Environmental Triggers for Vasculitis Katz, Guy; Wallace, Zachary S
Rheumatic diseases clinics of North America,
11/2022, Volume:
48, Issue:
4
Journal Article
Peer reviewed
Open access
Systemic vasculitides are autoimmune diseases characterized by vascular inflammation. Most types of vasculitis are thought to result from antigen exposure in genetically susceptible individuals, ...suggesting a likely role for environmental triggers in these conditions. Seasonal and geographic variations in incidence provide insight into the potential role of environmental exposures in these diseases. Many data support infectious triggers in some vasculitides, whereas other studies have identified noninfectious triggers, such as airborne pollutants, silica, smoking, and heavy metals. We review the known and suspected environmental triggers in giant cell arteritis, Takayasu arteritis, polyarteritis nodosa, Kawasaki disease, and antineutrophil cytoplasmic antibody-associated vasculitis.
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small- to medium-vessel necrotizing vasculitis responsible for excess morbidity and mortality (1). The AAVs, which include ...granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA), are among the most difficult types of vasculitis to treat. Although clinicopathologic disease definitions have been used traditionally to categorize patients into one of these three diagnoses, more recently ANCA specificity for either proteinase 3 (PR3) or myeloperoxidase (MPO) has been advocated for the purpose of disease classification (2). This is because differences in genetics, pathogenesis, risk factors, treatment responses, and outcomes align more closely with PR3- or MPO-ANCA type than with the clinocopathologic diagnosis. Moreover, classifying patients as GPA or MPA can be challenging because biopsies are not obtained routinely in most cases and existing classification systems can provide discrepant classification for the same patient (3). In this review, we address the recent literature supporting the use of ANCA specificity to study and personalize the care of AAV patients (Table 1). We focus particularly on patients with GPA or MPA.
Objective
A prior study showed that premature mortality among patients with end‐stage renal disease (ESRD) due to lupus nephritis (LN) persisted in the US between 1995 and 2006. The present study was ...undertaken to extend this analysis through 2014 to examine more recent trends, including key cause‐specific mortality trends.
Methods
Using the national registry of patients with ESRD, we identified all patients with incident ESRD due to LN between January 1, 1995 and December 31, 2014, divided into four 5‐year cohorts of ESRD onset by calendar year (1995–1999, 2000–2004, 2005–2009, 2010–2014). We assessed mortality within each cohort. Temporal trends in all‐cause mortality and cause‐specific mortality were examined, adjusting for covariates.
Results
We identified 20,974 individuals with incident ESRD due to LN from 1995 through 2014. The mortality rate per 100 patient‐years declined from 11.1 (95% confidence interval 95% CI 10.4–11.8) in 1995–1999 to 6.7 (95% CI 6.2–7.2) in 2010–2014 (P for trend < 0.01). Adjusted mortality hazard ratios in 2010–2014, compared with 1995–1999, were 0.68 (95% CI 0.58–0.78) for white patients, 0.67 (95% CI 0.57–0.78) for African American patients, and 0.51 (95% CI 0.38–0.69) for Hispanic patients. Deaths from cardiovascular disease (CVD) and infection declined by 44% and 63%, respectively, from 1995–1999 to 2010–2014 (P for trend < 0.01 for both).
Conclusion
In the more recent years of the period 1995–2014, there was a considerable reduction in all‐cause mortality among white, African American, and Hispanic patients, with reduced risk of death from CVD and infection. Collectively, these trends provide an important benchmark of improving care in this high‐risk population.
Fibrosis is a predominant feature of IgG4-related disease (IgG4-RD). B-cell depletion induces a prompt clinical and immunological response in patients with IgG4-RD, but the effects of this ...intervention on fibrosis in IgG4-RD are unknown. We used the enhanced liver fibrosis (ELF) score to address the impact of rituximab on fibroblast activation. The ELF score is an algorithm based on serum concentrations of procollagen-III aminoterminal propeptide, tissue inhibitor of matrix metalloproteinase-1 and hyaluronic acid.
Ten patients with active, untreated IgG4-RD were enrolled. ELF scores were measured and correlated with the IgG4-RD Responder Index, serum IgG4, circulating plasmablasts and imaging studies. Through immunohistochemical stains for CD3, CD20, IgG4 and α-smooth muscle actin, we assessed the extent of the lymphoplasmacytic infiltration and the degree of fibroblast activation in one patient with tissue biopsies before and after rituximab.
