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Objective To develop and validate the prognostic prediction model DU-VASC to assist the clinicians in decision-making regarding the use of platelet inhibitors (PIs) for the management of digital ulcers in patients with systemic sclerosis. Secondly, to assess the incremental value of PIs as predictor. Methods We analysed patient data from the European Scleroderma Trials and Research group registry (one time point assessed). Three sets of derivation/validation cohorts were obtained from the original cohort. Using logistic regression, we developed a model for prediction of digital ulcers (DUs). C-Statistics and calibration plots were calculated to evaluate the prediction performance. Variable importance plots and the decrease in C-statistics were used to address the importance of the predictors. Results Of 3710 patients in the original cohort, 487 had DUs and 90 were exposed to PIs. For the DU-VASC model, which includes 27 predictors, we observed good calibration and discrimination in all cohorts (C-statistic = 81.1% [95% CI: 78.9%, 83.4%] for the derivation and 82.3% [95% CI: 779.3%, 85.3%] for the independent temporal validation cohort). Exposure to PIs was associated with absence of DUs and was the most important therapeutic predictor. Further important factors associated with absence of DUs were lower modified Rodnan skin score, anti-Scl-70 negativity and normal CRP. Conversely, the exposure to phosphodiesterase-5 inhibitor, prostacyclin analogues or endothelin receptor antagonists seemed to be associated with the occurrence of DUs. Nonetheless, previous DUs remains the most impactful predictor of DUs. Conclusion The DU-VASC model, with good calibration and discrimination ability, revealed that PI treatment was the most important therapy-related predictor associated with reduced DU occurrence.

Objectives To characterize patients with positive anti-topoisomerase I (ATA) in lcSSc. Methods SSc patients enrolled in the EUSTAR cohort with a disease duration of ≤3 years at database entry were considered. We assessed the risk of major organ involvement in the following groups: ATA-lcSSc vs ACA-lcSSc and vs ANA without specificity (ANA)-lcSSc, and ATA-lcSSc vs ATA-dcSSc. Cox regression models with time-dependent covariates were performed with the following outcomes: new-onset interstitial lung disease (ILD), ILD progression [forced vital capacity (FVC) decline ≥10% and ≥5% vs values at ILD diagnosis), primary myocardial involvement (PMI), pulmonary hypertension (PH), any organ involvement and all-cause mortality. Results We included 1252 patients [194 ATA-lcSSc (15.5%)], with 7.7 years (s.d. 3.5) of follow-up. ILD risk was higher in ATA-lcSSc vs ACA- and ANA-lcSSc and similar to ATA-dcSSc, although with less frequent restrictive lung disease. The risk of FVC decline ≥10% (35% of ATA-lcSSc) was lower in ATA-lcSSc than in ATA-dcSSc, whereas FVC decline ≥5% occurs similarly between ATA-lcSSc (58% of patients) and other SSc subsets, including ATA-dcSSc. The risk of PMI was similar in ATA-lcSSc and ANA-lcSSc but lower than in ACA-lcSSc; no difference in PH and mortality risk was observed among lcSSc subsets. The risk of any organ involvement, PMI and PH was lower and the mortality tended to be lower in ATA-lcSSc vs ATA-dcSSc. Conclusion ATA-lcSSc patients have a high risk of ILD, albeit with a lower risk of progression compared with ATA-dcSSc, supporting careful screening for ILD in this subgroup.

