Jason Springer

Granulomatosis With Polyangiitis (Wegener’s): Impact of Maintenance Therapy Duration

AbstractTo determine outcomes in relation to duration of maintenance therapy in patients with granulomatosis with polyangiitis (Wegener’s) (GPA), we conducted a retrospective chart review of patients with GPA seen at a single vasculitis center from 1992 to 2010. All patients achieved remission defined by a Birmingham Vasculitis Activity Score for Wegener Granulomatosis (BVAS/WG) of 0 with either cyclophosphamide or methotrexate. After achieving remission all patients were started on maintenance therapy with either methotrexate or azathioprine.The study comprised 157 patients with a median follow-up of 3.1 years. Using a univariate model, the continuation of maintenance medications for >18 months showed a 29% reduction in hazard ratio (HR) for relapse (HR, 0.71; 95% confidence interval [CI], 0.42–1.19; p = 0.19). Treatment for >36 months showed a 66% reduction in hazard ratio for relapse (HR, 0.34; 95% CI, 0.15–0.76; p = 0.008). When length of treatment was considered as a continuous factor, longer courses had an inverse relationship with the risk of relapse (HR, 0.70; 95% CI, 0.58–0.84; p < 0.001), which remained significant after adjusting for prednisone dose (HR, 0.59; 95% CI, 0.42–0.83; p = 0.003). Fifty-two percent of relapses occurred while the patients were off maintenance therapy. Among all patients who relapsed on therapy, 52% of those receiving methotrexate were on <15 mg/week, and 67% of those receiving azathioprine were on ⩽50 mg/d. There were no differences between the short- and long-term maintenance therapy groups in overall adverse events or GPA-related morbidity.Discontinuation or use of low doses of maintenance therapy is associated with a higher relapse rate.

Thrombosis in vasculitis.

Purpose of reviewTo review the association of thrombosis and vasculitis and discuss some of the proposed causal mechanisms. Recent findingsIt is becoming increasingly evident that various systemic inflammatory diseases such as vasculitis are associated with an increased risk of both venous and arterial thrombosis. Increasing evidence supports the use of immunosuppression in the management of venous thrombosis in Behçets disease. An increased incidence of thromboembolic disease in antineutrophil cytoplasmic antibody-associated vasculitis has been recognized, especially during periods of active disease. In addition, a higher risk of ischemic heart disease in these patients has also been observed. As in giant cell arteritis, recent evidence supports the role of aspirin in the prevention of ischemic events in Takayasus disease. SummaryThromboembolic disease is an important complication of several forms of systemic vasculitis, and it may result in significant morbidity and mortality. Many questions such as the role for screening of asymptomatic patients, prevention of thrombosis, and duration of anticoagulation in patients with vasculitis remain unanswered. Future studies exploring the mechanisms of thrombosis and its link to inflammation may provide insights in predicting patients at a higher risk for thrombosis and improve outcomes.

Candida albicans prosthetic shoulder joint infection in a patient with rheumatoid arthritis on multidrug therapy.

C andida spp is a rare cause of infectious arthritis and even more a less common cause of prosthetic joint infection. There have been only 2 reports in the literature of a fungal prosthetic shoulder joint infection. One of these was in a known intravenous drug user. Tumor necrosis factor > (TNF->) inhibitors have been thought to predispose patients to fungal infections. However, there have been no reports of Candida joint infections complicating TNF-> inhibitor therapy. We present the first report of an infection with Candida albicans in a prosthetic shoulder joint in a nonintravenous drug user treated with multiple immunosuppressive agents including etanercept.

Editorial: Classifying Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitides According to ANCA Type or Phenotypic Diagnosis: Salt or Pepper?

