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Objectives As global vaccination campaigns against COVID-19 disease commence, vaccine safety needs to be closely assessed. The safety profile of mRNA-based vaccines in patients with autoimmune inflammatory rheumatic diseases (AIIRD) is unknown. The objective of this report is to raise awareness of reactivation of herpes zoster (HZ) following the BNT162b2 mRNA vaccination in patients with AIIRD. Methods The safety of the BNT162b2 mRNA vaccination was assessed in an observational study monitoring post-vaccination adverse effects in patients with AIIRD (n = 491) and controls (n = 99), conducted in two rheumatology departments in Israel. Results The prevalence of HZ was 1.2% (n = 6) in patients with AIIRD compared with none in controls. Six female patients aged 49 ± 11 years with stable AIIRD: RA (n = 4), Sjogren’s syndrome (n = 1), and undifferentiated connective disease (n = 1), developed the first in a lifetime event of HZ within a short time after the first vaccine dose in five cases and after the second vaccine dose in one case. In the majority of cases, HZ infection was mild, except a case of HZ ophthalmicus, without corneal involvement, in an RA patient treated with tofacitinib. There were no cases of disseminated HZ disease or postherpetic neuralgia. All but one patient received antiviral treatment with a resolution of HZ-related symptoms up to 6 weeks. Five patients completed the second vaccine dose without other adverse effects. Conclusion Epidemiologic studies on the safety of the mRNA-based COVID-19 vaccines in patients with AIIRD are needed to clarify the association between the BNT162b2 mRNA vaccination and reactivation of zoster.

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.

To the Editor: Systemic sclerosis (SSc) is a complex disease involving multiple pathophysiological pathways: autoimmunity, vasculopathy, and fibrosis, all of which are interrelated. Most of the damage consists of skin and lung fibrosis, and is accumulated within the first 2 years of disease in rapidly progressive patients with a serology of anti-SCL-70 or anti–RNA polymerase III (RNAP3)1. Indeed, this group of patients carry a great risk of morbidity and excess mortality. A combination “induction” therapy at an early stage—a window of opportunity—in which it is still possible to change the course of disease in this group of patients, is logical. We report herein our recent experience with early upfront combination therapy for progressive SSc, directed at different aspects of disease: iloprost for treating vasculopathy, rituximab (RTX) for blocking B cells, and mycophenolate mofetil (MMF) for inhibiting T cells. Until recently, the gold … Address correspondence to Dr. D. Rimar, Rheumatology Unit, Bnai Zion Medical Center, POB 4940, Haifa, 31048 Israel. Email: doronrimar{at}gmail.com.

Gastrointestinal (GI) involvement is almost universal in patients with systemic sclerosis (SSc) and is associated with significant disease-related morbidity and mortality.1 The entire GI tract can be involved and other disease features (eg, low mood, terminal organ failure and functional hand impairment) can result in significant nutritional impairment. Severe GI involvement has been reported to occur in ~10% of patients with SSc and often occurs early in the course of the disease.2 However, identification of patients at high risk of clinically significant weight loss is extremely challenging, including from the high prevalence of GI symptoms in patients with SSc. Therefore, there is a need to understand high-risk patients including potentially modifiable risk factors, with a view to early intervention strategies. Against this background, the aim of this study was to examine potential clinical risk factors of significant weight loss in patients with SSc. We performed an analysis of patients with SSc enrolled in the multinational, longitudinal European League Against Rheumatism (EULAR) Scleroderma Trials and Research (EUSTAR) database. In our study, we defined significant weight loss as 4.5 kg and/or least 5% of their body weight at 5 months onwards.3 Patients with a recorded second visit after 3 months and before 12 months were included in the analysis. We adopted a pragmatic approach (relevant to clinical practice) in …

