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Crowned dens syndrome (CDS) is defined as acute cervical or occipital pain due to a local inflammatory reaction related to calcifications in the ligaments surrounding the odontoid process. Virtually, all previous descriptions of CDS have related to calcium pyrophosphate dehydrate (CPPD) arthropathy.We prospectively identified a total of twenty-four consecutive inpatients with Crowned dens syndrome from January 2016 to December 2017 in our institution.All patients (age range 54 to 87 years, 67% females) presented with acute onset pain in the upper neck and/or occiput accompanied with extreme neck stiffness. Most patients (79%) had elevated inflammatory markers. Four patients underwent temporal artery biopsy, which was negative for arteritis in all cases, and one was subjected to lumbar puncture, which was non-contributory. Seventeen patients (71%) had known rheumatic disease on presentation: 10 patients had the diagnosis of calcium pyrophosphate dehydrate arthropathy, 3 patients had ankylosing spondylitis, 2 patients had rheumatoid arthritis, 1 patient had Behcet's disease, and 1 suffered from Familial Mediterranean Fever. In 4 more patients, crowned dens syndrome was the presenting symptom of calcium pyrophosphate dehydrate disease. All patients were treated with glucocorticoids as 0.5 mg/kg prednisone plus colchicine 0.5 mg bid resulting in dramatic improvement in both clinical (head/neck pain alleviated and cervical spinal mobility regained) and laboratory measures.Crowned dens syndrome should be considered, and craniocervical junction imaged in the context of acute cervical or occipital pain with stiffness and elevated inflammation markers not only in patients previously diagnosed with calcium pyrophosphate dehydrate arthropathy but also in diverse clinical settings.Key Points• This report highlights that crowned dens syndrome should be considered in various clinical setting besides calcium pyrophosphate dehydrate (CPPD) arthropathy.• Vigilance to this syndrome allows rapid treatment and may spare the patient unnecessary invasive procedures (i.e., temporal artery biopsy or lumbar puncture).

Objective Lysyl oxidase (LOX) is an extracellular enzyme that cross-links collagen fibrils. LOX was found to be increased in serum of SSc patients and was suggested to be related to skin fibrosis, yet a vascular source of LOX has been demonstrated in idiopathic pulmonary arterial hypertension (iPAH). We aimed to validate elevated LOX serum levels in SSc and to study its correlation with clinical characteristics and investigate its main source at the tissue level. Methods A total of 86 established SSc patients were compared with 86 patients with very early diagnosis of systemic sclerosis (VEDOSS), 110 patients with primary RP (PRP) and 80 healthy controls. LOX serum levels were determined by ELISA. Five lung and 12 skin biopsies from SSc patients were stained for LOX and compared with controls. Results Serum levels of LOX in SSc were significantly higher than in VEDOSS, PRP and healthy controls (P < 0.001). LOX inversely correlated with the diffusing capacity of the lung for carbon monoxide diffusing capacity (DLCO) in diffuse SSc (r = −0.376, P = 0.02). Patients with moderate to severe estimated systolic PAH had higher LOX levels (P < 0.01). Lung biopsies demonstrated intense LOX staining in SSc patients with PAH that was predominantly located in the endothelium of the remodelled pulmonary vessels. Conclusion Serum LOX levels are increased in established SSc and inversely correlate with the DLCO. LOX is elevated in patients with moderate to severe PAH and is located in the proliferating endothelium in lung arterioles, suggesting a possible role for LOX in SSc-associated PAH.

Background Polyarteritis Nodosa (PAN) is a necrotizing vasculitis predominantly affecting medium and small size arteries (1). Cyclophosphamide, a drug with narrow therapeutic range and poor safety profile, constitutes the treatment of choice for PAN vasculitis with major organ involvement. (2) Objectives To describe our clinical experience in treating refractory PAN with infliximab (a TNF inhibitor), a drug with good tolerability and better safety profile than cyclophosphamide. Methods Twenty-six PAN patients were admitted to our rheumatology unit between 2006 and 2017, of whom 9 patients, with severe and refractory disease, were treated with infliximab after failure of standard treatment. We describe herein the patients’ characteristics, clinical manifestations, severity and response to infliximab treatment and review the current literature. Results Complete remission was defined as the absence of features of active disease and withdrawal of prednisone therapy. Significant improvement was defined as clinical improvement and prednisone dose reduction of at least 50% or a 50% reduction in immune modulatory medications other than prednisone. After 4 months of treatment, 8/9 (89%) patients achieved significant improvement, with two of them achieving complete remission. Conclusion We suggest anti TNF agents, and in particular infliximab, are relatively safe and efficacious treatment options in refractory PAN A randomized controlled trial should be done in order to objectively evaluate infliximab in PAN. References [1] Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013; 65:1-11. [2] De Virgilio A, Greco A, Magliulo G, Gallo A, Ruoppolo G, Conte M, Martellucci S, de Vincentiis M. Polyarteritis nodosa: A contemporary overview. Autoimmun Rev. 2016; 15:564-70. Disclosure of Interests None declared