Over the past few decades, and through refinements of their definitions and knowledge gained of their genetic backgrounds and pathogeneses, it has been suggested that antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides could be divided into several subsets beyond the classical phenotypic diagnoses of granulomatosis with polyangiitis (Wegener’s) (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA). Particularly, some findings indicated that classifying patients according to ANCA status and specificity could be more pertinent in practice than the phenotypic MPA or GPA diagnosis, since ANCA status might correspond better to the differences in clinical presentations, genetic predispositions, therapeutic responses, relapse risk, and other outcomes (1–3). According to the Chapel Hill Consensus Conference (CHCC) nomenclature of vasculitides, phenotypic diagnosis of GPA, MPA, or EGPA remains the driving force, but the ANCA reactivity must be specified (for example, proteinase 3 [PR3]–ANCA–positive GPA or myeloperoxidase [MPO]–ANCA–positive MPA) (4). Perhaps the ANCA type and phenotypic diagnosis can provide complementary information. Two studies published in this issue of Arthritis & Rheumatology, which are among the first to have systematically looked at the differences and commonalities between patients with PR3ANCA–positive and MPO-ANCA–positive GPA or MPA, provide new and interesting, but also some, apparently, divergent findings (5,6). Miloslavsky et al (5) reanalyzed patients from 2 international randomized controlled trials (RCTs), the Wegener’s Granulomatosis Etanercept Trial (WGET) (7) and the Rituximab in ANCA-Associated Vasculitis (RAVE) trial (8), comparing patients with MPO-ANCA– positive GPA to those with PR3-ANCA–positive GPA or MPO-ANCA–positive MPA. PR3-ANCA–positive GPA patients from those 2 RCTs were also compared to a small subset of 15 patients with ANCA-negative GPA, all from the WGET. More than half of the patients (54%) were enrolled in those RCTs at the time of a relapse, rather than at disease onset. Patients with MPO-ANCA– positive GPA were more frequently female than patients with PR3-ANCA–positive GPA, but these subgroups’ clinical characteristics did not differ. More importantly and intriguingly, with an average follow-up of 18 months after RCT inclusion, relapse rates did not differ significantly between MPO-ANCA–positive GPA and PR3ANCA–positive GPA (Table 1). However, patients with MPO-ANCA–positive GPA were younger and experienced relapses more frequently than those with MPOANCA–positive MPA. The authors conclude that the “risk of relapse [. . .] was associated more closely with disease type than ANCA type” (5). Schirmer et al (6), in contrast, compared patients with MPO-ANCA–positive GPA, from their center’s cohort in Bad Bramstedt, Germany, to ageand sexmatched patients with PR3-ANCA–positive GPA and nonmatched patients with MPO-ANCA–positive MPA. They included no ANCA-negative patients. Compared to the study by Miloslavsky et al, the study by Schirmer et al included slightly fewer PR3-ANCA–positive GPA patients (118 versus 273), but more MPO-ANCA–positive GPA patients (59 versus 33) and MPO-ANCA–positive MPA patients (138 versus 44). Patients with MPO-ANCA– positive GPA in the study by Schirmer et al more often had limited disease and subglottic stenosis than patients with PR3-ANCA–positive GPA, but had less frequent Christian Pagnoux, MD, MPH, MSc: Mount Sinai Hospital, Toronto, Ontario, Canada; Jason Springer, MD, MS: Kansas University, Kansas City. Dr. Pagnoux has received consulting fees, speaking fees, and/ or honoraria from Hoffmann-La Roche, ChemoCentryx, BristolMyers Squibb, Euroimmun, Terumo-BCT, and GlaxoSmithKline (less than

Development and validation of case-finding algorithms for the identification of patients with anti-neutrophil cytoplasmic antibody-associated vasculitis in large healthcare administrative databases

10,000 each) and grant support from Hoffmann-La Roche, Bristol-Myers Squibb, Euroimmun, and Terumo-BCT. Address correspondence to Christian Pagnoux, MD, MPH, MSc, Vasculitis Clinic, Mount Sinai Hospital, 60 Murray Street, Suite 2-220, Toronto, Ontario M5T 3L9, Canada. E-mail: christian. pagnoux@sinaihealthsystem.ca. Submitted for publication July 26, 2016; accepted in revised form August 30, 2016.

Protective Role of Mast Cells in Primary Systemic Vasculitis: A Perspective

The aim of this study was to develop and validate case‐finding algorithms for granulomatosis with polyangiitis (Wegeners, GPA), microscopic polyangiitis (MPA), and eosinophilic GPA (Churg–Strauss, EGPA).

OP0138 Novel Role of Mast Cells in the Regulation of Large Vessel Vasculitis

Mast cells are important cells of the immune system. Although traditionally considered as key players in allergic and hypersensitivity reactions, emerging evidence suggests that mast cells have many complex roles in vascular disease. These include regulation of vasodilation, angiogenesis, activation of matrix metalloproteinases, apoptosis of smooth muscle cells, and activation of the renin angiotensin system. Mast cells are also known to play an immunomodulatory role via modulation of regulatory T-cell (Treg), macrophage and endothelial cell functions. This dual role of the mast cells is evident in myeloperoxidase anti-neutrophil cytoplasmic antibodies-mouse model of glomerulonephritis in which mast cell deficiency worsens glomerulonephritis, whereas inhibition of mast cell degranulation is effective in abrogating the development of glomerulonephritis. Our previous work demonstrated that mast cell degranulation inhibits lipopolysaccharide-induced interleukin 6 (IL-6) production in mice. This effect was not seen in histamine-1-receptor knockout (H1R−/−) mice suggesting a role for histamine in IL-6 homeostasis. In addition, mast cell degranulation-mediated decrease in IL-6 production was associated with an upregulation of suppressor of cytokine signaling-1 protein in the aorta. We propose that mast cells regulate large artery inflammation through T-cells, shifting a primarily Th1 and Th17 toward a Th2 response and leading to enhanced IL-10 production, activation Treg cells, and the inhibition of macrophage functions.