Background: The current subclassification of systemic sclerosis into cutaneous subtypes does not fully capture the heterogeneity of the disease. We aimed to compare the performances of stratification into LeRoy's cutaneous subtypes versus stratification by autoantibody status in systemic sclerosis. Methods: For this cohort study, we assessed people with systemic sclerosis in the multicentre international European Scleroderma Trials and Research (EUSTAR) database. Individuals positive for systemic-sclerosis autoantibodies of two specificities were excluded, and remaining individuals were classified by cutaneous subtype, according to their systemic sclerosis-specific autoantibodies, or both. We assessed the performance of each model to predict overall survival, progression-free survival, disease progression, and different organ involvement. The three models were compared by use of the area under the curve (AUC) of the receiver operating characteristic and the net reclassification improvement (NRI). Missing data were imputed. Findings: We assessed the database on July 26, 2019. Of 16 939 patients assessed for eligibility, 10 711 patients were included: 1647 (15·4%) of 10 709 were male, 9062 (84·6%) were female, mean age was 54·4 (SD 13·8) years, and mean disease duration was 7·9 (SD 8·2) years. Information regarding cutaneous subtype was available for 10 176 participants and antibody data were available for 9643 participants. In the prognostic analysis, there was no difference in AUC for overall survival (0·82, 95% CI 0·81–0·84 for cutaneous only vs 0·84, 0·82–0·85 for antibody only vs 0·84, 0·83–0·86 for combined) or for progression-free survival (0·70, 0·69–0·71 vs 0·71, 0·70–0·72 vs 0·71, 0·70–0·72). However, at 4 years the NRI showed substantial improvement for the antibody-only model compared with the cutaneous-only model in prediction of overall survival (0·57, 0·46–0·71 for antibody only vs 0·29, 0·19–0·39 for cutaneous only) and disease progression (0·36, 0·29–0·46 vs 0·21, 0·14–0·28). The antibody-only model did better than the cutaneous-only model in predicting renal crisis (AUC 0·72, 0·70–0·74 for antibody only vs 0·66, 0·64–0·69 for cutaneous only) and lung fibrosis leading to restrictive lung function (AUC 0·76, 0·75–0·77 vs 0·71, 0·70–0·72). The combined model improved the prediction of digital ulcers and elevated systolic pulmonary artery pressure, but did poorly for cardiac involvement. Interpretation: The autoantibody-only model outperforms cutaneous-only subsetting for risk stratifying people with systemic sclerosis in the EUSTAR cohort. Physicians should be aware of these findings at the time of decision making for patient management. Funding: World Scleroderma Foundation.

Hypereosinophilic syndrome (HES) is a rare and potentially life-threatening disorder. While many conditions can cause eosinophilia, it can also be provoked by rarer diseases such as vasculitis or myeloproliferative disorders. Here we present an almost fatal presentation of HES characterized with both vasculitis and clonal features. Treatment with combined chemo-immunotherapy allowed reversal of most of the complications. There is still much uncertainty in the diagnosis and management of HES, and research should be done to improve knowledge on pathophysiology and cytogenetics of this disease in order to improve treatment and prevent life-threatening complications.

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.

Systemic sclerosis (SSc) is an autoimmune disease in which environmental exposure to substances and agents may trigger disease onset or exacerbation. The most fatal complication of SSc is scleroderma renal crisis (SRC), the incidence of which is 2-3%. SRC usually occurs in the first 5 years from disease onset in diffuse-SSc patients with anti-topoisomerase 1 (ATA) or RNA polymerase 3 antibodies [1]. Other risk factors for SRC are pericardial effusion, tendon friction rub and steroid use. We report herein a case of scleroderma renal crisis (SRC), following covid-19 infection, in a limited-SSc patient who was in long remission prior to the infection without any risk factors for SRC. the temporal relationship and lack of other risk factors combine to suggest covid-19 infection as a possible trigger for SRC. We discuss the shared pathophysiology of covid-19 infection and SRC, including, vasculopathy, endothelial activation, hypercoagulability, cytokines release as interleukin 6, that may explain the possible role of covid-19 infection, as a trigger for SRC in SSc patients.

Objectives The level of detail included when describing nailfold videocapillaroscopy (NVC) methods varies among research studies, making interpretation and comparison of results challenging. The overarching objective of the present study was to seek consensus on the reporting standards in NVC methodology for clinical research in rheumatic diseases and to propose a pragmatic reporting checklist. Methods Based on the items derived from a systematic review focused on this topic, a three-step web-based Delphi consensus on minimum reporting standards in NVC was performed among members of the European League against Rheumatism (EULAR) Study Group on Microcirculation in Rheumatic Diseases and the Scleroderma Clinical Trials Consortium. Results A total of 319 articles were selected by the systematic review, and 46 items were proposed in the Delphi process. This Delphi exercise was completed by 80 participants from 31 countries, including Australia and countries within Asia, Europe, North America and South America. Agreement was reached on items covering three main areas: patient preparation before NVC (15 items), device description (5 items) and examination details (13 items). Conclusion Based on the available evidence, the description of NVC methods was highly heterogeneous in the identified studies and differed markedly on several items. A reporting checklist of 33 items, based on practical suggestions made (using a Delphi process) by international participants, has been developed to provide guidance to improve and standardize the NVC methodology to be applied in future clinical research studies.

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.

