And ANCA-associated Vasculitis Research Articles

Epitope Spreading in Immune-Mediated Glomerulonephritis: The Expanding Target

Epitope spreading is a critical mechanism driving the progression of autoimmune glomerulonephritis. This phenomenon, where immune responses broaden from a single epitope to encompass additional targets, contributes to the complexity and severity of diseases such as membranous nephropathy (MN), lupus nephritis (LN), and ANCA-associated vasculitis (AAV). In MN, intramolecular spreading within the phospholipase A2 receptor correlates with a worse prognosis, while LN exemplifies both intra- and intermolecular spreading, exacerbating renal involvement. Similarly, ANCA reactivity in AAV highlights the destructive potential of epitope diversification. Understanding these immunological cascades reveals therapeutic opportunities—targeting early epitope spreading could curb disease progression. Despite promising insights, the clinical utility of epitope spreading as a prognostic tool remains debated. This review provides a complete overview of the current evidence, exploring the dual-edged nature of epitope spreading, the intricate immune mechanisms behind it, and its therapeutic implications. By elucidating these dynamics, we aim to pave the way for more precise, targeted interventions in autoimmune glomerular diseases.

Real-life drug retention rate and safety of rituximab when treating rheumatic diseases: a single-centre Swiss retrospective cohort study

BackgroundIn Switzerland, rituximab (RTX) is licenced for the treatment of rheumatoid arthritis (RA) and ANCA-associated vasculitis (AAV) but is frequently used off-label to treat other auto-immune diseases (AID), especially connective tissue diseases (CTD). We aimed to characterise the use of RTX in AID in a real-life Swiss setting and compare RTX retention rates and safety outcomes between patients treated for RA, CTD and AAV.MethodsA retrospective cohort study of patients who started RTX in the Rheumatology Department for RA or AID. The RTX retention rate was analysed using Kaplan–Meier survival curves. Occurrences of serious adverse events (SAE), low IgG levels and anti-drug antibodies (ADA) were reported.ResultsTwo hundred three patients were treated with RTX: 51.7% had RA, 29.6% CTD, 9.9% vasculitis and 8.9% other AIDs. The total observation time was 665 patient-years. RTX retention probability at 2 years (95%CI) was similar for RA and CTD 0.65 (0.55 to 0.73), 0.60 (0.47 to 0.72) and lower for vasculitis 0.25 (0.09 to 0.45). Survival curves for RTX retention matched closely (p = 0.97) between RA and CTD patients but were lower for patients with vasculitis due to a higher percentage of induced remission. Patients with vasculitis (95%) and CTD (75%) had a higher rate of concomitant glucocorticoid use than RA (60%). Moderate to severe hypogammaglobulinaemia was observed more frequently in patients with vasculitis (35%) than with RA (13%) or CTD (9%) and was associated with an increased risk of presenting a first infectious SAE (HR 2.01, 95% CI 1.04 to 3.91). The incidence rate of SAE was 23.3 SAE/100 patient-years (36% were infectious). When searched, ADAs were observed in 18% of the patients and were detected in 63% of infusions-related SAE. 10 patients died during RTX treatment and up to 12 months after the last RTX infusion, 50% from infection.ConclusionRTX retention rates are similar for patients with RA and CTD but lower for those with vasculitis due to more frequent remission. Patients treated with RTX for vasculitis present more SAE and infectious SAE than patients with RA and CTD, potentially due to a higher use of concomitant glucocorticoids and the occurrence of hypogammaglobulinaemia.

Rapidly progressive glomerulonephritis secondary to anti-GBM disease associated with MPO-ANCA: a case report

BackgroundAnti-glomerular basement membrane (GBM) disease and ANCA-associated vasculitis (AAV) diseases are rare. It is associated with variable renal manifestations and increased mortality, thus requiring early aggressive treatment to minimize adverse outcomes and improve prognosis.Case presentationWe present the case of a male patient with 1-month onset of asthenia, adynamia, oliguria, and weight loss. Initial laboratory findings were indicative of severe kidney dysfunction. The urinalysis showed active sediment, but the urinary tract ultrasound was unaltered. As these findings were consistent with rapidly progressive glomerulonephritis, he received steroid pulses, and given the severity of the condition, renal replacement therapy was initiated. Other diagnostic tests revealed MPO-ANCA antibody levels of 26 mg/dl, pANCAs 1/320, and anti-GBM of 8 mg/dl. Kidney biopsy evidenced necrotizing glomerulonephritis with extracapillary proliferation in 90% of the glomeruli. The patient received plasma exchange (PE) therapy and intravenous (IV) cyclophosphamide (CYC) cycles; however, he presented with severe alveolar hemorrhage requiring the completion of 21 PE sessions and 3 CYC boluses. Pulmonary symptoms resolved, but the patient persisted dependent on dialysis. During the outpatient follow-up, monthly CYC were prescribed until circulating antibody levels were normal; however, the patient did not recover full kidney function and remained dependent on renal support.ConclusionsAnti-GBM and AAV diseases are rare; therefore, anti-GBM antibodies should be screened simultaneously in patients with ANCA positive, especially in older patients, due to the early morbidity and mortality typical of anti-GBM disease with comparable disease severity it represents.

