Welcome to the 13th International Congress on Autoimmunity interactive program

Background and Aims

COVID-19 pandemic affected our management of systemic vasculitides. To provide the best care, daily practice has had to be adjusted. We aimed to evaluate how successful we were in the management of systemic vasculitides during pandemic.

Methods

We analysed medical records of adult patients diagnosed with a systemic vasculitis before (Jan/2010-Feb/2020; overall 122 months) and during COVID-19 pandemic (Mar/2020 – Sep/2021; overall 19 months) at our secondary/tertiary medical centre. Variations in the frequency, delays to diagnosis (symptom duration time until diagnosis) and the baseline activity of the most commonly diagnosed vasculitides, i.e. GCA, IgA vasculitis, AAV and cryoglobulinemic vasculitis (CryoV) were recorded. Disease activity/severity was assessed by the BVAS (version 3) for small vessel vasculitides, and by assessing the development of permanent ischemic complications (permanent vision defect and/or ischemic stroke) in GCA.

Results

During the pandemic period, we diagnosed 122 new cases of GCA, IgAV, AAV, and CryoV (51, 33, 32, and 6 cases, respectively). Whereas the frequency per year of new GCA, IgAV and CryoV cases was comparable to pre-pandemic period, we diagnosed AAV nearly 3-times more frequently during the pandemic compared to average pre-pandemic year. Table 1 shows the median (IQR) symptom duration time and disease activity at presentation. In spite of the COVID-19 pandemic, neither was the symptom duration time longer nor was the baseline disease activity higher compared to the pre-pandemic decade.

Conclusions

The frequency of AAV increased during COVID-19 pandemic. Despite a lockdown during pandemic, we did not record any significant delay in diagnosing systemic vasculitides.

Background and Aims

Trained immunity (TI) is a de facto innate immune memory program of monocyte/macrophages, mechanistically characterized by immunometabolic and epigenetic changes sustaining persistent inflammatory activation with enhanced cytokine production. TI evolved as a protective mechanism against infections; however, maladaptive activation can cause detrimental inflammation and might be implicated in the pathogenesis of RMDs. In this study, we investigated the role of maladaptive TI in the pathogenesis of Giant Cell Arteritis (GCA).

Methods

Monocytes from a large cohort of clinically active GCA patients (ie, at diagnosis or during disease flares, n=19) and from age- and sex-matched healthy donors were subjected to polyfunctional determinations, including intracellular metabolomics, chromatin immunoprecipitation PCR, ATAC and RNA sequencing, and cytokine production assays. Tissue biopsies from GCA patients were evaluated with immunohistochemistry (IHC) to assess immunometabolic activation. Pharmacologic inhibition of immunometabolic changes underlying TI (ie, glycolysis) was evaluated ex vivo as a therapeutic strategy to suppress cytokine production.

Results

GCA monocytes exhibited hallmark molecular features of TI. Specifically, these included typical immunometabolic changes (eg, increased glycolysis and glutaminolysis through the TCA cycle), epigenetic changes promoting transcription of genes governing pro-inflammatory activation, and enhanced IL-6 production upon inflammatory challenge. IHC revealed that GCA lesions are highly glycolytic microenvironments, and pharmacologic inhibition of glycolysis with 2-deoxy-glucose effectively dampened IL-6 production.

Conclusions

This study reveals the deleterious potential of maladaptive TI in the pathogenesis of GCA, and the therapeutic potential of inhibiting TI for the treatment of this condition.

Background and Aims

Historically complement system was not considered to play a role in ANCA associated-vasculitis (AAV), whereas recent experimental and clinical studies have suggested that the complement cascade, through the alternative pathway, is deeply involved in the pathogenesis of AAV. C5a receptor (Cd88) blockade in mice was shown to protect against MPO vasculitis and Avacopan (formerly CCX168), which is a selective inhibitor of C5a receptor, was shown to reduce the pro-inflammatory effects of C5a.

Methods

The critical trials validating the possible use of Avacopan in clinical practice will be reviewed. A Phase 1 clinical trial in healthy volunteers aimed at examining safety. The Phase 2 trial CLEAR assessed the possibility to reduce or replace glucocorticosteroid in the treatment of AAV. The Phase 3 ADVOCATE trial compared the ability of an Avacopan-based regimen combined with Cyclophosphamide (CYC) or Rituximab (RTX) vs a glucocorticoid-based scheme to induce and sustain remission in AAV patients in the long term.

Results

Safety has been assured over a large range of doses. Compared to glucocorticosteroid-based scheme, the Avacopan regimen combined with CYC or RTX was non-inferior at week 26 and superior at week 52 in sustaining remission

Conclusions

The results of these trials opened new therapeutic prospects for patients with AAV. The possible indications for Avacopan in specific subsets of patients with AAV, and the putative implications in the treatment of other immune-mediated kidney diseases (e.g., C3 GN, lupus nephritis, membranous nephropathy, IgA nephropathy, and others) will be extensively examined.