Autologous hematological stem cell transplantation (HSCT) is a novel therapy for systemic sclerosis (SSc) that has been validated in three randomized controlled trials.To report the first Israeli experience with HSCT for progressive SSc and review the current literature.Five SSc patients who were evaluated in our department and were treated by HSCT were included. Medical records were evaluated retrospectively. Demographic, clinical, and laboratory data were recorded. Continuous data are presented as the mean ± standard deviation. Categorical variables are presented as frequencies and percentages.Five SSc patients were treated with HSCT. Four patients were adults (mean age 53 ± 12 years) and one was a 12-year-old pediatric patient. All patients were female. HSCT was initiated 1.4 ± 0.8 years after diagnosis. Two patients were RNA POLIII positive, two were anti-topoisomerase 1 positive, and one only antinuclear antibodies positive. All patients had skin and lung involvement. The mean modified Rodnan Skin Score was 29 ± 4.7 before HSCT, which improved to 10.4 ± 9.6 after HSCT. The forced vital capacity improved from 68 ± 13% to 90 ± 28%. Diffusing capacity of the lungs for carbon monoxide increased by 6%. Among severe adverse events were cyclophosphamide-related congestive heart failure, antithymocyte globulin-related capillary leak syndrome, and scleroderma renal crisis. All symptoms completely resolved with treatment without sequela. No treatment related mortality was recorded.HSCT is an important step in the treatment of progressive SSc in Israel. Careful patient selection reduces treatment related morbidity and mortality.

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 …

Cytokines are signaling molecules secreted and sensed by immune and other cell types, enabling dynamic intercellular communication. Although a vast amount of data on these interactions exists, this information is not compiled, integrated or easily searchable. Here we report immuneXpresso, a text-mining engine that structures and standardizes knowledge of immune intercellular communication. We applied immuneXpresso to PubMed to identify relationships between 340 cell types and 140 cytokines across thousands of diseases. The method is able to distinguish between incoming and outgoing interactions, and it includes the effect of the interaction and the cellular function involved. These factors are assigned a confidence score and linked to the disease. By leveraging the breadth of this network, we predicted and experimentally verified previously unappreciated cell-cytokine interactions. We also built a global immune-centric view of diseases and used it to predict cytokine-disease associations. This standardized knowledgebase (http://www.immunexpresso.org) opens up new directions for interpretation of immune data and model-driven systems immunology.

Autologous haematological stem cell transplantation (AHSCT) for rapidly progressive severe systemic sclerosis (SSc) is the only treatment, so far, allowing long-term improvement in overall and event-free survival.1 2 The COVID-19 pandemic has challenged experts regarding decisions on AHSCT in these high-risk patients.3 Increased risk for severe COVID-19 infection in SSc is related to lung and heart involvement4 and is enhanced by high-dose immunosuppressive drugs and antithymocyte globulins used for conditioning to eliminate autoreactive cells before AHSCT and to allow reset of tolerance during the immune reconstitution period, lasting around 12 months after transplant.1 3 Several centres have stopped AHSCT activity for SSc during the pandemic for safety considerations. Others decided to continue, believing that the benefit of AHSCT is greater than the …

