Browsing by Author "Fritzler, Marvin J"

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    A case of aggressive atypical anti-GBM disease complicated by CMV pneumonitis
    (2019-01-31) Sporinova, Barbora; McRae, Susanna A; Muruve, Daniel A; Fritzler, Marvin J; Nasr, Samih H; Chin, Alex C; Benediktsson, Hallgrimur
    Abstract Background Anti-glomerular basement membrane (anti-GBM) disease is characterized by circulating IgG glomerular basement membrane antibodies and is clinically expressed as a rapidly progressive crescentic glomerulonephritis (GN), with 30–60% of patients also developing pulmonary hemorrhage. Classically, the renal biopsy shows glomerular crescent formation, bright linear staining of glomerular basement membranes (GBM) for IgG on direct immunofluorescence (IF), and the serologic presence of circulating anti-GBM antibodies. Recently, patients with linear IgG IF staining, undetectable circulating anti-GBM antibodies and glomerular changes atypical for anti-GBM disease have been described as “atypical anti-GBM disease”, with a distinctly more benign clinical course than typical anti-GBM disease. We present a case report of a patient with negative anti-GBM serology but positive linear IgG staining by IF, severe diffuse crescentic and endocapillary proliferative glomerulonephritis, and renal failure, complicated by severe pulmonary hemorrhage after immunosuppression, likely due to cytomegalovirus (CMV) pneumonitis. Case presentation A 24-year-old man was admitted to hospital with hemoptysis and renal failure. Investigations for anti-GBM serology by addressable laser bead immunoassay (ALBIA) was negative for anti-GBM antibodies. Renal biopsy showed diffuse endocapillary proliferative glomerulonephritis with membranoproliferative features and diffuse circumferential crescents. Direct IF showed strong linear staining for IgG along GBMs. The patient’s hemoptysis improved with immunosuppression, but 1 month later he was readmitted with gross hemoptysis, which was refractory to further cyclophosphamide, plasma exchange and rituximab. Bronchoalveolar lavage (BAL) and blood work confirmed CMV pneumonitis, and the patient’s hemoptysis resolved with ganciclovir, though he became dialysis dependent. Conclusions This case demonstrates an atypical presentation of anti-GBM disease with both crescents and endocapillary hypercellularity and negative serology. The patient is dialysis dependent, unlike most previously described patients with atypical anti-GBM disease. The course was complicated by CMV pneumonitis, which contributed to the severity of the pulmonary manifestations and added diagnostic difficulty.
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    A case series evaluating the impact of Hepatitis C eradication using direct acting antivirals on primary biliary cholangitis-associated autoimmunity
    (2018-06-25) Nguyen, Henry H; Khathlan, Abdullah; Fritzler, Marvin J; Swain, Mark G
    Abstract Background Chronic Hepatitis C Virus (HCV) infection has been commonly linked to the development of autoimmunity, in part through activation of B cells. B cells are also postulated to play a pathogenic role in the autoimmune liver disease Primary Biliary Cholangitis (PBC). Patients with concurrent PBC and HCV infection carry an increased risk of more progressive disease, although the mechanism underlying this effect is poorly understood. Utilizing a case series of patients with concurrent PBC and HCV, the aim of this study was to evaluate for the potential impact of HCV eradication upon autoimmunity/autoantibody production. Case presentation A case series evaluating three patients with co-existing PBC-HCV infection receiving non-interferon based HCV treatments with direct-acting antivirals (DAA). One of three patient received Ursodeoxycholic acid (UDCA; 13 mg/kg/day) during the treatment period. Sustained virological response (SVR) to DAA’s was assessed using a HCV Quantitative Nucleic Acid Test (Abbott). Autoantibodies associated with autoimmune liver diseases (including PBC) and liver biochemistry, were measured before, during and after DAA treatment (Mitogen Advanced Diagnostics Laboratory, Calgary, Canada). All patients achieved an SVR, as determined by negative HCV RNA test 12 weeks post-DAA therapy. Titres of anti-mitochondrial antibodies (AMA-M2), anti- branched-chain 2-oxo-acid dehydrogenase complex and 2-oxo glutarate dehydrogenase complex (anti-3E-BPO), and anti- tripartite motif-containing protein 21 (TRIM21/Ro52) remained unchanged, despite successful HCV eradication. Two of the three patients exhibited a transient decrease in some autoantibody titres during DAA treatment, but these returned to baseline levels post-DAA therapy. Conclusions Within the limitations of a case series, our results suggest that HCV co-infection may not be a significant driver of PBC-related autoimmunity/autoantibody production. However, a larger n-value is required to truly assess for the effect of HCV eradication on autoantibody production.