Syk Activation in Circulating and Tissue Innate Immune Cells in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

Syk is a cytoplasmic protein tyrosine kinase that plays a role in signaling via B cell and Fc receptors (FcR). FcR engagement and signaling via Syk is thought to be important in antineutrophil cytoplasm antibody (ANCA) IgG-mediated neutrophil activation. This study was undertaken to investigate the role of Syk in ANCA-induced myeloid cell activation and vasculitis pathogenesis. Phosphorylation of Syk in myeloid cells from healthy controls and ANCA-associated vasculitis (AAV) patients was analyzed using flow cytometry. The effect of Syk inhibition on myeloperoxidase (MPO)-ANCA IgG activation of cells was investigated using functional assays (interleukin-8 and reactive oxygen species production) and targeted gene analysis with NanoString. Total and phosphorylated Syk at sites of tissue inflammation in patients with AAV was assessed using immunohistochemistry and RNAscope in situ hybridization. We identified increased phosphorylated Syk at critical activatory tyrosine residues in blood neutrophils and monocytes from patients with active AAV compared to patients with disease in remission or healthy controls. Syk was phosphorylated in vitro following MPO-ANCA IgG stimulation, and Syk inhibition was able to prevent ANCA-mediated cellular responses. Using targeted gene expression analysis, we identified up-regulation of FcR- and Syk-dependent signaling pathways following MPO-ANCA IgG stimulation. Finally, we showed that Syk is expressed and phosphorylated in tissue leukocytes at sites of organ inflammation in AAV. These findings indicate that Syk plays a critical role in MPO-ANCA IgG-induced myeloid cell responses and that Syk is activated in circulating immune cells and tissue immune cells in AAV; therefore, Syk inhibition may be a potential therapeutic option.

Clinicopathological characteristics and disease chronicity in native kidney biopsies in Flanders.

The Flemish Collaborative Glomerulonephritis Group (FCGG) registry provides complete population data on kidney disease epidemiology in the region of Flanders (Belgium), as it captures all native kidney biopsies performed in its population of 6.5 million inhabitants. From 2017 until 2019, 2054 adult kidney biopsies were included from 26 nephrology centers (one biopsy per patient). Data on nephrotic and nephritic syndrome were available in 1992 and 2026 biopsies, respectively. In a subgroup of 898 biopsies containing ≥10 glomeruli from 2018 to 2019, disease chronicity was graded using the Mayo Clinic Chronicity Score (MCCS). The association between clinical variables and MCCS was determined using simple and multiple linear regression models. Nephrotic syndrome (present in 378 patients, 19.0%) was most frequently caused by minimal change disease in younger patients (18-44 years), membranous nephropathy in older patients (45-74 years) and amyloidosis in the elderly (>75 years). Nephritic syndrome (present in 421 patients, 20.8%) was most frequently caused by immunoglobulin A nephropathy (IgAN) in younger patients (18-64 years) and ANCA-associated vasculitis (AAV) in older patients (>64 years). AAV and IgAN were the most frequent underlying diagnoses in biopsies in which crescents were identified. In multivariable analysis, acute and chronic kidney disease and diagnoses of diabetic kidney disease, nephrosclerosis and hyperoxaluria/hypercalcemic nephropathy were associated with the highest MCCS increases. The FCGG registry validates data from previous Western European registries and provides a snapshot of disease chronicity in the whole biopsied Flemish population.

Palpable purpura: is it associated with vasculitis or not? A single-center experience.

