (PR3-ANCA) production in vitro. We found that only some influenza vaccines stimulated PR3-ANCA production in this patient. We demonstrated that this unusual response was associated with those vaccines that contained viral ribonucleic acid (RNA), the natural ligand for Toll-like receptor-7. Exome sequencing of the patient's DNA did not show any mutation in any of the molecules associated with Toll-like receptor signalling. We propose that hyper-reaction to viral RNA in the influenza vaccine may have contributed to the development of AAV following influenza vaccination in this patient.