The aims of this study were to evaluate the prevalence of metabolic syndrome (MetS) in psoriatic arthritis (PsA) patients according to the most recent definition in a Mediterranean population and to determine its association with biomarkers of inflammation and serum adipocytokine levels.Demographic, clinical, and laboratory data were collected on 74 patients with PsA and 82 control subjects. The presence of MetS was determined according to the current "harmonization" definition. Serum adipocytokines were analyzed. Continuous variables were compared by t test and discrete variables by χ test. Multivariate regression models compared the association between the presence of MetS and the blood levels of adipocytokines.The prevalence of MetS was higher in PsA patients compared with the control group: 54.8% versus 36.6%, respectively (P = 0.02; odds ratio, 2.33; 95% confidence interval, 1.16-4.69). The main difference between the 2 groups was waist circumference. No association was found between MetS and parameters of articular and skin disease activity or treatment. Leptin levels and leptin/adiponectin ratio were higher in PsA patients compared with control subjects: 83.4 versus 51.7 ng/mL (P = 0.001) and 6.3 × 10 versus 4.1 × 10 (P = 0.015), respectively. There was no significant difference in the adiponectin levels between the groups.The prevalence of MetS was higher in PsA patients compared with non-PsA control subjects in this Mediterranean population. Clinicians caring for PsA patients ought to be aware of the increased risk of MetS in PsA patients, confirmed in different regions worldwide. The increased MetS seems to be linked to central obesity in these patients, and appropriate treatment recommendations are advised.

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

Background Semaphorins are a family of proteins, involved in axon-guidance, malignancy spread and angiogenesis. Semaphorin 3A (sema3A) is recognized also as “immune semaphorin”, it is expressed on regulatory T cells and has been shown to enhance their inhibitory effect of CD4+ T cell pro-inflammatory function and replication. We have reported a decreased serum levels of sema3A in systemic lupus erythematosus (SLE) compared to healthy controls and in correlation with SLE disease activity [1]. Sema3A was found to be over expressed in podocytes and epithelial cells in in animal models with diabetic nephropathy. Increased urinary sema3A was also detected in diabetic patients with proteinuria and in contrast-induced acute renal injury [2-3]. Objectives To assess urine sema3A secretion in SLE patients with and without renal involvement compared to rheumatoid arthritis patients as disease control and healthy controls. Methods 50 ml of fresh urine samples were collected, centrifuged and the supernatant was then concentrated up to 50 times the initial concentration and subjected to specific human Sema3A ELISA kit (MBS732622, San Diego, CA, USA). Results Thirty-eight lupus patients fulfilling the 2012 SLICC criteria were recruited, 33 (87%) of whom were women, at a mean age of 35±12 years. Eight patients had active nephritis (21%) and additional 5 had a history of nephritis but were in remission. APLA was diagnosed in 13 (34%) of patients. Disease activity was evaluated by the Systemic lupus erythematosus disease activity index 2000 (SLEDAI 2K) and was 8.2±7.7. Sema3A was lower in lupus patients compared to rheumatoid arthritis and healthy controls, 4.9±3.9 ng/mL, 8.5±2.7ng/mL, 9.855±1.7ng/mL, p=0.0006. Lupus nephritis patients demonstrated lower urine sema3A concentration compared to lupus patients without renal involvement 4±3.4 ng/ml, 6.5±3.8 ng/ml, p=0.03. Sema 3A reversely correlated with proteinuria r=-0.43 p=0.006 and SLEDIA2K -0.3, p=0.04, but not with creatinine concentration, disease duration and complement concentration. There was no difference in urinary sema3A between SLE patients with or without APLA syndrome. Conclusion Urinary excretion of Sema 3A was found to be decreased in the SLE patients with renal disease, reversely correlating with disease activity and proteinuria. These findings are in line with previous reports of decreased serum level of Sema3A in SLE, that may result in reduced efficacy of regulatory T cells, driving autoimmunity and kidney damage. The discrepancy between low sema3A urinary excretion in SLE nephropathy and increased urinary secretion in other “non- auto immune” conditions with renal damage, suggests that sema3A in the kidneys is protective in autoimmune diseases and detrimental in “non-auto immune” conditions. This differential effect of sema3A may has to do with different populations of effector cells and different expression of sema3A receptors (nuropilin1). Further studies should evaluate semphorin 3A role in lupus nephritis and its potential as a treatment option. References [1] Vadasz Z, Haj T, Halasz K, Rosner I, et al. Semaphorin 3A is a marker for disease activity and a potential immunoregulator in systemic lupus erythematosus. Arthritis Res Ther;14(3):R146. [2] Mohamed R, Ranganathan P, Jayakumar C, et al. Urinary semaphorin 3A correlates with diabetic proteinuria and mediates diabetic nephropathy and associated inflammation in mice. J Mol Med (Berl)2014;92:1245-1256. [3] Ning L, Li Z, Wei D, et al. Urinary semaphorin 3A as an early biomarker to predict contrast-induced acute kidney injury in patients undergoing percutaneous coronary intervention. Braz J Med Biol Res. 2018;51(4) Disclosure of Interests None declared

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.