The most common cutaneous manifestation of small vessel vasculitis is palpable purpura. Etiology includes various causes such as infections, malignancies, drugs, and systemic vasculitides. The number of studies that evaluated the etiology of patients presenting with palpable purpura in the adult age group is minimal. This study aimed to determine the etiology in patients presenting with palpable purpura and analyze the clinical features associated with this pathology. We included 85 patients over 18years old who presented with palpable purpura in the study. The presenting demographic characteristics, medical history, systemic examination findings, laboratory, imaging, and histopathological results, and initial treatment of the patients were recorded. At the end of data collection, statistical analyses were performed to determine the patients' final diagnoses and organ involvement. Etiological evaluation revealed Ig A vasculitis (IgAV) in 58.8% (n = 50) of the cases, cutaneous leukocytoclastic vasculitis (CLV) in 23.5% (n = 20), and ANCA-associated vasculitis (AAV) in 3.5% (n = 3). Rheumatologic disease-associated vasculitis (RDaV) was detected in 7.1% (n = 6) of the patients. In 7.1% (n = 6) of the patients, the biopsy results were not compatible with vasculitis (NVH). Palpable purpura can occur due to many reasons. Ig A vasculitis was the most common cause of palpable purpura in our study. • All clinicians should recognize and know palpable purpura and its differential diagnosis. • IgA vasculitis is the most common cause of palpable purpura in adult patients. • In our study, Anca-associated vasculitis (AAV) was found in 3 (3%) of 85 adult patients with palpable purpura.

TGF-β1/Smad Signalling in Proliferative Glomerulonephritis Associated with Autoimmune Diseases.

Glomerulonephritis is a common cause of chronic kidney disease, which has emerged as a major cause of end-stage renal disease. Autoimmune diseases, such as Systemic Lupus Erythematosus (SLE) and ANCA-associated vasculitis (AAV) are often associated with proliferative glomerulonephritis. Transforming growth factor-β1 (TGF-β1) is a cytokine with pleiotropic effects in chronic renal diseases, based on in vivo and in vitro studies. The Smad-dependent signalling pathway plays an important role in the regulation of renal fibrosis (excessive production of extracellular matrix [ECM]) and inflammation. However, clinical trials targeting TGF-β1 have presented disappointing results, suggesting that the downstream signalling is quite complex. The diversity of the effects may associate with the interactions between TGF-β1 signalling and other downstream signalling, as well as the different cellular responses, which TGF-β1 promotes. Recently, macrophage chemoattract and epigenetic effects have also been identified as new mechanisms, wherefore TGF-β1/Smad signalling mediates renal injury. This review provides an overview of the role of TGF-β1/Smad signalling pathway from in vivo and in vitro studies in the pathogenesis of glomerulonephritis and particularly in proliferative glomerulonephritis, which is associated with autoimmune diseases.

A Severe Presentation of Systemic Lupus Erythematosus (SLE) and ANCA-Associated Vasculitis (AAV) Overlap Syndrome

A Severe Presentation of Systemic Lupus Erythematosus (SLE) and ANCA-Associated Vasculitis (AAV) Overlap Syndrome

A Transient Increase in the Serum ANCAs in Patients with SARS-CoV-2 Infection: A Signal of Subclinical Vasculitis or an Epiphenomenon with No Clinical Manifestations? A Pilot Study.

A relationship is emerging between SARS-CoV-2 infections and ANCA-associated vasculitis (AAV) because: (i) the pulmonary involvement of COVID-19 may mimic that observed in patients with AAV; (ii) the two diseases may occur together; (iii) COVID-19 may trigger AAV. However, few cases of AAV have been identified so far in COVID-19 patients. To define the frequency of ANCA autoimmunity in patients with SARS-CoV-2 infection, we analyzed the serum ANCAs and the serum PR3 and MPO antigens by immunoassays in 124 adult patients with a diagnosis of SARS-CoV-2 infection (16 were asymptomatic and 108 were hospitalized) and 48 control subjects. The serum ANCAs were significantly higher in the hospitalized patients compared with either the controls or the asymptomatic patients and increased with the progression of the COVID-19 severity. After one week of hospitalization, the values were significantly lower. In contrast, no differences emerged among the controls, asymptomatic and hospitalized patients for the PR3 and MPO serum levels. None of the patients had clinical signs of AAV with the exception of a severe pulmonary involvement. Further studies are necessary to define whether the increase in the serum ANCAs might mask subclinical vasculitis in a percentage of patients with SARS-CoV-2 infection or it is an epiphenomenon of SARS-CoV-2 infection with no clinical manifestations.

Significance of antineutrophil cytoplasmic antibody positivity in patients with systemic sclerosis: a single-centre pilot study in Korea.