The ELF score was increased in patients with IgG4-RD compared with healthy controls (8.3±1.4 vs 6.2±0.9; p=0.002) and correlated with the number of organs involved (R(2)=0.41; p=0.04). Rituximab induced significant reductions in the ELF score, the number of circulating plasmablasts and the IgG4-RD Responder Index (p<0.05 for all three parameters). Rituximab reduced both the lymphoplasmacytic infiltrate and myofibroblast activation. IgG4-RD relapse coincided with recurrent increases in the ELF score, indicating reactivation of collagen deposition.
The ELF score may be a clinically useful indicator of active fibrosis and the extent of disease in IgG4-RD. B-cell depletion has the potential to halt continued collagen deposition by attenuating the secretory phenotype of myofibroblasts in IgG4-RD lesions.
Objective
Four autoantigens have been described recently in IgG4‐related disease (IgG4‐RD): prohibitin, annexin A11, laminin 511‐E8, and galectin‐3. However, no external validation has been ...performed, and the possibility that some individuals break tolerance to more than 1 autoantigen has not been explored. We undertook this study to evaluate the relative frequencies of antibody responses against these autoantigens in order to explore the role of adaptive immune response in IgG4‐RD.
Methods
Autoantibody responses against prohibitin, annexin A11, and laminin 511‐E8 were measured among a clinically diverse cohort of IgG4‐RD patients (n = 100) using enzyme‐linked immunosorbent assays. Autoantibody responses were correlated with disease severity and organ distribution.
Results
The frequencies of IgG4 autoantibody responses against prohibitin (10%), annexin A11 (12%), and laminin 511‐E8 (7%) were not significantly different from those of controls. A portion of the cohort (n = 86) had been analyzed previously at our center for anti–galectin‐3 antibody responses, with 25 patients (29%) having IgG4 anti–galectin‐3 antibodies. Of these 86 patients, 32 (37%) had IgG4 antibodies to ≥1 of the 4 autoantigens and 12 (14%) showed reactivity with ≥2 of the tested antigens. The subset of patients with ≥2 autoantibodies had higher total levels of IgG1, IgG2, IgG4, and C‐reactive protein, were more commonly hypocomplementemic, and were more likely to have visceral organ involvement.
Conclusion
Antibodies against prohibitin, annexin A11, and laminin 511‐E8 were found in only a small portion of patients with IgG4‐RD. A subset of IgG4‐RD patients, however, had IgG4 antibodies against ≥2 autoantigens. These patients presented with robust IgG subclass elevations, complement consumption, and visceral organ involvement. This broader break in immunologic tolerance in IgG4‐RD was associated with more severe disease.
To summarize the findings of studies investigating patients with rheumatoid arthritis (RA) and risk of acute and postacute COVID-19 outcomes 3 years into the pandemic.
Most studies early in the ...pandemic included all patients with systemic autoimmune rheumatic diseases (SARDs), not only those with RA, due to limited sample size. Many of these studies found that patients with SARDs were at higher risk of COVID-19 infection and severe outcomes, including hospitalization, hyperinflammation, mechanical ventilation, and death. Studies performed later were able to focus on RA and found similar associations, while also identifying RA-specific factors such as immunosuppressive medications, disease activity/severity, and interstitial lung disease as risk factors for severe COVID-19. After COVID-19 vaccination, the risks for COVID-19 infection and severity were reduced for patients with RA, but a gap between the general population persisted, and some patients with RA are susceptible to breakthrough infection after vaccination. Preexposure prophylaxis, effective treatments, and changes in viral variants have also contributed to improved COVID-19 outcomes throughout the pandemic. Emerging data suggest that patients with RA may be at risk for postacute sequelae of COVID-19 (PASC).
Although COVID-19 outcomes have improved over the pandemic for patients with RA, some experience poor acute and postacute outcomes after COVID-19. Clinicians and patients should remain vigilant about risk mitigation for infection and consider early treatment for RA patients with COVID-19. Future studies are needed to investigate clinical outcomes and mechanisms of PASC among patients with RA.
Patients with end-stage renal disease (ESRD) due to lupus nephritis (LN) have high rates of premature death.
To assess the potential effect on survival of renal transplant among patients with ESRD ...due to LN (LN-ESRD) in the United States.
Nationwide cohort study.
United States Renal Data System, the national database of nearly all patients with ESRD.
Patients with incident LN-ESRD who were waitlisted for a renal transplant.
First renal transplant was analyzed as a time-varying exposure. The primary outcomes were all-cause and cause-specific mortality. Time-dependent Cox regression analysis was used to estimate the hazard ratio (HR) of these outcomes associated with renal transplant in the primary analysis. Sequential cohort matching was used in a secondary analysis limited to patients with Medicare, which allowed assessment of time-varying covariates.