Autoinflammatory diseases are characterized by recurrent episodes of fever and localized or systemic inflammation and are caused by monogenic defects of innate immunity. The skin is commonly involved with various manifestations including erysipelas like rash and urticaria. Although vasculitis has been described in many autoinflammatory diseases, it has not been recognized as a characteristic feature of these diseases and autoinflammatory diseases are not listed as an etiology for vasculitis associated with a systemic disease in the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. We describe herein 3 patients with different autoinflammatory diseases in whom leukocytoclastic vasculitis was one of the major and presenting symptoms. A review of the vast evidence in the literature for vasculitis in the spectrum of autoinflammatory diseases and a suggested pathophysiology is presented. We suggest the term autoinflammatory associated vasculitis to describe vasculitis associated with autoinflammatory diseases. Autoinflammatory diseases should be considered within the differential diagnosis of vasculitis.

Polyarteritis nodosa (PAN) is a necrotizing vasculitis predominantly affecting medium and small size arteries. Cyclophosphamide, a drug with narrow therapeutic range and poor safety profile, constitutes the treatment of choice for PAN vasculitis with major organ involvement. To describe our clinical experience in treating refractory PAN with infliximab (a TNF inhibitor), a drug with good tolerability and better safety profile than cyclophosphamide. Twenty-six PAN patients were admitted to our rheumatology unit between 2006 and 2017, of whom nine patients, with severe and refractory disease, were treated with infliximab after failure of standard treatment. We describe herein the patients’ characteristics, clinical manifestations, severity and response to infliximab treatment and review the current literature. Complete remission was defined as the absence of features of active disease and withdrawal of prednisone therapy. Significant improvement was defined as clinical improvement and prednisone dose reduction of at least 50% or a 50% reduction in immune modulatory medications other than prednisone. After 4 months of treatment, 8/9 (89%) patients achieved significant improvement, with two of them achieving complete remission. We suggest that anti-TNF agents, and in particular infliximab, are relatively safe and efficacious treatment options in refractory PAN. A randomized controlled trial should be done in order to objectively evaluate infliximab in PAN.

Objective Fibrosis is a major cause of morbidity and mortality in systemic sclerosis (SSc). Levels of lysyl oxidase (LOX), an extracellular enzyme that stabilizes collagen fibrils, have been found to be elevated in the skin of SSc patients, but have not been evaluated in the serum or correlated with the clinical parameters. We undertook this study to evaluate serum LOX levels in SSc patients and to correlate these levels with clinical parameters of SSc. Methods SSc patients were evaluated for demographic features, clinical manifestations, routine laboratory tests, serum autoantibodies, serum LOX concentrations, and nailfold capillaroscopy patterns. They underwent pulmonary function testing, echocardiography, and high-resolution computed tomography scans of the lung, assessment of skin fibrosis by the modified Rodnan skin thickness score (MRSS), and assessment of disease severity and activity by the Medsger severity scale and the Valentini activity index. Results Twenty-six SSc patients were evaluated and compared with 25 healthy controls and with 9 disease control patients with primary myelofibrosis. Almost 62% of the SSc patients (16 of 26) had limited cutaneous SSc (lcSSc), while 38% had diffuse cutaneous SSc (dcSSc) (10 of 26); 31% of the patients (8 of 26) had lung involvement. The LOX concentration in SSc patients was higher than that in healthy controls and similar to that in disease controls (P < 0.0001), and it was significantly higher in patients with dcSSc than in those with lcSSc (P = 0.006). The LOX concentration correlated with the MRSS in patients without lung fibrosis. Conclusion This study is the first to demonstrate high serum LOX levels in SSc patients that correlate specifically with skin fibrosis. These correlations suggest that LOX levels may serve as a novel biomarker of fibrosis. Future studies are warranted to determine whether LOX is a potential therapeutic target in SSc.