We investigated whether antineutrophil cytoplasmic antibody (ANCA) positivity at diagnosis may be associated with the cross-sectional clinical features at diagnosis and predicting all-cause mortality during follow-up in Korean patients with systemic sclerosis (SSc). In addition, we assessed the incidence of SSc and ANCA-associated vasculitis (AAV) overlap syndrome in patients with ANCA positivity. We retrospectively reviewed the clinical and laboratory features through the medical records of 177 SSc patients who fulfilled the inclusion and exclusion criteria. SSc was classified by the 2013 American College of Rheumatology/European League Against Rheumatism classification criteria. AAV was classified by the 2007 European Medicine Agency algorithms and the 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. The median age was 52 years, and 23 patients were males. The detection rate of ANCA in Korean patients with SSc was 20.3%. Unlike a previous study, ANCA positivity at diagnosis was significantly associated with neither the cross-sectional clinical and laboratory variables at diagnosis nor the rate of all-cause mortality during follow-up in Korean patients with SSc. However, three female patients (8.3%) with ANCA could be classified as having microscopic polyangiitis (MPA) during follow-up. No significant associations of ANCA positivity with the cross-section clinical features or all-cause mortality during follow-up were observed in this study. But, given that 3 of 36 SSc patients with ANCA were classified as having AAV based on the histological confirmation, we suggest that physicians should consider recommending a biopsy when AAV is strongly suspected in SSc patients with ANCA.

Renal and overall outcomes of double-positive (ANCA and anti-GBM antibodies) patients compared to ANCA-associated vasculitis patients with severe renal involvement: A multicenter retrospective study with systematic renal pathology analysis

Objective Double-positive patients (DPPs), combining serum and/or histological findings for glomerular basement membrane (GBM) disease and anti-neutrophil cytoplasmic antibodies (ANCAs), are rare and poorly described. This study aimed to compare characteristics between DPPs and ANCA-associated vasculitis (AAV) patients with severe renal involvement. Method This retrospective multicentre study compared 33 DPPs and 45 AAV patients with severe renal involvement (serum creatinine > 300 μmol/L), all with biopsy-proven nephropathy. Results All DPPs (including 18% exhibiting negative serum anti-GBM antibodies) presented severe acute kidney failure with histological GBM involvement. Compared to AAV patients, they had higher serum creatinine (719 vs 501 μmol/L; p = 0.006) and a higher proportion of patients requiring initial renal replacement therapy (82% vs 36%; p < 0.001). Berden classification differed significantly (p = 0.003), with more crescentic glomerulonephritis and fewer sclerotic lesions in DPPs. One-year renal survival was significantly lower in DPPs than in AAV patients (27% vs 64%; p < 0.0002). With comparable proportions of ANCA subtypes (two-thirds with anti-myeloperoxidase autoantibodies), numbers of extrarenal manifestations (mostly pulmonary in two-thirds), remission-inducing immunosuppressants, and median follow-ups (3 years) between groups, relapse rates were similar: 9.1% of DPPs and 10% of AAV patients. Conclusion Although DPPs have features of both kinds of vasculitis, the anti-GBM component is the dominant phenotype, with more severe renal presentation and prognosis compared to AAV patients with severe renal failure. Simultaneous testing of both antibodies and systematically performed renal biopsy should be recommended in all rapidly progressing glomerulonephritis patients to recognize this difficult-to-treat, rare disease.

Subclinical CMV viremia is associated with increased nosocomial infections and prolonged hospitalization in patients with systemic autoimmune diseases.

Subclinical cytomegalovirus (CMV) viremia has been associated with other infections, prolonged hospitalization, and mortality in select immunosuppressed populations. We examined the incidence and outcomes of subclinical CMV viremia in hospitalized patients with systemic autoimmune diseases (AD) [systemic lupus erythematosus (SLE) or anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV)] using a highly sensitive CMV assay. Prospectively collected samples were obtained from AD hospitalized patients at study entry with a second sample collected 1 week later or at hospital discharge. Controls included age- and gender- matched inpatients without AD and outpatients with AD. All samples were tested in batch using the Abbott RealTime CMV for investigational use assay (RT assay), with a LLOD (LLOQ) at 21 IU/mL (32 IU/mL). Twenty-three inpatients (10 SLE, 8 AAV, 5 controls), and 31 outpatient controls were recruited. Subclinical CMV viremia was found in 61% (11/18) of inpatient AD subjects, 3% (1/31) of outpatient AD subjects, and in none of the five inpatient controls (p<0.001). CMV viremia was associated with increased median length of ICU stay (13 vs. 4 days, p=0.033), hospital stay (17 vs. 9 days, p=0.014) and increased nosocomial infections (7 vs. 1, p=0.007). CMV viremia was not associated with overall severity of illness nor with disease-specific activity or damage. Over one-half of hospitalized AD patients in our cohort had detectable CMV viremia, which was associated with increased length of hospital stay and nosocomial infections. These data suggest that further study of the immunomodulatory effects of subclinical CMV viremia in AD is warranted.