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    Clinical associations and potential novel antigenic targets of autoantibodies directed against rods and rings in chronic hepatitis C infection
    (BioMed Central, 2013-03-19) Stinton, Laura M; Myers, Robert P; Coffin, Carla S; Fritzler, Marvin J
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    Emerging technologies in autoantibody testing for rheumatic diseases
    (2017-07-24) Olsen, Nancy J; Choi, May Y; Fritzler, Marvin J
    Abstract Testing for the presence of antinuclear antibodies (ANAs) is a key step in the diagnosis of systemic lupus erythematosus (SLE) and other systemic autoimmune rheumatic diseases (SARD). The standard slide-based indirect immunofluorescence (IIF) test is widely used, but is limited by a relative lack of specificity for SLE and not all SARD-ANAs are detected. Alternative immunoassays that might offer enhanced diagnostic and prognostic information have evolved, and some of these have entered clinical practice. This review summarizes the current state of ANA testing and multiplex techniques for detecting other autoantibodies, the possibility of point-of-care testing, and approaches for applications in early disease stages.
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    Long-term exposure to a mixture of industrial SO2, NO2, and PM2.5 and anti-citrullinated protein antibody positivity
    (2020-07-29) Zhao, Naizhuo; Smargiassi, Audrey; Hatzopoulou, Marianne; Colmegna, Ines; Hudson, Marie; Fritzler, Marvin J; Awadalla, Philip; Bernatsky, Sasha
    Abstract Background Studies of associations between industrial air emissions and rheumatic diseases, or diseases-related serological biomarkers, are few. Moreover, previous evaluations typically studied individual (not mixed) emissions. We investigated associations between individual and combined exposures to industrial sulfur dioxide (SO2), nitrogen dioxide (NO2), and fine particles matter (PM2.5) on anti-citrullinated protein antibodies (ACPA), a characteristic biomarker for rheumatoid arthritis (RA). Methods Serum ACPA was determined for 7600 randomly selected CARTaGENE general population subjects in Quebec, Canada. Industrial SO2, NO2, and PM2.5 concentrations, estimated by the California Puff (CALPUFF) atmospheric dispersion model, were assigned based on residential postal codes at the time of sera collection. Single-exposure logistic regressions were performed for ACPA positivity defined by 20 U/ml, 40 U/ml, and 60 U/ml thresholds, adjusting for age, sex, French Canadian origin, smoking, and family income. Associations between regional overall PM2.5 exposure and ACPA positivity were also investigated. The associations between the combined three industrial exposures and the ACPA positivity were assessed by weighted quantile sum (WQS) regressions. Results Significant associations between individual industrial exposures and ACPA positivity defined by the 20 U/ml threshold were seen with single-exposure logistic regression models, for industrial emissions of PM2.5 (odds ratio, OR = 1.19, 95% confidence intervals, CI: 1.04–1.36) and SO2 (OR = 1.03, 95% CI: 1.00–1.06), without clear associations for NO2 (OR = 1.01, 95% CI: 0.86–1.17). Similar findings were seen for the 40 U/ml threshold, although at 60 U/ml, the results were very imprecise. The WQS model demonstrated a positive relationship between combined industrial exposures and ACPA positivity (OR = 1.36, 95% CI: 1.10–1.69 at 20 U/ml) and suggested that industrial PM2.5 may have a closer association with ACPA positivity than the other exposures. Again, similar findings were seen with the 40 U/ml threshold, though 60 U/ml results were imprecise. No clear association between ACPA and regional overall PM2.5 exposure was seen. Conclusions We noted positive associations between ACPA and industrial emissions of PM2.5 and SO2. Industrial PM2.5 exposure may play a particularly important role in this regard.
