Mehrdad Maz

2012 provisional classification criteria for polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative

The objective of this study was to develop EULAR/ACR classification criteria for polymyalgia rheumatica (PMR). Candidate criteria were evaluated in a 6-month prospective cohort study of 125 patients with new onset PMR and 169 non-PMR comparison subjects with conditions mimicking PMR. A scoring algorithm was developed based on morning stiffness >45 minutes (2 points), hip pain/limited range of motion (1 point), absence of RF and/or ACPA (2 points), and absence of peripheral joint pain (1 point). A score ≥4 had 68% sensitivity and 78% specificity for discriminating all comparison subjects from PMR. The specificity was higher (88%) for discriminating shoulder conditions from PMR and lower (65%) for discriminating RA from PMR. Adding ultrasound, a score ≥5 had increased sensitivity to 66% and specificity to 81%. According to these provisional classification criteria, patients ≥50 years old presenting with bilateral shoulder pain, not better explained by an alternative pathology, can be classified as having PMR in the presence of morning stiffness>45 minutes, elevated CRP and/or ESR and new hip pain. These criteria are not meant for diagnostic purposes.

2015 Recommendations for the management of polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative

Therapy for polymyalgia rheumatica (PMR) varies widely in clinical practice as international recommendations for PMR treatment are not currently available. In this paper, we report the 2015 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) recommendations for the management of PMR. We used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology as a framework for the project. Accordingly, the direction and strength of the recommendations are based on the quality of evidence, the balance between desirable and undesirable effects, patients’ and clinicians’ values and preferences, and resource use. Eight overarching principles and nine specific recommendations were developed covering several aspects of PMR, including basic and follow-up investigations of patients under treatment, risk factor assessment, medical access for patients and specialist referral, treatment strategies such as initial glucocorticoid (GC) doses and subsequent tapering regimens, use of intramuscular GCs and disease modifying anti-rheumatic drugs (DMARDs), as well as the roles of non-steroidal anti-rheumatic drugs and non-pharmacological interventions. These recommendations will inform primary, secondary and tertiary care physicians about an international consensus on the management of PMR. These recommendations should serve to inform clinicians about best practices in the care of patients with PMR.

Patient-reported Outcomes in Polymyalgia Rheumatica

Objective. To prospectively evaluate the disease course and the performance of clinical, patient-reported outcome (PRO) and musculoskeletal ultrasound measures in patients with polymyalgia rheumatica (PMR). Methods. The study population included 85 patients with new-onset PMR who were initially treated with prednisone equivalent dose of 15 mg daily tapered gradually, and followed for 26 weeks. Data collection included physical examination findings, laboratory measures of acute-phase reactants, and PRO measures. Ultrasound evaluation was performed at baseline and Week 26 to assess for features previously reported to be associated with PMR. Response to corticosteroid treatment was defined as 70% improvement in PMR on visual analog scale (VAS). Results. At baseline, 77% had hip pain in addition to shoulder pain and 100% had abnormal C-reactive protein or erythrocyte sedimentation rate. On ultrasound, 84% had shoulder findings and 32% had both shoulder and hip findings. Response to corticosteroid treatment occurred in 73% of patients by Week 4 and was highly correlated with percentage improvement in other VAS measures. Presence of ultrasound findings at baseline predicted response to corticosteroids at 4 weeks. Factor analysis revealed 6 domains that sufficiently represented all the outcome measures: PMR-related pain and physical function, an elevated inflammatory marker, hip pain, global pain, mental function, and morning stiffness. Conclusion. PRO measures and inflammatory markers performed well in assessing disease activity in patients with PMR. A minimum set of outcome measures consisting of PRO measures of pain and function and an inflammatory marker should be used in practice and in clinical trials in PMR.

2015 recommendations for the management of polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative.

Therapy for polymyalgia rheumatica (PMR) varies widely in clinical practice as international recommendations for PMR treatment are not currently available. In this paper, we report the 2015 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) recommendations for the management of PMR. We used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology as a framework for the project. Accordingly, the direction and strength of the recommendations are based on the quality of evidence, the balance between desirable and undesirable effects, patients’ and clinicians’ values and preferences, and resource use. Eight overarching principles and nine specific recommendations were developed covering several aspects of PMR, including basic and follow‐up investigations of patients under treatment, risk factor assessment, medical access for patients and specialist referral, treatment strategies such as initial glucocorticoid (GC) doses and subsequent tapering regimens, use of intramuscular GCs and disease modifying anti‐rheumatic drugs (DMARDs), as well as the roles of non‐steroidal anti‐rheumatic drugs and non‐pharmacological interventions. These recommendations will inform primary, secondary and tertiary care physicians about an international consensus on the management of PMR. These recommendations should serve to inform clinicians about best practices in the care of patients with PMR.

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

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.

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

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)

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