Impact of interstitial lung disease on mortality in ANCA-associated vasculitis: A systematic literature review and meta-analysis.

Several retrospectivee described the association of interstitial lung disease (ILD) and ANCA-associated vasculitis (AAV). However, the relationship between the ILD and mortality in AAV patients have not been established so far. This study aims to estimate the relevance of AAV-associated-ILD (AAV-ILD) and mortality risk by conducting a systematic review and meta-analysis.A comprehensive systematic review was conducted in accordance with the guidelines of PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses). PubMed, Embase.com and the Cochrane Library (Wiley) were searched for original observational studies. Summary estimates were derived with a random-effects model and reported as risk ratio (RR), tested for publication bias and heterogeneity. Ten retrospective cohort studies were included, comprising 526 AAV-ILD patients enrolled from 1974 to 2018. Meta-analysis yielded a pooled RR of 2.90 (95% confidence interval 1.77–4.74) for death among those with AAV-ILD compared to control group. UIP pattern was associated with an even poorer prognosis in comparison to non-UIP pattern (RR 4.36, 95% confidence interval 1.14–16.78). Sensitivity analysis suggested that the meta-RR result was not skewed by a single dominant study. ILD might be associated with a higher mortality risk in AAV patients.

Assessment of glucocorticoid tapering in large vessel and anti-neutrophil cytoplasmic antibody-associated vasculitides.

Glucocorticoids (GC) remain integral to large vessel vasculitis (LVV) and ANCA-associated vasculitis (AAV) treatment. We aimed to assess real-world GC tapering trajectories among patients referred for LVV or AAV and identify factors associated with 'delayed' tapering. Patients first assessed at a vasculitis clinic July 2017-August 2019 for LVV or AAV and taking GC were included. Delayed tapering was defined as prednisone >10 mg above target based on tapering recommendations (2010 British Society of Rheumatology Guidelines for Giant Cell Arteritis, 2015 CanVasc AAV Recommendations). We compared characteristics of patients with delayed and appropriate tapering and assessed barriers to timely tapering though chart reviews and referring physician surveys. 160 patients (65 LVV, 95 AAV) were taking GC at their first visit. Among the 42 (26%) patients with delayed tapering, mean daily prednisone dose was 39.2 mg (SD 14) compared to a target of 15.2 mg (SD 15). Pulse GC were administered to 19/42 (45%) patients with delayed tapering compared to 26/118 (22%) with appropriate tapering (p<0.05). Mean Birmingham Vasculitis Activity Score at treatment onset and GC duration were not significantly different between the two groups. Vision loss and/or stroke was more frequent in LVV referrals who experienced delayed (9/21, 43%) vs. appropriate (6/44, 14%) tapering (p<0.05). Managing risk of vasculitis flare was the most common challenge to tapering GC among surveyed referring physicians. In one quarter of patients referred for LVV or AAV taking GC, tapering was slower than recommended. Promoting timely tapering may reduce GC toxicity.

P0380INFECTION PROFILE AND ASSOCIATED RISK FACTORS IN AGGRESSIVE GLOMERULONEPHRITIS TREATED WITH INDUCTION AND MAINTENANCE REGIMENS OF IMMUNOSUPPRESSIVE THERAPY