Deficiency of Adenosine Deaminase 2 in Adult Siblings: Many Years of a Misdiagnosed Disease With Severe Consequences

Background Our previous reports suggested that mast cell-mediated innate immune up-regulation plays a key role in vascular inflammation (1-2). The literature also document increased presence of mast cells in the temporal arteries of patients with giant cell arteritis, a type of large vessel vasculitis (LVV) (3). The activation of Toll-like receptor-4 (TLR4) has been implicated in the recruitment of dendritic cells and T-cells into the aortic wall in LVV. Endothelial cells, Th17 T-cells and macrophages produce interleukin 6 [IL-6] which is important in the pathogenesis of LVV. The mechanism by which mast cells modulate the pathogenesis of LVV is not known. Objectives The objective of this study was to test the hypothesis that mast cell degranulation will regulate lipopolysaccharide (LPS, a TLR4 ligand)-induced systemic production of IL6. Methods Two month old male C57BI6/J mice were randomized into 4 groups (N=4/group). They were injected intraperitoneally with saline (control), Compound 48/80 (mast cell degranulator, 1mg/kg), LPS (1mg/kg) or C48/80+LPS. Animals were sacrificed 24 h after injections, and serum IL-6 levels, aortic expressions of mRNAs encoding IL-6, TLR4 and suppressor of cytokine signaling-1 (Socs-1) were determined. Data were analyzed for statistical significance and p<0.05 was considered significant. Results C48/80 injection did not increase serum levels of IL-6 or aortic expression of IL-6 mRNA compared to control. LPS injection significantly enhanced serum IL-6 (350±146 pg/ml vs 21.3±5.5 pg/ml) and aortic IL-6 gene expression (18.0±5.4 fold vs 1.03±0.025 fold). LPS-induced increase in serum IL-6 levels and IL-6 gene expression in the aorta were significantly reduced when mast cell degranulation was simultaneously induced by C48/80 (IL-6: 350±146 pg/ml vs 101±13 pg/ml; IL-6 mRNA: 18.0±5.4 vs 4.3±0.5 fold change). In comparison to controls, the aortic expression of Socs-1 mRNA was 2-fold and 3-fold higher in LPS-treated, and C48/80+LPS-treated mice, respectively. Aortic expression of TLR4 was not affected by any of the treatments. Conclusions The results demonstrate that mast cell degranulation decreases aortic expression of IL-6 mRNA as well as systemic production of IL-6. The decreased expression of IL-6 was associated with increased expression of Socs-1 in aortic tissues. One mechanism by which mast cells regulate LPS-induced systemic production of IL-6 may be by inhibiting the expression of IL-6 mRNA in the vasculature through Socs-1 activation. Since mast cells release many immunomodulatory substances further studies are warranted to identify the regulatory factors. References Talreja J, Kabir MH, Filla B, Stechschulte DJ, Dileepan KN. Histamine induces Toll-like receptor 2 and 4 expression in endothelial cells and enhances sensitivity to Gram-positive and Gram-negative bacterial cell wall components. Immunology. 113:224-33, 2004. Raveendran VV, Tan X, Sweeney ME, Levant B, Slusser J, Stechschulte DJ, Dileepan KN. Lipopolysaccharide induces H1 receptor expression and enhances histamine responsiveness in human coronary artery endothelial cells. Immunology. 132:578-88, 2011. Mayranpaa MI, Trosien JA, Nikkari ST, Kovanen PT. Mast cells associate with T-cells and neointimal microvessels in giant cell arteritis. Clin Exp Rheum. 26 (3 Suppl 49):S63-6, 2008. Acknowledgements Supported by NIH grants R01-HL070101 & 3R01-HL070101-04S1, and Joseph & Elizabeth Carey Arthritis Fund and Audrey Smith Fund from KU Endowment Association. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.2639

SAT0355 Inhibition of Human Aortic Endothelial IL-6 Levels by Candida Albicans Water-Soluble Fraction (CAWS)