The objective of this study is to review the data on entheseal involvement in systemic disorders. A Pubmed search utilizing the indexing terms "enthesis" and "enthesitis" was conducted and the data pertinent to the aim of the review was extracted and organized in accordance with the preplanned structure of the manuscript. A number of cadaver-based studies, as well as studies using ultrasonography and magnetic resonance imaging, have detailed new distinct aspects of enthesis physiology and pathology in a variety of rheumatic and non-rheumatic systemic disorders. Major progress has been done in characterization of separate components of the enthesis organ, imaging of entheses, elaboration of the role and features of entheseal disease in spondyloarthropathies, juvenile idiopathic arthritis, osteoarthritis, familial Mediterranean fever, hyperuricemia, and other systemic conditions. The knowledge acquired and summarized herein shows that entheses can be affected in various ways in variety of medical disorders with different pathogenesis. Better understanding of the risk factors, mechanisms and natural history of enthesopathies is warranted. The current progress in the understanding of entheseal involvement in systemic disorders represents just the first step in resolving the entheses-related enigmas.

Anti-tumor necrosis factor (TNF) agents have become central players in the management of autoimmune and rheumatic disease. With the wide use of anti-TNF agents today, we have become aware of rare autoimmune complications as systemic lupus erythematosus and psoriasis, yet rarely has large vessels vasculitis been described. We herein describe a case of cytoplasmic anti-neutrophil cytoplasmic antibody (c-ANCA) (with myeloperoxidase (MPO) antibodies)-associated large vessel vasculitis (aortitis) that developed during anti-TNF treatment for ankylosing spondylitis. Awareness of this rare, but serious, adverse event of these commonly used agents in rheumatic diseases is of importance.

Background Approach to the diagnosis of axial spondyloarthrithis (axSpA) has changed in the last decade, with the aim of diagnosing the disease in its early form. Objectives The objective of this study was to explore change in the diagnostic pattern of axSpA in Northern Israel over the last 15 years. Methods Patients with the clinical diagnosis of axSpA from six rheumatology practices affiliated with the Rheumatology Unit of the Bnai Zion Medical Center in Haifa, Israel were recruited to the study. Ankylosing Spondylitis (AS) was diagnosed in the presence of sacroiliitis grade 2 or more on X-ray films; all other patients were considered as having non-radiographic axSpA. All patients were subdivided by time periods to 5 groups, and percentages of patients diagnosed in the non-radiographic stage of the disease, as well as patient demographic data were compared using exact Fisher test. Results One hundred twenty five patients were subdivided to 5 groups by periods of diagnoses (before 2000, 2001–2004, 2005–2008, 2009–2012, 2013–2016). Gradual increase in a proportion of patients diagnosed with non-radiographic axSpA was observed over years, with statistical significance achieved in 2013–2016 (p Conclusions Progressive increase in the proportion of patients diagnosed with non-radiographic form of axSpA over years was observed in this study. This finding, made on the basis of real life data, reflects change in the diagnostic approach to spondyloarthritis during the last decades. Disclosure of Interest None declared

We evaluated the effects of hyperoxia on pulmonary inflammatory changes in sepsis induced by cecal ligation and puncture (CLP) in rats. Seven groups were studied: sham-operated rats breathing air for 20 or 48 h; CLP breathing air for 20 or 48 h; and CLP + 100% oxygen for 20 h, or 70% oxygen for 48 h, or 100% oxygen intermittently (6 h/d) for 48 h. Video microscopy was used to monitor lung macromolecular leak, microvascular flow velocity, and shear rates, and lung morphometry was used for leukocyte infiltration and solid tissue area. Cell counts, tumor necrosis factor α, and nitrites were determined in peripheral blood and lung lavage fluid. Expression of adhesion molecules in blood leukocytes was evaluated by flow cytometry. Cecal ligation and puncture induced inflammation manifested in leukopenia, left shift, thrombocytopenia, increased expression of L selectin and CD11, increased serum and lavage fluid tumor necrosis factor α and leukocytes, and increased lung tissue area, macromolecular leak, and sequestration of leukocytes. Inhalation of 100% oxygen for 20 h increased nitrites (P < 0.01) and decreased leukocyte count in lavage fluid (P < 0.05) and attenuated lung macromolecular leak and changes in solid tissue area (P < 0.01). Inhalation of 70% oxygen (48 h) attenuated expression of adhesion molecules (P < 0.001) but failed to attenuate markers of lung inflammation. In contrast, intermittent 100% oxygen exerted favorable effects on markers of inflammation, attenuated leukocyte expression of L selectin and CD11 (P < 0.01), decreased pulmonary sequestration of leukocytes (P < 0.001), and ameliorated changes in macromolecular leak (P < 0.01) and lung solid tissue area (P < 0.05). Our data support the beneficial effects of safe subtoxic regimens of normobaric hyperoxia on the systemic and pulmonary inflammatory response following CLP.