Abstract Background and Aims Infections remain an important contributor to the morbidity and mortality of immunosuppressive (IS) therapy in aggressive glomerulonephritis. We sought to investigate the infection profile and associated risk factors in a compiled cohort of patients with lupus nephritis (LN), cryoglobulinemic vasculitis (CryoVas) and ANCA-associated vasculitis (AAV) treated with induction and maintenance IS regimens. Method A total of 162 patients (101 with LN, 24 with CryoVas and 37 with AAV) were retrospectively reviewed for any infection that occurred from initiation of induction therapy. Infections were graded (1-5) according to the Common Terminology Criteria for Adverse Events. Infection site and type of microorganism were also recorded. Univariate and multivariate Cox proportional hazard regression analysis were performed in order to identify independent risk factors for infection. Results Eighty-two patients (50.6%) had at least one infection with a total 179 episodes of infection occurring during a median follow-up of 12 months (IQR:4-36.25 months). The majority of patients (64 of 82) had infections during the first 24 months since IS treatment initiation with a 24-month infection-free rate of 55%. The most common site was lung infection (in 32.7% of patients), while 39.5% of patients had bacterial infections (1.8% with Mycobacterium tuberculosis). 36.7% of patients had severe infections (grade 3 or higher) with 4.4% of infection-related deaths (8 patients). The most common induction regimen was cyclophosphamide in addition to corticosteroids (62%), while 43% received either mycophenolate mofetil or azathioprine in addition to corticosteroids as a maintenance regimen. In univariate Cox regression analysis, chronic obstructive pulmonary disease (HR 3.91; 95% CI, 1.76-8.68, p=0.001), pulmonary involvement in the setting of systemic disease (HR 2.35; 95% CI, 1.26-4.37, p=0.007), pulse methylprednisolone (HR 2.7; 95% CI, 1.7-4.31, p=0.001) and high-dose (≥30 mg/day) oral corticosteroids (HR 3.38; 95% CI, 2.11-5.43, p=0.001) were risk factors for infection. In multivariate Cox regression analysis, high-dose oral corticosteroids (HR 2.67; 95% CI, 1.5-4.76, p=0.001) remained an independent predictor of infection risk. Of the risk factors associated with severe infections (grade 3 or higher), in univariate analysis we identified pulmonary involvement in the setting of systemic disease (HR 3.65; 95% CI, 1.72-7.77, p=0.001), pulse methylprednisolone (HR 3.56; 95% CI, 1.7-7.3, p=0.001), high-dose (≥30 mg/day) oral corticosteroids (HR 3.56; 95% CI, 1.77-7.16, p=0.001), estimated GFR (HR 0.98; 95% CI, 0.98-0.99, p=0.01) and AAV (by comparison to CryoVas and LN) (HR 2.81; 95% CI, 1.39-5.66, p=0.004) as risk factors for infection. After multivariate adjustment, pulmonary involvement in the setting of systemic disease (HR 2.38; 95% CI, 1.01-5.73, p=0.05) and high-dose oral corticosteroids (HR 2.44; 95% CI, 1.04-5.72, p=0.04) were identified as independent predictors of infection risk. Conclusion Infections occur frequently with current immunosuppressive regimens in aggressive glomerulonephritis. In addition to pulmonary involvement in the setting of systemic disease, a high dose corticosteroid regimen was the most significant risk factor for infection.

Worldwide trends in all-cause mortality of auto-immune systemic diseases between 2001 and 2014.

To describe changes in the 2001-2014 mortality of 6 autoimmune systemic diseases (AISDs), namely Systemic Lupus Erythematosus (SLE), Systemic Sclerosis (SSc), Idiopathic Inflammatory Myopathies (IIM), Sjögren's Syndrome (SS), Mixed Connective Tissue Disease (MCTD) and ANCA-associated vasculitis (AAV) at the country-, continent-, and world-levels. Mortality data were retrieved from the World Health Organization (WHO) mortality database for each disease, based on ICD-10 codes. We computed age-standardized mortality rate (ASMR) as the estimated number of deaths per million inhabitants and its 95% confidence interval (95%CI). The association between gender, geographical areas and disease-specific mortality was analyzed using multivariate Poisson regression. The 2001-2014 temporal trends were analyzed using Jointpoint software. In 2014, the worldwide ASMR for SLE was 2.68 (95%CI: 2.62-2.75) deaths/millions inhabitants, 1.46 (1.42-1.51) for SSc, 0.47 (0.44-0.49) for IIM, 0.17 (0.15-0.18) for SS, 0.11 (0.10-0.13) for MCTD and 0.53 (0.50-0.56) for AAV, with ASMRs generally lower in Europe than in North America, Latin America and Asia. Between 2001 and 2014, the worldwide ASMR decreased significantly for SSc (-0.71%/year), IIM (-1.65%/year) and AAV (-1.01%/year; p<.001 for all) and increased for SS (+1.53%/year, p=.01). The worldwide ASMR of SLE decreased significantly between 2001 and 2003 (-6.37%, p<.05) before increasing slightly between 2004 and 2014 (+0.58%, p<.01). We observed a strong heterogeneity of standardized mortality rates across all countries analyzed for 6 autoimmune diseases. Those results further highlight the impact of world-wide inequities and major gaps in access to care and strategies for diagnosis and management of rare diseases, a crucial finding for world-wide physicians, patient associations and policy makers.