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

Background Vasculitides are formally classified by artery size: large, medium or small, yet some overlap is evident as in Takayasu, a large vessel vasculitis manifesting also in retinal arterioles. Nailfold videocapillaroscopy (NVC) enables us to inspect changes in microvasculature. Only several small uncontrolled case series of light capillary microscopy in adult patients with vasculitis were reported in the literature, describing avascular areas and microhemorrhages in granulomatosis with polyangiitis (GPA) patients [1-2] and in [4] Behcet disease, and thin and tortuous capillaries in Takayasu arteritis [5]. Objectives To characterize nailfold capillary changes by NVC in patients with autoimmune vasculitis compared to healthy controls. Methods Consecutive autoimmune vasculitis patients fulfilling the aCR criteria and age and gender matched healthy controls were evaluated by NVC using Optilia Mediscope with a magnification of X200. Patients with peripheral artery disease and ischemic heart disease were excluded. Capillaroscopy images were centrally analyzed. NVC was analyzed, noting: architecture, number of capillaries per field, capillary width, capillary morphology, microhemorrhages, peri-capillary stippling (PCS)- hemosiderin deposits probably representing former capillary leak, slow capillary flow (“rolling” or sludging of red blood cells) and avascularity. Continuous data are presented as the mean ± SD. Categorical variables are presented as frequencies and percentages. Comparisons of continues variables were made using 2-tailed t-tests and differences between groups by a 1-Way aNOVA. Results Seventeen patients with active vasculitis, 8 patients with vasculitis in remission (11 polyarteritis nodosum, 2 GPA, 3 eosinophilic granulomatosis with polyangiitis, 2 microscopic polyangiitis, 2 Takayasu, 3 Sjogren vasculitis (one with cryoglobulinemia), 1 primary central nervous system vasculitis and 1 lupus vasculitis) were compared to 25 age and sex matched healthy controls. The mean age (59 ±18 vs. 51±19 vs. 52±15), and the percent of females (53%, 50%, 60%), were similar between the groups. Patients with active vasculitis demonstrated higher rate of “rolling”, 74.1%±27 vs. 12.5%±22 vs. 6.5%±12.7, p Conclusion Patients with active vasculitis demonstrate capillary abnormalities, namely: “rolling”, microhemorrhages, avascular areas and neoangiogenesis. PCS may be a specific sign of active vasculitis. NVC is an easy, readily available additive tool in the management of vasculitis. Further studies are needed to ascertain the role of NVC in vasculitis. References [1] Sendino Revuelta a, Barbado Hernandez FJ, Torrijos Eslava a, Gonzalez anglada I, Pena Sanchez de Rivera JM, Vazquez Rodriguez JJ. Capillaroscopy in vasculitis.An Med interna. 1991;8(5):217-20. Spanish. [2] HJ anders, C Headecke, T Sigl, K Kruger. Avascular areas on nailfold capillary microscopy of patients with Wegener’s granulomatosis. Clin Rheumatol. 19:86-8, 2000 [3] aytekin S, Yuksel EP, aydin F, Senturk N, Ozden MG, Canturk T, Turanli aY. Nailfold capillaroscopy in Behcet disease, performed using videodermoscopy. Clin Exp Dermatol. 2014;39(4):443-7. [4] Javinani a, Pournazari M, Jamshidi aR, Kavosi H. Nailfold videocapillaroscopy changes in Takayasu arteritis and their association with disease activity and subclavian artery involvement. Microvasc Res. 2019;122:1-5 Disclosure of interests None declared

We appreciate the interest of Akiyama et al in our report and thank them for the data presented in their letter.1 2 Akiyama et al have presented a thorough literature review and have described a positive and efficacious effect of tocilizumab in 11 cases of refractory polyarteritis nodosa (PAN) described in 6 case series. Indeed, the use of tocilizumab, an interleukin (IL)-6 inhibitor, in vasculitis is gaining evidence in the literature, specifically in large vessel vasculitis including giant cell arteritis and Takayasu arteritis.3 4 Nevertheless, it should be noted that although the …

Background Crowned Dens Syndrome (CDS) is defined as acute cervical or occipital pain, usually associated with elevated acute phase reactants, due to local inflammatory reaction related to calcifications in the ligaments surrounding the odontoid process. Virtually all previous descriptions of CDS have been related to calcium pyrophosphate dehydrate (CPPD) arthropathy. Objectives To evaluate patients admitted with acute neck pain and/or headacke for CDS not only in those with CPPD arthropathy but also in patients with other rheumatic diseases Methods Twenty four cases of CDS treated in Zion Medical Centre in 2016–2017 were prospectively reviewed. Patients were evaluated according to clinical and laboratory features, background rheumatic disease, response to treatment and invase investigational procedures undertaken. Results All patients (age range 54 to 87 years, 67% females) presented with acute onset pain in upper neck and/or occiput accompanied with extreme neck stiffness. Nineteen of 24 patients (79%) had elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Five patients (21%) complained on concomitant severe diffuse headache. Four of those underwent temporal artery biopsy, which was negative for arteritis in all cases, and one was subjected to lumbar puncture, which was non-contributory. The diagnosis of CDS was based on computed tomography imaging in all patients, with precipitations of calcium pyrophosphate dehydrate seen most often in transverse ligament (figure 1) or in alar ligaments. Seventeen patients (71%) had known rheumatic disease on presentation: 10 patients had the diagnosis of CPPD arthropathy, 3 patients had ankylosing spondylitis, 2 patients had rheumatoid arthritis, 1 patient had Behcet’s disease and 1 suffered from Familial Mediterranean Fever (table 1). In 4 more patients CDS was the presenting symptom of CPPD disease, diagnosed during hospitalisation. 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. Conclusions CDS should be considered and craniocervical junction exposed in the context of acute cervical or occipital pain with stiffness and elevated inflammation markers not only in patients previously diagnosed with CPPD, but rather in diverse clinical settings. Particularly, CDS should be recognised as a possible alternative diagnosis in older patients referred with suspicion to giant cell arteritis because of new headache and elevated ESR/CRP. While generally believed to be a rare phenomenon, CDS was seen in 24 patients in 400-bed general hospital within 2 years and is probably widely underdiagnosed. Disclosure of Interest None declared