Objective.To describe the Israeli experience of treating adult-onset Still’s disease (AOSD) with tocilizumab (TCZ).Methods.Israeli rheumatologists who treated AOSD with TCZ filled in questionnaires on symptoms, number of tender and swollen joints, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and dosage of prednisone at initial TCZ administration, after 6 months, and at the end of followup.Results.Nine male and 6 female patients, aged 33 ± 12 years, mean disease duration 9 years (range: 1–25) were identified. They had used a mean of 3.6 disease-modifying drugs, including 10 patients with tumor necrosis factor blockers. Intravenous TCZ 8 mg/kg was administered every 4 weeks (12 patients) or every 2 weeks (3 patients). All patients completed at least 6 months of treatment. The mean followup period was 15.7 ± 9 months. At the onset of therapy, despite the use of prednisone (27.6 ± 26.3 mg/d), all patients reported joint pain. Fever was reported in 9 patients, rash in 7, pleuritis in 3, and hepatitis in 2 before TCZ use, with mean ESR and CRP levels of 60 ± 28 mm/h and 11.6 ± 15 mg/dl, respectively. After 6 months of treatment and at the end of followup, the number of tender and swollen joints, the ESR and CRP levels, and the prednisone dosage decreased significantly. Only 2 patients still complained of mild arthralgias, and none reported systemic symptoms at the end of followup.Conclusion.TCZ 8 mg/kg was extremely efficacious in treating adult patients with refractory Still’s disease. Both TCZ and interleukin 1 blockade should be considered in the treatment algorithm of AOSD. Randomized controlled studies are needed to validate these findings.

Semaphorin 3A (sema3A) plays a regulatory role in immune responses, mainly affecting the activation of regulatory T cells. It has been found to correlate with disease activity in rheumatoid arthritis and systemic lupus erythematosus (SLE). To investigate the expression of sema3A in patients with systemic sclerosis (SSc) compared to healthy controls and SLE disease controls and to correlate it with clinical characteristics, 27 SSc patients, 42 SLE patients and 28 healthy controls were enrolled. Serum level of sema3A was measured by ELISA, and expression of sema3A on regulatory T cells was evaluated by FACS analysis. SSc patients were evaluated for demographics, clinical manifestations, routine laboratory results, nailfold videocapillaroscopy, pulmonary function tests, echocardiograms, modified Rodnan skin score, and disease activity and severity scores. Serum levels of semaphorin 3A were lower in SSc compared to healthy controls 14.38 ± 5.7 versus 27.14 ± 8.4 ng/ml, p < 0.0001 and similar to SLE 15.7 ± 4.3 ng/ml. The expression of semaphorin 3A on regulatory T cells was also lower in SSc compared to healthy controls 61.7 ± 15.7 versus 88.7 ± 3. 7 % (p < 0.0001). Semaphorin 3A serum level inversely correlated with the duration of disease: r = −0.4, p = 0.036 and with low C4 level r = 0.66, p = 0.026. SCL-70 antibody positivity was associated with a lower semaphorin 3A level (difference in mean of 3.44, p = 0.06). Sema3A expression is low in SSc serum and more specifically on regulatory T cells. This may help explain the reduced activation of regulatory T cells in SSc.

Background Fibrosis and vasculopathy are the major concerns in systemic sclerosis (SSc), the pathogenesis of which is not clear. Lysyl oxidase (LOX) is an extracellular copper enzyme that cross-links collagen and elastin, thus stabilizing collagen fibrils [1]. In a preliminary study, LOX was found to be overexpressed in SSc patients and was suggested to be related to diffuse disease [2]. We evaluated skin and lung biopsies from 11 SSc patients and were able to show LOX located in the epidermis in the skin and in the endothelium of blood vessels within the dermis and in lung tissue. It is not clear whether the source of elevated LOX levels in SSc is damaged vascular endothelium or fibrotic tissues. Objectives To evaluate LOX serum level of patients with SSc compared to patients with very early diagnosis of SSc (VEDOSS), patients with primary Raynaud9s phenomena (PRP) and healthy controls in order to validate the elevated levels in SSc and to delineate its source. Methods We prospectively evaluated patients for demographics, clinical manifestations and laboratory results including blood count, chemistry, urine examination, autoantibodies and serum LOX concentration determined by ELISA. We further evaluated lung function tests, echocardiography, lung high resolution CT scans, as needed, and determined lung involvement, modified Rodnan skin score (mRSS), Medsger disease severity scale and Valentini activity index [3]. Results 86 SSC patients (76 women and 10 men) at a mean age of 49±12.4 were evaluated and compared with 110 patients with VEDOSS, 86 patients with PRP, and 80 age and gender matched healthy controls. Of the SSc patients, 42 had diffuse disease- 23 of them with lung fibrosis, and 44 had limited disease. LOX concentration in SSc was higher than VEDOSS, PRP and healthy controls, 12.8±7.5 ng/ml vs. 9.7±7.4 ng/ml vs. 8.1±5.4 vs. 8.9±5.1 ng/ml, respectively (p Conclusions LOX level was found to be high in the serum of patients with SSc correlating with disease severity and inversely correlated with lung diffusion, suggesting a vascular source of LOX excretion in SSc. LOX was not elevated in patients with VEDOSS or PRP. Our study confirms our former observation of elevated LOX level in SSc and suggests LOX to be a possible biomarker of disease severity and vasculopathy in SSC. References Csiszar K, et al. Lysyl oxidases: a novel multifunctional amine oxidase family. Prog. Nucleic Acid Res. Mol. Biol. 2001;70: 1–322. Rimar D et al. Brief report: lysyl oxidase is a potential biomarker of fibrosis in systemic sclerosis. Arthritis Rheumatol. 2014;66(3):726–30 Hudson M, et al. Update on indices of disease activity in systemic sclerosis. Semin Arthritis Rheum 2007;37(2):93–8. Disclosure of Interest None declared