Association of NCF1 polymorphism with systemic lupus erythematosus and systemic sclerosis but not with ANCA-associated vasculitis in a Japanese population

Genome-wide association studies of systemic lupus erythematosus (SLE) in Chinese and Korean populations demonstrated strong association of single nucleotide polymorphisms (SNPs) located in the GTF2I-NCF1 region, rs73366469 (GTF2I), rs117026326 (GTF2I), rs80346167(GTF2IRD1) and rs201802880 (NCF1). This region has also been associated with susceptibility to Sjögren syndrome and rheumatoid arthritis; however, association studies with systemic sclerosis (SSc) and ANCA-associated vasculitis (AAV) have not been reported. Here we made an attempt to confirm their associations with SLE in the Japanese population, to find the primarily associated SNP, and to investigate whether these SNPs are also associated with susceptibility to SSc and AAV. By genotyping these four SNPs on 842 SLE, 467 SSc, 477 AAV patients and 934 healthy controls, striking association was confirmed in Japanese SLE. In addition, these SNPs were significantly associated with susceptibility to SSc, but not with AAV. Conditional logistic regression analysis revealed that the association of NCF1 rs201802880, a missense SNP encoding p.Arg90His, can account for the association of other SNPs by linkage disequilibrium. These results suggested that GTF2I-NCF1 region is associated with susceptibility to multiple autoimmune rheumatic diseases but not with AAV, and the primarily associated variant may be the missense SNP in NCF1.

11. Accelerated UIP: a special challenge

IntroductionInterstitial lung disease (ILD) is a progressive fibrotic disease of the lung parenchyma. The lungs are the most common site in rheumatic diseases. ILD may be idiopathic or caused by connective tissue diseases, rheumatoid arthritis, drugs, and infection and radiation therapy. The severity of lung involvement may vary considerably, and, in some cases, it can lead to irreversible fibrosis leading to respiratory failure and eventually death. Although progress has been made in understanding of the disease, there are still significant challenges with the diagnosis and treatment of ILD. This case illustrates the diagnostic and treatment dilemmas.Case description67-year-old gentleman presented with a 4-year history of gradual onset of shortness of breath and dry cough with worsening over 18 months. Additionally, he developed ENT problems including nasal obstruction, polyposis, intermittent crusting with epistaxis and change in voice. He was treated with nasal douches, intermittent short courses of Prednisolone and antibiotics. He then developed joint pains with stiffness and weight loss. He had no other features of CTD or vasculitis. He was a BT Telecom office worker with no exposure to environmental agents, no family history and was an ex-smoker. Other medical history included type 2 diabetes and benign prostate hypertrophy. He was on metformin, finasteride, tamsulosin, fluoxetine and omeprazole.He had grade 2 finger clubbing with inspiratory bibasal crepitations. There was mild joint synovitis and systemic review was otherwise unremarkable. CT scan showed interstitial lung disease with UIP pattern. Initial lung function tests showed normal spirometry with TLCo 84% and KCO 86% predicted. Bloods revealed ACE 100, RF 16, MPO-ANCA 6.0, Eosinophilia 0.82 and CRP 7. A CT scan of the sinuses revealed bilateral ethmoidal polyps and moderate deviation of the nasal septum to the right.Initial treatment with glucocorticoids improved his joints, ENT symptoms significantly and respiratory symptoms marginally. However, his breathlessness and cough deteriorated over the next 6 months alongside lung function and DLco. Repeat CT scan showed progression of ILD with interval worsening of the honeycomb with reducing lung volume. He was tried on MMF but unfortunately deteriorated rapidly which led to hospital admission. CT scan showed new ground glass changes; it was thought to be acute exacerbation of underlying ILD with possible super added infection. He received high dose steroids and antibiotics with no improvement. Serial CXR showed rapid progression consistent with diffuse alveolar damage and he died 8 days after hospital admission.DiscussionThis case wasn’t straightforward. It was difficult to make a unifying diagnosis based on clinical presentation and the investigations. Given the predominant ENT and respiratory symptoms with low levels of MPO the most likely unifying diagnosis considered was primary systemic ANCA vasculitis. Although rare, ILD changes are also seen in MPO positive ANCA vasculitis. The association between interstitial lung disease (ILD) and ANCA-associated vasculitis (AAV), particularly myeloperoxidase MPO - ANCA has been described in the last 2 decades. Given the mild clubbing and rapidly progressing UIP, the alternative diagnosis could have been IPF. However, ENT symptoms and joint pains are usually not associated with IPF. Given the initial response to steroids, further immunosuppression with MMF was started. However, a few days later he was hospitalised due to severe dyspnoea and episodes of haemoptysis. The CT showed new GCO changes on the background of UIP changes and no PE. The dilemma was whether it was drug-induced acute exacerbation of interstitial pneumonitis or natural acceleration of UIP. It was unclear whether he had 2 different pathologies. Disease stratification and early identification of patients who are more prone to progress, and thus in need of more aggressive treatment, is important in the field of ILD.Key learning pointsThere is still significant challenge in the diagnosis and management of ILD. It was unclear whether this case was IPF or MPO vasculitis. There are no specific diagnostic markers and there are no consensus clear guidelines on managing ILD. Although considerable progress has been made in understanding ILD, curing and eliminating interstitial lung disease is still a distant goal. A clearer understanding of how the cells fail to adequately repair the lung and key pathogenetic pathways are much needed and require further exploration. Current clinical trials are studying agents that reduce the fibrotic signalling within the lung, reduce pulmonary hypertension associated with interstitial lung disease, and alleviate oxidative stress. Early diagnosis, monitoring and MDT input are essential to improve overall outcomes. This case illustrates the complexity faced by clinicians in the management of ILD patients in the real-life setting and raises a number of points outside of the clinical guidelines.Conflict of interestThe authors declare no conflicts of interest.