Magnetic resonance imaging (MRI), which has recently become the leading imaging modality in the study of ankylosing spondylitis (AS), has not been evaluated in the assessment of disease-specific changes at the craniocervical junction (CCJ) in patients with AS.To describe the spectrum of active inflammatory lesions at the CCJ using MRI in a cohort of patients with AS and neck pain.The study included 18 patients with AS presenting with neck pain and a control group of 9 fibromyalgia patients matched for age and levels of neck pain. All patients underwent a focused rheumatologic examination, X-ray of the cervical spine, and a 3T MRI study, which included STIR, CUBE T2, FSE and FSE FAT SAT sequences before and after administration of gadolinium.The median age of AS patients was 43 years with a median disease duration of 7 years. Fifteen of 18 patients were under biologic treatment. Seven of 18 AS patients had evidence of cervical syndesmophytes on X-ray films. Active inflammatory lesions of atlanto-occipital joints and apical and alar ligaments were detected in MRIs in 2 out of the 18 patients with AS and in none of the patients with fibromyalgia. Both AS patients with active inflammation of CCJ detected on MRI received treatment with biological agents prior to and during the study.Active inflammation of both entheses and joints of the CCJ can be demonstrated by MRI in patients with AS.

Background A wide spectrum of structural changes in the elements of craniocervical junction in patients with ankylosing spondylitis (AS) has been recently described in a retrospective study using computed tomography [1]. The clinical significance of these findings requires further elaboration. Objectives To explore and describe inflammatory MR imaging findings in the craniocervical junction in patients with AS and neck pain. Methods Eighteen patients with AS and continuing neck pain, as well as 9 patients with fibromyalgia of the same age and similar level of severity of neck pain, who served as a control group, underwent relevant rheumatologic examination, X-ray of cervical spine and MRI study, which included STIR, CUBE T2, FSE and FSE FAT SAT sequences before and after administration of gadolinium. Results In the AS group, 12 males and 6 females diagnosed by 1984 New York criteria, of median age 40.5 years (range 31–61 years) and median disease duration of 8 (range 1–35) years, with 13 under treatment with anti-TNF agents were studied. All patients suffered from neck pain, with median VAS of 7 (range 2.5–10). Range of neck spine motion was limited in all but 3 patients. Seven of 18 patients had evidence of cervical syndesmophytes on X-ray. In addition to expected findings of syndesmophytes, active inflammatory lesions were seen in MR imaging in two of 18 patients with AS and in none with fibromyalgia (Fig. 1). Both AS patients with positive MRI were on anti-TNF therapy during the study and did not have syndesmophytes at the cervical spine as also by X-ray films. Conclusions Active inflammation of both entheses and joints of the craniocervical junction was demonstrated by MRI in some patients with AS and persistent neck pain. Active lesions at the craniocervical junction should be included in the differential diagnosis of neck pain in AS. References Slobodin G, Shpigelman A, Dawood H, Rimar D, Croitoru S, Boulman N, Rozenbaum M, Kaly L, Rosner I, Odeh M. Craniocervical junction involvement in ankylosing spondylitis. Eur Spine J. 2015 Dec;24(12):2986–90. Disclosure of Interest None declared

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

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.

Anakinra is a biological drug used in rheumatoid arthritis and several autoinflammatory diseases. Its main side effects are injection site reactions and increased infection rate. We present a 28-year-old man with familial Mediterranean fever, whose disease went into remission on anakinra, with concomitant flare of his ulcerative colitis.