Background Familial Mediterranean Fever (FMF) is an autoinflammatory disease characterized by recurrent attacks of fever and serositis. A relation between FMF and Ankylosing Spondylitis (AS) has been suggested in small cohort studies, although there is no consensus regarding the role of HLA B27. Colchicine, the mainstay treatment in FMF, does not improve the axial or peripheral symptoms due to spondylarthropathy. There are controversial data about the efficacy of Tumor Necrosis Factor Alpha (TNF α) blockade in FMF patients (1). Objectives Efficacity of Tumor Necrosis Factor Alpha in FMF patients with axial spondyloarthropathy. Methods We report our experience in 4 patients with intractable FMF treated with oral colchicine and supplemental IV colchicine (2), that were treated with TNF α blockade for symptomatic axial spondylarthropathy). Results A 26- year-a old man with MEFV mutations V726A and E148Q, negative for HLAB27, with concomitant ulcerative colitis was treated with infliximab and then with adalimumab; and 3 women (42, 48 and 55 years old), two of them treated with infliximab and one treated with adalimumab. The three women were homozygous for the M694V mutation. All developed severe to moderate adverse events: exacerbation of FMF in 2 of them, and myositis and ulcerative colitis exacerbation in the male patient, and staphylococcus aureus sepsis in another patient. Three of them had to stop the TNF α blockade treatment. One patient developed psoriatic rash, with no need to stop the treatment. Conclusions In our limited experience, TNF α blockade in patients with both intractable FMF and AS is not very effective and may be associated with severe adverse events. Little is known about the possible interaction between intravenous colchicine and anti-TNF treatment. References 1. Bilgen SA, Kilic L, Akdogan A, Kiraz S, Kalyoncu U, Karadag O, Ertenli I, Dogan I, Calguneri M. Effects of anti-tumor necrosis factors agents for familial Mediterranean fever patients with chronic arthritis and/or sacroiliitis who were resistant to colchicine treatment. J clin Rheumatol 2011;7:358-62. 2. Rozenbaum M, Boulman N, Feld J, Avshovich N, Petrovich S, Elias M, Slobodin G, Rosner I. Intravenous colchicine treatment for six months: adjunctive therapy in Familial Mediterranean fever (FMF) unresponsive to oral colchicine. Clin Exp Rheumatol 2009; 27 (2 suppl 53) S 105. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.1994