Background and Aims

Patients with MPO-ANCA vasculitis often suffer from fatigue as observed in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In the current study, we evaluated mitochondrial gene expression, cell free mitochondrial DNA (mtDNA) integrity, mitochondrial mass and cellular death in MPO-ANCA vasculitis patients and healthy controls, as possible biomarkers for fatigue in these patients.

Methods

Mitochondrial gene expression (Dloop, ND4, CyB) was assessed through qPCR. Cell free mitochondrial DNA integrity was defined as the ratio of small to large fragments of 16S-RNA as determined by qPCR. Flow Cytometry with Annexin V (AnV) and Propidium Iodide was used to evaluate cell death.

Results

Expression of ND4 and CyB was reduced in fatigued MPO-ANCA patients (0.26 (0.26); 0.23 (0.19)) when compared to healthy controls (0.47 (0.12); 0.41 (0.09)), (p=0.02; p<0.001) respectively. mtDNA integrity was higher in fatigued MPO-ANCA (1.09 (0.02)) patients when compared to both healthy controls (1.02 (0.05)) (p=0.01) and non-fatigued MPO patients (1.05 (0.04) (p=0.04). Cell death as measured by AnV mean fluorescent intensity was higher in fatigued MPO-AAV patients (22521.5 (19521.4)), than in non-fatigued patients (12522.2 (3579.3)) (p=0.06) and healthy controls (5782.8 (3066.4)) (p=0.01).

Conclusions

A large proportion of AAV patients suffer from co-morbid ME/CFS. These symptoms may be linked to a novel mitochondrial signature affecting the efficiency of the electron transport chain, leading to mitochondrial dysregulation and increased cellular death. Further investigation may lead to the development of pivotal clinical interventions for AAV patients suffering from ME/CFS. 

Funding: Dutch Kidney Foundation (17PhD01) Arthritis Society (19-0558)

Background and Aims

Mass vaccination against SARS-CoV-2 has been the most effective strategy to combat against COVID-19 pandemic. However, different immune-mediated diseases, including cases of myocarditis or glomerulonephritis (GN) have been reported, being anti-neutrophil cytoplasmic antibodies (ANCA) associated vasculitis one of the possible side effects caused by the mass-scale vaccination.

Our aim was to evaluate the incidence of new ANCA positive patients during 2021 in comparison with 2019, before the pandemics.

Methods

This retrospective study included patients from University Hospital Marqués de Valdecilla (reference population: 580,000 inhabitants) who debuted with ANCA (anti-MPO, anti-PR3), and/or anti-MBG antibodies during 2021 discarding the presence of inflammatory bowel disease and who received vaccination against SARS-CoV-2. Likewise, patients who debuted with these autoantibodies in 2019 were also included in order to stablish the corresponding comparisons.

Results

A total of 35 patients presented ANCA or anti-MBG for the first time during 2021, being this number of 15 during 2019. While in 2019, 73.3% of the patients presented anti-MPO antibodies and only 13.3% presented anti-PR3 antibodies, in 2021, 45.7% and 42.9% presented anti-MPO and anti-PR3 antibodies, respectively. Despite the important increase in the prevalence of anti-PR3 antibodies no significant differences were observed between both years (p=0.09). 27 out of 35 patients (77.1%) developed ANCA after receiving SARS-CoV-2 vaccine, being in the 88.6% of the cases BNT162b2 vaccine.

Conclusions

An increase in the development of ANCA has been observed during 2021 in comparison with 2019 which could be due to the administration of SARS-CoV-2 vaccine.

Background and Aims

Cryoglobulinemic Vasculitis (CV) is a rare autoimmune-lymphoproliferative systemic disorder with multiple organ involvement. We aimed at investigating the prevalence and outcome of COVID-19, the safety and immunogenicity of COVID-19 vaccines in a wide CV cohort by a multicenter survey.

Methods

CV subjects were consecutively recruited at 11 Italian referral centers. CV diagnosis, clinico-serological parameters, COVID-19 tests, and vaccination immunogenicity were carried out according to current methods.

Results

Four-hundred-thirty unselected CV patients (130 M; mean age 70±10.96 years) were recruited from February 2020 to October 2021. COVID-19 prevalence was significantly higher in CV patients compared to the Italian general population (p<0.005); furthermore, we observed a higher mortality in CV subjects with COVID-19 compared to those without (p<0.01). An older age (≥60 years) correlated with a worse COVID-19 outcome. Vaccine was administered in 87% of patients, and 50% received a boostering dose. Disease flares/worsening following the vaccination were significantly less frequent than those associated to COVID-19 (p=0.0012). CV patients showed an impaired vaccination immunogenicity compared to controls (p<0.05), as well an increased no-response rate after the booster.

Conclusions

CV patients have a higher risk to develop COVID-19, as well of more severe disease manifestations. Vaccines had a good safety profile in CV patients and of note, the vaccine-related side effects/disease flares were significantly lower compared to those COVID-19-related. However, a quarter of vaccinated individuals do not show detectable seroconversion; this is a major challenge for clinicians. Overall, a close monitoring of these frail patients during the ongoing pandemic is particularly advisable.