Sacroiliitis, inflammation of the sacroiliac joint (SIJ), is the hallmark of ankylosing spondylitis and spondyloarthritis (SpA) in general. The arsenal of recommended diagnostic modalities for imaging of the SIJ is scanty and, in practice, includes only conventional X-rays and magnetic resonance imaging (MRI). This review suggests that bone scintigraphy, particularly single-photon emission computed tomography (SPECT) with calculation of indices, or SPECT in combination with low-dose computed tomography (CT) can be a sensitive and specific tool for the diagnosis of sacroiliitis and can be used as part of the individualized approach to the diagnosis of axial SpA. In addition, [18F]fluoride positron emission tomography (PET)/CT imaging and immunoscintigraphy, using labeled monoclonal anti-cytokine antibodies, are promising methods of current scientific interest in this field.

Q fever is a zoonotic bacterial disease caused byCoxiella burnetii. Tumor necrosis factor-alpha (TNF-α) plays a pivotal role in the defense against infection with this Gram-negative coccobacillus. Theoretically, patients who are treated with anti-TNF-αmedications are at risk for developing chronic Q fever. We present two patients who developed Q fever while being treated with anti-TNF-αagents and discuss the significance of timely diagnosis ofC. burnetiiinfection in these patients.

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.

Semaphorin 3A (sema3A) plays a regulatory role in immune responses with effects on both T and B regulatory cells. Familial Mediterranean fever (FMF) is an autoinflammatory disease, yet a possible role for regulatory T and B cells has been described.17 FMF patients during attack and then in remission, 8 FMF patients with smoldering disease and 12 healthy controls were enrolled. Sema3A in serum and its expression on regulatory T and B cells was evaluated. Clinical parameters of FMF patients were assessed.Semaphorin 3A serum level was lower in FMF patients during attack, smoldering disease or remission than healthy controls, (242.3±9.8 ng/ ml vs. 258.9±11.5 ng/ml vs. 232.5±22.7 ng/ml vs. 323.3±160.2 ng/ml, respectively p0.05). This decrease was specifically noted on regulatory B and T cells in FMF patients during attack and in smoldering disease and normalized in remission.Sema3A expression on T and B regulatory lymphocytes is low in FMF patients during attack and in smoldering disease compared to the expression in remission and healthy controls. These results are in line with previous descriptions suggesting a possible role of regulatory T cells in termination of FMF attacks. Further studies are needed to verify these preliminary findings.

Cryopyrin-associated periodic syndrome (CAPS) includes three overlapping disorders: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal onset multisystem inflammatory disorder (NOMID). Once considerate separate entities, these hereditary autoinflammatory disorders have been found to share a common genetic basis, pathogenesis and treatment and are therefore now considered a continuous clinical spectrum of a single entity. CAPS is caused by dominantly inherited or de novo NRLP3 mutations

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.

Purpose Available studies of craniocervical junction (CCJ) involvement in ankylosing spondylitis (AS) are based on conventional radiography, which has limited ability in the definition of many elements of the CCJ. The goal of the present study was to describe the spectrum of computed tomography (CT) findings in the CCJ in a cohort of patients with AS. Methods CT scans of the cervical spine of 11 patients with AS and 33 control subjects were reviewed, and imaging findings related to the CCJ were assessed. The standard anatomic intervals describing the CCJ were measured and compared to accepted normal standards. Findings representing pathology were described, categorized by localization, and relation to joints or ligaments of the CCJ. Results All AS patients were males with median age of 48 years and median disease duration of 20 years. The calculated median-modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) for the cervical spine was 8.5 ranging from 0 to 27. Disease-related changes in one or more elements of the CCJ were detected in all patients. Atlanto-occipital joints were involved in 8 patients, while 3 patients had disease of the atlanto-dental articulation. Enthesopathy of the CCJ was observed in 7 patients. Conclusions The CCJ is frequently involved in AS patients with advanced disease and may be independent on the mSASSS. Both articulations and ligaments of CCJ may be affected in AS patients.

Aortitis, which is well described in patients with other spondyloarthritides, has been rarely cited in relation to psoriatic arthropathy (PsA). Two patients with known PsA, who developed aortitis, are reported herein. The PubMed database was searched using the following keywords: aortitis, Takaysu arteritis, PsA, ankylosing spondylitis, reactive arthritis, inflammatory bowel disease. The relevant articles were critically reviewed and pertinent data organized. Analysis of 5 cases of aortitis in patients with PsA, including the 2 cases reported herein, revealed no specific pattern of PsA joint involvement in the patients who developed aortitis. All aortic segments can be involved and complications, such as insufficiency of the aortic valve and stenosis of the major aortic branches, have been described. The genetic association involving the IL12B locus may be involved in the clinical association of aortitis and spondyloarthritis.

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.

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

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.