Disease patterns and manifestations may vary among different populations and change over time. The purpose of our study was to define the demographic, clinical, roentgenologic, and laboratory findings in a recent cohort of psoriatic arthritis patients followed up in rheumatology clinics in northern Israel. We conducted a cross-sectional study of 149 psoriatic arthritis patients. Demographic, clinical, laboratory, and radiological data, with emphasis on the pattern of arthritis, treatment regimens, and co-morbidities were obtained from patient interviews and rheumatology file reviews. The mean age of our patients was 58.2, with a female preponderance (57.3%). Skin involvement preceded the arthritis or was diagnosed simultaneously in 90.1% of cases. The most common joint involvement was an RA-like arthritis (49.7% of the patients) correlating positively with age, female gender, and disease duration. Dactylitis and nail involvement were observed in 33.6 and 36.2% of the patients, respectively. Radiographic bone erosions were noted in a third of the patients, correlating with DIP and RA-like arthritis patterns. Most patients were treated with methotrexate (73.8%) and a combination therapy (41.4%). An increased incidence of hypertension, hyperlipidemia, and diabetes mellitus was noted in our cohort compared to the general Israeli population. Our survey, the first of its kind conducted in Israel, noted a relative increase in the polyarticular manifestation of PsA and a decrease in spondyloarthropathy, compared to historic series, with more aggressive disease found in women above the age of sixty. These findings are in line with recent surveys.

Pamidronate, along with other bisphosphonates, has been used for treatment of bone pain secondary to malignant involvement or metastatic disease for years. Some data, however, have also accumulated on the utility of pamidronate in a variety of benign conditions frequently handled by rheumatologists. This study aims to review the available published data regarding the potential use of pamidronate in rheumatology practice. Methods include the review of relevant articles retrieved by a PUBMED search utilizing the index term "pamidronate". All available randomized control trials, open trials, and case series, as well as properly reported case studies evaluating usage of pamidronate in rheumatic disorders, have been included in the literature review. The efficacy of pamidronate in patients with spondyloarthropathies; synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome; hypertrophic osteoarthropathy; osteoporotic vertebral fractures; chronic back pain due to disk disease or spinal stenosis; Charcot arthropathy; transient osteoporosis; and complex regional pain syndrome-I, has been demonstrated in more than 40 reports, the majority of which, however, were not controlled studies. In some of reviewed conditions, aside from providing analgesic relief, pamidronate may also have disease-modifying properties. While used in different doses in a variety of rheumatic disorders, pamidronate was generally reported to be well tolerated with an overall good safety profile. Pamidronate may represent an effective and safe choice for a spectrum of rheumatic patients, suffering from intractable musculoskeletal pain, unresponsive to traditionally recommended therapies. Large randomized, controlled studies examining the efficacy of pamidronate in the rheumatic conditions are urgently needed.

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 Interleukin (IL)-6 −/− mice develop spontaneous mature onset obesity, while the influence of the pharmacological blockade of IL-6 on body weight in humans has not been previously reported. The aim of the present study was to observe weight change in patients treated with tocilizumab (TCZ). Methods Twenty-one consecutive patients who started new treatment with TCZ were enrolled in the study. Sixteen consecutive patients who started treatment with infliximab (IFX) formed the control group. Height and weight of all patients were registered and Body Mass Index (BMI) calculated before the first treatment and at week 16. The Mann–Whitney or paired Wilcoxon test were used for comparisons between or within groups, respectively. Results The study demonstrated that treatment with TCZ was accompanied with significant weight gain and BMI increase ( p = 0.04), while IFX treatment did not result in any significant weight change during the 16-week period. Conclusions Weight gain can be seen in some patients during the pharmacological blockade of IL-6. The phenomenon and metabolic pathways involved should be further investigated.