Infectious complications of rituximab therapy in renal disease.

Rituximab, an anti-CD20 monoclonal antibody, was originally used to treat B-cell malignancies. Its use has significantly increased in recent years, as it is now also used to treat a variety of autoimmune diseases including rheumatoid arthritis and ANCA-associated vasculitis (AAV). Initial studies suggested that the adverse effects of rituximab were minimal. Though the risk of malignancy with rituximab-based immunosuppressive regimens appears similar to that of the general population, there are now concerns regarding the risk of infectious complications. Rituximab has been associated with serious infections, including Pneumocystis jiroveci pneumonia (PJP) and the reactivation of hepatitis B virus (HBV) and tuberculosis (TB). The risk of infection appears to be the result of a variety of mechanisms, including prolonged B-cell depletion, B-cell–T-cell crosstalk, panhypogammaglobulinaemia, late-onset neutropenia and blunting of the immune response after vaccination. Importantly, the risk of infectious complications is also related to individual patient characteristics and the indication for rituximab. Individualization of treatment is, therefore, crucial. Particular attention should be given to strategies to minimize the risk of infectious complications, including vaccinating against bacterial and viral pathogens, monitoring white cell count and immunoglobulin levels, prophylaxis against PJP and screening for HBV and TB.

Myeloperoxidase-Antineutrophil Cytoplasmic Antibody (ANCA)-Positive and ANCA-Negative Patients With Granulomatosis With Polyangiitis (Wegener's): Distinct Patient Subsets.

To examine the relationship of antineutrophil cytoplasmic antibody (ANCA) type and ANCA-associated vasculitis (AAV) diagnosis with demographic features, disease manifestations, and clinical outcomes. We focused on patients who account for the differences between ANCA type and disease type classifications: anti-myeloperoxidase (MPO)-ANCA-positive and ANCA-negative patients with granulomatosis with polyangiitis (Wegener's) (GPA). We performed a pooled analysis of the Wegener's Granulomatosis Etanercept Trial and the Rituximab in ANCA-Associated Vasculitis trial comparing patients with MPO-ANCA-positive GPA and patients with ANCA-negative GPA to patients with proteinase 3 (PR3)-ANCA-positive GPA and patients with MPO-ANCA-positive microscopic polyangiitis (MPA). Of the 365 patients analyzed, 273 (75%) had PR3-ANCA-positive GPA, 33 (9%) had MPO-ANCA-positive GPA, 15 (4%) had ANCA-negative GPA, and 44 (12%) had MPO-ANCA-positive MPA. MPO-ANCA-positive GPA patients were younger at diagnosis compared to MPO-ANCA-positive MPA patients (53 versus 61 years; P = 0.02). Their disease manifestations and rates of relapse were similar to those of PR3-ANCA-positive GPA patients. Relapse was more frequent in MPO-ANCA-positive GPA patients than in patients with MPO-ANCA-positive MPA at trial entry as well as at 12 and 18 months. ANCA-negative patients with GPA had lower Birmingham Vasculitis Activity Score for Wegener's Granulomatosis scores at trial entry than PR3-ANCA-positive patients with GPA (4.5 versus 7.7; P < 0.01), primarily because of a lower prevalence of renal involvement. We were unable to demonstrate important clinical differences between MPO-ANCA-positive and PR3-ANCA-positive patients with GPA. The risk of relapse was associated more closely with disease type than with ANCA type in this patient cohort. These findings deserve consideration in the assessment of relapse risk in patients with AAV.