Objective Describe the clinical characteristics and histopathology findings in a family with two siblings affected with deficiency of adenosine deaminase 2 (DADA2). Both patients presented in childhood with polyarthritis and developed significant neurological and gastrointestinal features of DADA2 in ear, including variable degrees of immunologic and hematologic manifestations. Methods Adenosine Deaminase 2 (ADA2; also known as cat eye syndrome chromosome region, candidate 1 gene; CECR1) exon sequencing and serum ADA2 levels were performed to confirm the diagnosis of DADA2. Comparison of serum adenosine deaminase 2 levels was made to DADA2 patients, carriers, and healthy controls in Patient 2. Autopsy specimens from brain and liver tissues were submitted for analysis. Results Both patients were found to carry a previously reported rare intronic missense mutation predicted to affect the transcript splicing (c.973-2A > G; rs139750129) and an unreported missense mutation p.Val458Asp (c.1373T > A; V458D). Both brothers started therapy with a tumor necrosis factor inhibitor following the molecular diagnosis of DADA2 with good response and were eventually tapered off prednisone. However, Patient 1 died 18 months later due to complications of end-stage liver disease. His autopsy showed evidence for nodular hyperplasia of the liver often seen in common variable immunodeficiency (CVID) and numerous small, old infarcts throughout the brain that had not been demonstrated on prior MRI/MRA imaging. Conclusion These cases emphasize the importance of recognition of DADA2 in adults, compare CNS imaging modalities to pathologic findings and suggest similarities in liver pathology between DADA2 and CVID. MRI may not be most sensitive method to identify small subcortical infarcts in patients suspected to have DADA2.

Case of NOD2-Associated Autoinflammatory Disease Successfully Treated With Sulfasalazine.

Background Serum interleukin-6 (IL-6) has been shown to closely follow disease activity in large vessel vasculitis1. Prior research by our group has demonstrated that mast cell degranulation downregulates lipopolysaccharide (LPS) induced aortic expression of IL-6 in vivo. This is accompanied by aortic upregulation of SOCS-12. This effect is lost in histamine 1 receptor knockout mice suggesting that histamine is a primary mediator of aortic IL-6 inhibition. Prior studies have also demonstrated that mice injected with Candida albicans water-soluble fraction (CAWS) develop coronary and aortic arteritis3. The mechanism through which arteritis is induced by CAWS remains poorly understood. Objectives The objective of this study is to determine the effects of histamine and CAWS on IL-6 production by human aortic endothelial cells (HAEC) in vitro. Methods HAEC were cultured with histamine (10μM), LPS (100ng/mL), CAWS (10μg/mL), CAWS (1μg/mL) or a combination of these. After 22 hours, levels of IL-6 and 6-ketoprostaglandin-F1α, a breakdown product of prostacyclin, were measured. Microculture tetrazolium (MTT) assays were used to determine cell viability. Results IL-6 levels were significantly lower in cells treated with CAWS 10μg/mL compared to controls (175.2±11.9 vs 270.0 pg/mL, p=0.006). Similarly, IL-6 levels were significantly lower with the addition 10μg/mL CAWS to LPS compared to LPS alone (359.8±37.74 vs 2906.5±318.02, p=0.0001). No significant differences were seen between the 10μg/mL and the 1μg/mL CAWS concentrations. Histamine synergistically enhanced IL-6 levels over LPS alone (3758.0±38.18 vs 2906.5±318.0, p=0.028). CAWS had no effect on prostacyclin levels compared to controls. MTT assays demonstrated no differences in cell viability in CAWS or histamine treated cells compared to controls. Conclusions Our experiments suggest that CAWS inhibits IL-6 production in HAEC. Since IL-6 is a key cytokine in the development of large vessel vasculitis we suspect that endothelial cells do not play a role in CAWS mediated arteritis. Similarly, the inhibitory effects of histamine do not appear to be mediated through endothelial cells. Future research will focus on the in vivo effects of histamine on the development of CAWS mediated vasculitis. References Weyand CM, Fulbright JW, Hunder GG, Evans JM, Goronzy JJ. Treatment of giant cell arteritis: interleukin-6 as a biologic marker of disease activity. Arthritis and rheumatism. May 2000;43(5):1041–1048. Springer J, Raveendran V., Smith D., Maz M., Dileepan K. Novel role of mast cells in the regulation of large vessel vasculitis. Paper presented at: European League Against Rheumatism 2014 meeting; June 12th, 2014, 2014; Paris, France. Nagi-Miura N, Shingo Y, Adachi Y, et al. Induction of coronary arteritis with administration of CAWS (Candida albicans water-soluble fraction) depending on mouse strains. Immunopharmacology and immunotoxicology. 2004;26(4):527–543. Acknowledgement Supported by Basic Science Development Award from Department of Medicine at the University of Kansas. Disclosure of Interest None declared