Etanercept is a fusion protein that consists of extracellular ligand binding domain of the tumor necrosis factor alpha (TNF) receptor (p75) coupled with the Fc portion of human IgG. It binds TNF-α, thus blocking its interaction with TNF-α receptor. TNF-α is a proinflammatory cytokine that has a pivotal role in the inflammatory response in rheumatoid arthritis (RA). It also induces chemokine production and upregulates adhesion molecules. Indeed, etanercept is a mainstay therapy in RA [1]. Several pulmonary adverse reactions have been reported in patients treated with etanercept, the most important of which is tuberculosis. Other pulmonary complications include: granulomatous reaction, namely sarcoidosis (26 cases in the literature) [1–3], lung rheumatoid nodules [4], drug induced lupus related pleural effusion [5], and pulmonary lymphohistiocytic reactions [6]. In this report, we describe a case of severe RA pseudoempyematous pleural effusion that appeared with etanercept therapy and resolved promptly after its discontinuation.

Gout is rare among young women. The prevalence of gout is increasing in the western world and the Far East, probably owing to life style changes. The association between hyperuricemia and gout, the metabolic syndrome and atherosclerosis is stronger in women. 40 years ago, the increased prevalence of hyperuricemia and gout in Filipino men living in the United States was described. Recently, Filipino men and women living in the western world were found to have increased risk of the metabolic syndrome and atherosclerosis. We describe two unusual cases of gout in premenopausal Filipino women living in Israel, both of which suffered from hypertension. We also describe the current knowledge about gout in women, in general, and in migrant Asian women, in particular, with an emphasis on its relations to the metabolic syndrome and atherosclerosis. The occurrence of gout in relatively young migrant Filipino women might signal a change in the epidemiology of this disease, and might signal that these women are more prone to develop the metabolic syndrome and its complications.

Background Tofacitinib is a novel inhibitor of Janus kinase (JAK) 3 and JAK1 [1]. The JAK inhibitors are in the focus of research in myriad of other inflammatory diseases as it seems the JAK- (signal transducer and activator of transcription) STAT pathway has a central role in cytokines9 signal transduction. We herein describe a case of refractory polyarteritis nodosa (PAN) successfully treated with tofacitinib.Preliminary evidence for the role of JAK-STAT pathway in vasculitis has been recently published [2]. A 28 years-old man had been diagnosed with PAN at the age of 14. He presented with livedo reticularis, arthritis and skin nodules with fibrinoid necrosis, as confirmed by biopsy. Immunologic panel at the time of diagnosis was negative for ANCA, ANA, SSA, SSB, RF, and complement levels were normal. He was treated with azathioprine and methotrexate for several years and was in complete remission. Three years prior the initiation of tofacitinib his disease flared and he began suffering from necrotizing vasculitis of the scrotum and calves, abdominal pain and polyarthritis with high CRP levels (160–300 mg/l) for which he received recurrent intravenous solumedrol pulses and oral prednisone therapy of 40–60 mg daily in between pulses. Numerous treatments including, infliximab, adalimumab, rituximab, etanercept, tocilizumab, potassium iodide and cyclophosphamide intravenous and oral failed to achieve remission. Subsequently, he was hospitalized for reevaluation and was treated by plasma exchange for 3 weeks with partial remission, but had to discontinue the treatment due to central line sepsis. At this point he was in severe long standing inflammatory state for 3 years with high CRP levels low albumin (3 mg/dl) and ongoing leukocytosis. Objectives To evaluate the activity of the JAK-STAT pathway guiding the treatment with tofacitinib. Methods We have profiled his peripheral blood cells using mass cytometry (CyTOF), a single cell proteomics platform capable of simultaneously measuring the expression up to 45 proteins on each cell and on millions of cells. This provided a high-dimensional immune cell type profile of his immune system, both in cell abundance as well as the activity of the JAK1 and 3 along with STAT 3 pathways in response to stimulation with interleukin 6, specifically in CD4+ and CD8+ T cells subsets (figure 1). Results We initiated treatment with tofacitinib 10 mg BID that resulted in prompt normalization of his CRP, albumin and leukocyte count, resolution of skin ulcers and relief of pain. Prednisone therapy was soon tapered from 60 mg to 10 mg daily. Reevaluating the response of the JAK-STAT pathway to IL-6 stimulation after treatment confirmed attenuated response of the CD8+T and CD4+T cell (figure 1). After one year of follow-up the patient remained in complete remission. Conclusions In conclusion, this is the first report in the literature of treatment of refractory PAN vasculitis with tofacitinib. Using high resolution mass cytometry technology we were able to tailor and monitor therapy. References Vadasz Z, Rimar D, Toubi E. The new era of biological treatments. Isr Med Assoc J. 2014 Dec;16(12):793–8 Hartmann B, et al. The STAT1 Signaling Pathway In Giant Cell Arteritis. 2013 ACR/ARHP Annual Meeting, Plenary Session II, abstract number: 1691. Disclosure of Interest None declared