During the study period, 9659 patients with LN-ESRD were waitlisted for a renal transplant, of whom 5738 (59%) had a transplant. Most were female (82%) and nonwhite (60%). Transplant was associated with reduced all-cause mortality (adjusted HR, 0.30 95% CI, 0.27 to 0.33) among waitlisted patients. Adjusted HRs for cause-specific mortality were 0.26 (CI, 0.23 to 0.30) for cardiovascular disease, 0.30 (CI, 0.19 to 0.48) for coronary heart disease, 0.41 (CI, 0.32 to 0.52) for infection, and 0.41 (CI, 0.31 to 0.53) for sepsis.
Unmeasured factors may contribute to the observed associations; however, the E-value analysis suggested robustness of the results.
Renal transplant was associated with a survival benefit, primarily due to reduced deaths from cardiovascular disease and infection. The findings highlight the benefit of timely referral for transplant to improve outcomes in this population.
National Institutes of Health.
Objective
IgG4‐related disease (IgG4‐RD) can cause fibroinflammatory lesions in nearly any organ, leading to organ dysfunction and failure. The IgG4‐RD Responder Index (RI) was developed to help ...investigators assess the efficacy of treatment in a structured manner. The aim of this study was to validate the RI in a multinational investigation.
Methods
The RI guides investigators through assessments of disease activity and damage in 25 domains, incorporating higher weights for disease manifestations that require urgent treatment or that worsen despite treatment. After a training exercise, investigators reviewed 12 written IgG4‐RD vignettes based on real patients. Investigators calculated both an RI score as well as a physician's global assessment (PhGA) score for each vignette. In a longitudinal assessment, 3 investigators used the RI in 15 patients with newly active disease who were followed up over serial visits after treatment. We assessed interrater and intrarater reliability, precision, validity, and responsiveness.
Results
The 26 physician investigators included representatives from 6 specialties and 9 countries. The interrater and intrarater reliability of the RI was strong (0.89 and 0.69, respectively). Correlations (construct validity) between the RI and PhGA were high (Spearman's r = 0.9, P < 0.0001). The RI was sensitive to change (discriminant validity). Following treatment, there was significant improvement in the RI score (mean change 10.5 95% confidence interval (95% CI) 5.4–12, P < 0.001), which correlated with the change in the PhGA. Urgent disease and damage were captured effectively.
Discussion
In this international, multispecialty study, we observed that the RI is a valid and reliable disease activity assessment tool that can be used to measure response to therapy.
IgG4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory condition that can affect multiple organs and lead to tumefactive, tissue-destructive lesions. Reports have described ...inflammatory aortitis and periaortitis, the latter in the setting of retroperitoneal fibrosis (RPF), but have not distinguished adequately between these 2 manifestations. The frequency, radiologic features, and response of vascular complications to B cell depletion remain poorly defined. We describe the clinical features, radiology findings, and treatment response in a cohort of 36 patients with IgG4-RD affecting large blood vessels.
Clinical records of all patients diagnosed with IgG4-RD in our center were reviewed. All radiologic studies were reviewed. We distinguished between primary large blood vessel inflammation and secondary vascular involvement. Primary involvement was defined as inflammation in the blood vessel wall as a principal focus of disease. Secondary vascular involvement was defined as disease caused by the effects of adjacent inflammation on the blood vessel wall.
Of the 160 IgG4-RD patients in this cohort, 36 (22.5%) had large-vessel involvement. The mean age at disease onset of the patients with large-vessel IgG4-RD was 54.6 years. Twenty-eight patients (78%) were male and 8 (22%) were female. Thirteen patients (36%) had primary IgG4-related vasculitis and aortitis with aneurysm formation comprised the most common manifestation. This affected 5.6% of the entire IgG4-RD cohort and was observed in the thoracic aorta in 8 patients, the abdominal aorta in 4, and both the thoracic and abdominal aorta in 3. Three of these aneurysms were complicated by aortic dissection or contained perforation. Periaortitis secondary to RPF accounted for 27 of 29 patients (93%) of secondary vascular involvement by IgG4-RD. Only 5 patients demonstrated evidence of both primary and secondary blood vessel involvement. Of those treated with rituximab, a majority responded positively.
IgG4-RD is a distinctive, unique, and treatable cause of large-vessel vasculitis. It can also involve blood vessels secondary to perivascular tumefactive lesions. The most common manifestation of IgG4-related vasculitis is aortitis with aneurysm formation. The most common secondary vascular manifestation is periaortitis with relative sparing of the aortic wall. Both primary vasculitis and secondary vascular involvement respond well to B cell depletion therapy.
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