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    Rheumatoid arthritis-relevant DNA methylation changes identified in ACPA-positive asymptomatic individuals using methylome capture sequencing
    (2019-07-31) Shao, Xiaojian; Hudson, Marie; Colmegna, Ines; Greenwood, Celia M T; Fritzler, Marvin J; Awadalla, Philip; Pastinen, Tomi; Bernatsky, Sasha
    Abstract Objective To compare DNA methylation in subjects positive vs negative for anti-citrullinated protein antibodies (ACPA), a key serological marker of rheumatoid arthritis (RA) risk. Methods With banked serum from a random subset (N = 3600) of a large general population cohort, we identified ACPA-positive samples and compared them to age- and sex-matched ACPA-negative controls. We used a custom-designed methylome panel to conduct targeted bisulfite sequencing of 5 million CpGs located in regulatory or hypomethylated regions of DNA from whole blood (red blood cell lysed). Using binomial regression models, we investigated the differentially methylated regions (DMRs) between ACPA-positive vs ACPA-negative subjects. An independent set of T cells from RA patients was used to “validate” the differentially methylated sites. Results We measured DNA methylation in 137 subjects, of whom 63 were ACPA-positive, 66 were ACPA-negative, and 8 had self-reported RA. We identified 1303 DMRs of relevance, of which one third (402) had underlying genetic effects. These DMRs were enriched in intergenic CpG islands (CGI) and CGI shore regions. Furthermore, the genes associated with these DMRs were enriched in pathways related to Epstein-Barr virus infection and immune response. In addition, 80 (38%) of 208 RA-specific DMRs were replicated in T cells from RA samples. Conclusions Sequencing-based high-resolution methylome mapping revealed biologically relevant DNA methylation changes in asymptomatic individuals positive for ACPA that overlap with those seen in RA. Pathway analyses suggested roles for viral infections, which may represent the effect of environmental triggers upstream of disease onset.
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    Statin-induced anti-HMGCR myopathy: successful therapeutic strategies for corticosteroid-free remission in 55 patients
    (2020-01-08) Meyer, Alain; Troyanov, Yves; Drouin, Julie; Oligny-Longpré, Geneviève; Landon-Cardinal, Océane; Hoa, Sabrina; Hervier, Baptiste; Bourré-Tessier, Josiane; Mansour, Anne-Marie; Hussein, Sara; Morin, Vincent; Rich, Eric; Goulet, Jean-Richard; Chartrand, Sandra; Hudson, Marie; Nehme, Jessica; Makhzoum, Jean-Paul; Zarka, Farah; Villeneuve, Edith; Raynauld, Jean-Pierre; Landry, Marianne; O’Ferrall, Erin K; Ferreira, Jose; Ellezam, Benjamin; Karamchandani, Jason; Larue, Sandrine; Massie, Rami; Isabelle, Catherine; Deschênes, Isabelle; Leclair, Valérie; Couture, Hélène; Targoff, Ira N; Fritzler, Marvin J; Senécal, Jean-Luc
    Abstract Objective To describe successful therapeutic strategies in statin-induced anti-HMGCR myopathy. Methods Retrospective data from a cohort of 55 patients with statin-induced anti-HMGCR myopathy, sequentially stratified by the presence of proximal weakness, early remission, and corticosteroid and IVIG use at treatment induction, were analyzed for optimal successful induction and maintenance of remission strategies. Results A total of 14 patients achieved remission with a corticosteroid-free induction strategy (25%). In 41 patients treated with corticosteroids, only 4 patients (10%) failed an initial triple steroid/IVIG/steroid-sparing immunosuppressant (SSI) induction strategy. Delay in treatment initiation was independently associated with lower odds of successful maintenance with immunosuppressant monotherapy (OR 0.92, 95% CI 0.85 to 0.97, P = 0.015). While 22 patients (40%) presented with normal strength, only 9 had normal strength at initiation of treatment. Conclusion While corticosteroid-free treatment of anti-HMGCR myopathy is now a safe option in selected cases, initial triple steroid/IVIG/SSI was very efficacious in induction. Delays in treatment initiation and, as a corollary, delays in achieving remission decrease the odds of achieving successful maintenance with an SSI alone. Avoiding such delays, most notably in patients with normal strength, may reset the natural history of anti-HMGCR myopathy from a refractory entity to a treatable disease.