The role of regulatory T cells (T-regs) in familial Mediterranean fever (FMF) was never evaluated. Preliminary studies that we have conducted suggested a rise in the number of regulatory T cells after FMF attacks reaching a maximal level at 7 days. The aim of this study was to evaluate the percentage and activity of regulatory T cells in FMF. Six patients with refractory FMF and six healthy controls were evaluated. The percentage of T-reg cells and forkhead box protein 3 (Foxp3) expression was evaluated and compared between four states: FMF in remission, FMF at the first day of an attack, FMF 7 days after the start of the attack, and healthy controls. Four females and two males were included. All patients had FMF with high severity score, 2.8 ± 0.4 (0-3). The mean age was 31.6 ± 6.2. The mean age at onset was 9.3 ± 9.3. The mean colchicine dose was 2.6 mg ± 0.4. The expression of Foxp3 7 days after the attacks was significantly higher than in FMF at the first day of the attack, FMF in remission, and healthy controls 10.08 ± 2.36 vs. 7.005 ± 0.3 vs. 5.3 ± 1.06 vs. 4.44 ± 1.8; p < 0.05 (Fig.1). The percentage of T-regs in peripheral blood was not statistically different between the four groups. Theexpression of Foxp3 by T-regs increases 7 days after attacks of FMF. Anti-inflammatory cytokines interleukin-10 and TGF-β are known to activate T-regs and have been reported to increase in FMF attacks in line with the present findings. It is suggested that T-regs may have a role in terminating FMF attacks.

The clinical implications of computed tomography (CT) detected sacroiliac joint (SIJ) changes compatible with sacroiliitis has been rarely discussed in the literature. The aim of the present study was to describe prevalence and clinical correlations of sacroiliitis, noted incidentally by abdominal CT in patients referred for non-musculoskeletal complaints, utilizing the New York radiological grading criteria for reference. Five hundred ninety-eight CT scans of the abdomen of patients 18–55 years old, performed at a community medical center, were prospectively examined for the presence of imaging changes consistent with sacroiliitis. Patients with the evidence of bilateral sacroiliitis of grade ≥2 were interviewed and underwent a rheumatologic examination. Twenty-two patients (13 females) were enrolled. Only eight patients (six males) had a history and clinical picture compatible with previously undiagnosed axial spondyloarthritis (SpA). Only the presence of erosions/joint space irregularity and/or inhomogeneous osseous sclerosis around SIJs on CT correlated with the clinical diagnosis of axial SpA. Dense homogenous osseous sclerosis was unrelated to axial SpA and was seen almost exclusively in females. The prevalence of incidental CT sacroiliitis is low, while the New York radiological grading criteria for diagnosing sacroiliitis may be inappropriate for CT imaging. CT noted erosions of the SIJ appear to be a reliable diagnostic sign of sacroiliitis, while the significance of the osseous sclerosis, seen on CT adjacent to SIJs requires better understanding.