Background Semaphorin 3A (sema 3A), is now recognized as a potent immuno-regulator during all stages of the immune response. Sema 3A expression has been recognized on T regulatory cells as a suppressive marker, contributing to the regulatory properties of these cells [1]. Decreased expression of sema 3A and correlation with disease activity has been reported in rheumatoid arthritis patients and systemic lupus erthematosus (SLE) [2,3]. The expression of sema 3A hasn9t been evaluated in systemic sclerosis (SSc) thus far. Objectives To compare sema 3A serum levels in patients with SSc to SLE patients (disease control) and healthy controls. To measure expression of sema 3A in whole blood and on regulatory T-cells and correlate it with demographic, clinical and laboratory parameters in SSc. Methods 27 SSc patients were evaluated for demographics, clinical manifestations, routine laboratory results, serum autoantibodies, sema 3A serum levels (measured by commercial ELISA kit) and expression on regulatory T cells CD 4+ CD 25 bright (by flow cytometry), nailfold videocapillaroscopy patterns, pulmonary function tests, echocardiograms, high resolution lung CT scans, modified Rodnan skin score (mRSS), Medsger disease severity scale and Valentini activity index. Sema 3A serum levels were also evaluated in 42 sex and age matched SLE patients (disease control) and 28 healthy controls. Results Twenty seven SSc patients (10 with diffuse cutaneous disease) were evaluated and compared with healthy controls and disease controls (SLE). Sema 3A expression in SSc patients was lower than healthy controls as measured by flow cytometry on regulatory T cells 61.7% ±15.7 vs. 88.7% ±3.6 (p Conclusions The expression of sema 3A is reduced in SSc patients and inversely correlates with disease duration and scl-70 antibodies production. Sema 3A role in the prevention of autoimmunity has been suggested to be mediated by its effect on regulatory T cells. Regulatory T cells have been reported in the literature to be reduced and functionally impaired in SSc. Our finding of low levels of sema 3A in SSc correlating with disease duration is in line with the literature and may serve to explain the impairment regulatory T cells in SSc. Further studies are needed to assess the cause-effect relations between sema 3A, regulatory T cells and disease progression in SSc. References Vadasz Z, Toubi E. Semaphorins: Their Dual Role in Regulating Immune-Mediated Diseases.Clin Rev Allergy Immunol. 2013 Feb 9. [Epub ahead of print]. Takagawa S, Nakamura F, Kumagai K, et al. Decreased semaphorin3A expression correlates with disease activity and histological features of rheumatoid arthritis.BMC Musculoskelet Disord. 2013;14:40. Vadasz Z, Haj T, Halasz K, et al. Semaphorin 3A is a marker for disease activity and a potential immunoregulator in systemic lupus erythematosus.Arthritis Res Ther. 2012 14;14(3):R146. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3403

Background Fibrosis is a major concern in patients with systemic sclerosis (SSc), the pathogenesis of which is not clear. Lysyl oxidase (LOX) is an extracellular copper enzyme that cross-links collagen and elastin, thus stabilizing collagen fibrils [1]. LOX was found to be overexpressed in patients with primary myelofibrosis (PMF), a disease with severe fibrosis [2]. In SSc, LOX was found to be elevated in the skin but has not been evaluated in the serum [3] in correlation with clinical parameters. Objectives To evaluate LOX serum level of patients with SSc compared to normal controls and to patients with PMF. To correlate this serum level to clinical parameters. Methods We prospectively evaluated patients with SSc for demographics, clinical manifestations and laboratory results including blood count, chemistry, urine examination, autoantibodies and serum LOX concentration determined by ELISA. We further evaluated lung function tests, echocardiography, lung high resolution CT scans, as needed, and determined lung involvement, modifies Rodnan skin score (mRSS), Medsger disease severity scale and Valentini activity index [4]. Results Twenty four women and 2 men with SSc at a mean age of 48±12.6 were evaluated and compared with 25, age and gender matched healthy controls and 9 patients with PMF. Of the SSc patients, 10 had diffuse disease- 8 of them with lung fibrosis, and 17 had limited disease. LOX concentration in SSc was higher than healthy controls and similar to PMF, 58.4±4.8 ng/ml vs. 28.4±2.5 ng/ml vs. 44.6±9.4 ng/ml (p Conclusions This is the first study to demonstrate high serum levels of LOX in SSc patients. These levels specifically correlate with skin fibrosis, lung fibrosis and disease severity - which reflects organ damage including fibrosis. We suggest that LOX has an important role in the pathophysiology of SSc and may serve as an objective assay for evaluation of disease severity. Our results suggest that LOX may be a promising future target of therapy in SSc. Future studies are warranted in order to determine the precise effects of such therapy. References Csiszar K et al. “Lysyl oxidases: a novel multifunctional amine oxidase family”. Prog. Nucleic Acid Res. Mol. Biol. 2001;70: 1–322. Papadantonakis N, Matsuura S, Ravid K. Megakaryocyte pathology and bone marrow fibrosis: the lysyl oxidase connection. Blood 2012;120(9):1774-81 Chanoki M, et al. Increased expression of lysyl oxidase in skin with scleroderma. Br J Dermatol 1995;133(5):710-5. Hudson M, et al. Update on indices of disease activity in systemic sclerosis. Semin Arthritis Rheum 2007;37(2):93-8. Disclosure of Interest None Declared

Familial Mediterranean Fever (FMF) is an autoinflammatory disease characterized by recurrent attacks of fever and serositis. A relation between FMF and Ankylosing Spondylitis (AS) has been suggested in small cohort studies, although there is no consensus regarding the role of HLA B27. Colchicine, the mainstay treatment in FMF, does not improve the axial or peripheral symptoms due to spondylarthropathy. There are controversial data about the efficacy of Tumor Necrosis Factor Alpha (TNF α) blockade in FMF patients [1].