A cohort of patients with recently diagnosed axial spondyloarthritis (SpA) was characterized with emphasis on gender differences and factors leading to delay in diagnosis. Clinical, laboratory, and imaging data of 151 consecutive patients diagnosed with ankylosing spondylitis or undifferentiated SpA in 2004–2009 and satisfying the new ASAS classification criteria for axial SpA, was collected and analyzed. Seventy-nine men and 72 women were enrolled. Both groups (men and women) had similar age of onset of disease-related symptoms, as well as similar delay time to diagnosis, follow-up duration and frequency of anti-TNF treatment. Inflammatory back pain, as a first symptom related to SpA, was reported more often by men, while women had more pelvic, heel, and widespread pain (WP) during the course of the disease. At the time of diagnosis, men were more limited in chest expansion and showed increased occiput-to-wall distance compared to women. Elevated erythrocyte sedimentation rate and/or C-reactive protein were detected in a similar proportion of men and women. Presence of WP in women almost doubled the delay in the diagnosis of SpA. No other differences in disease presentation or burden were demonstrated to correlate with delay in diagnosis.

Kikuchi Fujimoto disease (KFD) is a rare, benign disorder, usually characterized by cervical lymphadenopathy. Most available data on KFD has come from the Far East. We examined the characteristics of KFD in Israel.A retrospective analysis of the records of all patients diagnosed as KFD in seven medical centers in Israel and all the cases previously reported as having occurred in Israel in the literature.Nineteen patients were included, 13 new cases and six from the literature. Mean age of patients was 23 (range 9-50) years. Female/male ratio was 1.1:1. Cervical lymphadenopathy, the hallmark of KFD in the Far East (97%), was less frequent in Israel (44%). However, Israeli patients presented more often with generalized (26%) or retroperitoneal (21%) lymphadenopathy (P0.01). Systemic signs such as fever (73%), night sweats (21%), weight loss (21%), hepatomegaly or splenomegaly (25%), and elevated sedimentation rate (52%) were more common in Israeli patients compared to most reports from other parts of the world, excluding Germany (P0.05). Leukopenia was evident in most Israeli patients (72%) in contrast to other countries (P0.01). Clinical presentation of KFD in Germany was comparable to Israel in most aspects.The clinical presentation of KFD in Israel often resembles a systemic disease with fever, leukopenia and generalized or retroperitoneal lymphadenopathy in more than half of the cases, contrary to the presentation in the Far East, which typically includes cervical lymphadenitis, and less frequently, systemic manifestations.

ObjectiveWe assessed cardiac conduction properties in patients with psoriatic arthritis (PsA).MethodsElectrocardiogram (ECG) scans of 92 patients with PsA were compared to 92 age and sex matched nonpsoriatic, nonarthritic patients from general practice serving as controls.ResultsPR interval was found to be significantly longer in the PsA group compared to controls, 159.6 ± 21 ms versus 151.3 ± 26 ms, respectively (p = 0.021). No statistical difference was found with respect to the QRS interval or other atrial or ventricular conduction disturbances studied. No correlation was found between the PR interval and disease duration or PsA subtype. The use of non-steroidal antiinflammatory drugs did not affect the PR interval. Methotrexate was not found to influence the PR interval, compared to other disease modifying antirheumatic drugs. Two PsA patients (2.1%) had a PR interval > 0.2 ms. Their prolonged PR interval could not be explained by medication use. The abnormal prolongation of the PR interval was asymptomatic, requiring no additional intervention. No patient had complete heart block.ConclusionOur study may suggest subtle involvement of the atrioventricular node in patients with PsA.

Hepatic encephalopathy and myxedema coma share clinical features: coma, ascites, anemia, impaired liver functions, and a “metabolic” electroencephalogram (EEG). Hyperammonemia, a hallmark of hepatic encephalopathy, has also been described in hypothyroidism. Differentiation between the 2 conditions, recognition of their possible coexistence, and the consequent therapeutic implications are of utmost importance. We describe a case of an 82-year-old woman with a history of mild chronic liver disease who presented with hyperammonemic coma unresponsive to conventional therapy. Further investigation disclosed severe hypothyroidism. Thyroid hormone replacement resulted in gain of consciousness and normalization of hyperammonemia. In patients with an elevated ammonia level, altered mental status, and liver disease, who do not have a clear inciting event for liver disease decompensation, overwhelming evidence of hepatic decompensation, or who do not respond to appropriate therapy for hepatic encephalopathy, hypothyroidism should be considered and evaluated.

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. Familial Mediterrenean Fevere (FMF) is an autoinflammatory disease; yet a possible role for regulatory T cells has been described.

Purpose: It was the aim of this study to evaluate the results of a prospective study in a single medical center using ceftazidime monotherapy in cancer patients with chemotherapy-induced grade IV febrile neutropenia and a low risk for gram-negative bacteremia. Subjects and Methods: Thirty-eight patients were admitted with low-risk grade IV febrile neutropenia after chemotherapy for solid tumors. The median patient age was 57 years (range 18–74). Sixteen patients (42%) developed febrile neutropenia after the first cycle of current chemotherapy line, 9 patients (24%) received 2–3 cycles and 13 patients (34%) received more than 3 chemotherapy cycles before manifesting febrile neutropenia. Five patients were treated with prophylactic granulocyte colony-stimulating factor commenced 24 h after completion of the chemotherapy cycle. Empiric monotherapy with intravenous ceftazidime was started on admission and administered 2 g every 8 h. Results: The mean polymorphic nuclear cell count on admission was 231 cells/mm3. Ceftazidime therapy was well tolerated. Twenty-five (66%) patients responded with clinical improvement and complete resolution of fever within 48 h after initiation of ceftazidime therapy. Thirty-two (84%) patients were afebrile after 72 h of therapy. Thirty-three patients (87%) remained on unmodified ceftazidime therapy throughout their hospitalization. Five patients (13%) subsequently required modification of the treatment regimen for various reasons. Mean duration of fever and neutropenia were 2 (1–10) days and 4 (1–11) days, respectively. None of the patients discontinued therapy because of adverse effects. No positive blood cultures were obtained. No events of septic shock were observed. Mean duration of hospitalization was 6 days (range 3–12). Conclusion: In our series, monotherapy with intravenous ceftazidime appears safe and effective in cancer patients with low-risk grade IV febrile neutropenia after cytotoxic chemotherapy and may appreciably reduce antibiotics costs.

To the Editor: Anti-tumor necrosis factor (anti-TNF) compounds are regarded as some of the most potent agents available for treatment of psoriasis vulgaris, with 80% of patients achieving at least a 75% reduction of their baseline skin lesions after 10 weeks of therapy1. Palmoplantar pustular psoriasis (PPP) is a chronic inflammatory skin condition characterized by recurrent eruptions of sterile pustules on erythematous skin, hyperkeratosis, and fissures on the palms and soles. Successful treatment options are usually limited. PPP has long been regarded as a localized variant of pustular psoriasis. Some authors have proffered that this pathological condition may not represent so much a subtype of psoriasis as a drug hypersensitivity reaction, as in acute generalized exanthematous pustulosis2,3. Increased expression of TNF has been identified as an important pathophysiological mechanism in different types of chronic inflammation, including psoriasis and psoriatic arthritis. Despite the evident efficacy of anti-TNF therapies in this setting, many have described pustular psoriasis occurring as an adverse event of these agents in patients without prior psoriasis, such as those receiving anti-TNF therapy for rheumatoid arthritis (RA)2,3,4 … Address correspondence to Prof. I. Rosner, Rheumatology, Bnai Zion Medical Center, PO Box 4940, Haifa, 31048 Israel. E-mail: rosneri{at}tx.technion.ac.il

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

A patient with ankylosing spondylitis, after demonstrating incomplete clinical response to adalimumab, received three monthly infusions of pamidronate along with continuing TNF-alpha blockade. Complete disappearance of the back pain was reported after the second pamidronate infusion. The perspectives of the combination therapy with TNF-alpha inhibitor and pamidronate are discussed.

Oral colchicine therapy has been shown effective both in controlling the symptoms and preventing the development of amyloidosis in FMF. However, 5 to 10% of FMF patients are resistant to this conventional therapy.

Context: Lyme arthritis, a manifestation of tick-borne Lyme disease, can prove to be refractory to classic treatment. Case Report: We present a case of a 48-year-old male, diagnosed with chronic Lyme arthritis, refractory to recurrent and prolonged courses of doxycycline, ceftriaxone, as well as hydroxychloroquine and methotrexate. The patient responded partially to tumor necrosis factor (TNF)-alpha blockade by etanercept and, finally, entered long-term remission after his treatment was switched to tocilizumab. Conclusion: Off label treatment by biologic disease modifying antirheumatic drugs can be considered in selected patients with severe antibiotic-resistant Lyme arthritis.C.

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].