Outcomes in progressive systemic sclerosis treated with autologous hematopoietic stem cell transplantation compared with combination therapy.

OBJECTIVES: Autologous hematopoietic stem cell transplantation (AHSCT) has been shown to improve long-term survival for early diffuse progressive systemic sclerosis (SSc) compared with cyclophosphamide. Cyclophosphamide, however, does not provide a long-term benefit in SSc. The combination of mycophenolate mofetil (MMF) and rituximab is a potent alternative regimen. We aimed to retrospectively compare the outcomes of SSc patients who underwent AHSCT to patients who met the eligibility criteria for AHSCT but received upfront combination therapy with MMF and rituximab. METHODS: Repeated assessments of modified Rodnan Skin Score (mRSS), forced vital capacity (FVC), and diffusing capacity (DLCO) values were conducted. Clinical improvement was defined as an mRSS decrease > 25% or an FVC increase > 10%. Event-free survival (EFS) was defined in the absence of persistent major organ failure or death. RESULTS: Twenty-one SSc patients in the combination therapy group were compared with sixteen in the AHSCT group. Age, sex and disease duration were similar between the two groups. Clinical improvement at 12 months was seen in 18 (86%) patients in the combination group compared with 13 (81%) in the AHSCT group (p= 0.7). The hazard ratio for EFS at 24 months favored the combination group (HR = 0.09, P= 0.04). During follow-up, both groups exhibited a significant and comparable reduction in mRSS and an increase in FVC values at each time interval up to 24 months. CONCLUSION: MMF and rituximab compared with AHSCT in SSc patients eligible for AHSCT resulted in similar skin and lung clinical improvement with a better safety profile at 24 months.

Approach to a patient with monoarticular disease.

PURPOSE: To reassess the diagnostic approach to a patient with a monoarticular disease in light of the up-to-date medical literature and to examine the practical utility of traditional and newer imaging tools in the setting of monoarthritis. RESULTS: The monoarticular disease can represent a medical emergency on the one hand and be a diagnostic conundrum on the other. The management rules of patients with monoarthritis have been established long ago, but various pitfalls still lead physicians off the right diagnosis at times. Septic, pseudoseptic arthritis and hemarthrosis are the most common diagnoses made in patients with an acute presentation, and a decision not to perform a diagnostic arthrocentesis is the most prevalent cause of misdiagnosis in this setting. Many rheumatic and infectious diseases can present with more indolent monoarthritis; careful history and physical examination frequently provide clues to the straightforward diagnosis in some cases, but the extensive investigation is needed in others. Imaging methods become indispensable in individuals with the non-inflammatory monoarticular disease, with magnetic resonance imaging being the gold standard for diagnosing pigmented villonodular synovitis, lipoma arborescence, avascular necrosis, or neuropathic arthropathy. CONCLUSIONS: A great variety of medical disorders can present as a monoarticular disease. The disease presentation dictates different diagnostic behavior, while knowing the available imaging methods' diagnostic potential should further shorten the diagnostic process.

Tocilizumab (TCZ) Decreases Angiogenesis in Rheumatoid Arthritis Through Its Regulatory Effect on miR-146a-5p and EMMPRIN/CD147.

Background: Angiogenesis is a major contributor to the development of inflammation during Rheumatoid arthritis (RA), as the vascularization of the pannus provides nutrients and oxygen for the infiltrating immune cells and proliferating synoviocytes. Tocilizumab (TCZ) is an anti-IL-6 receptor antibody that is used in the treatment of RA patients, and has been shown to exert anti-inflammatory effects. However, its effects on angiogenesis are not fully elucidated, and the molecular mechanisms regulating this effect are unknown. Methods: We evaluated the concentrations of several pro- and anti-angiogenic factors and the expression levels of several microRNA molecules that are associated with RA and angiogenesis in serum samples obtained from 40 RA patients, before and 4 months after the initiation of TCZ treatment. Additionally, we used an in vitro co-culture system of fibroblasts (the HT1080 cell line) and monocytes (the U937 cell line) to explore the mechanisms of TCZ action. Results: Serum samples from RA patients treated with TCZ exhibited reduced circulating levels of EMMPRIN/CD147, enhanced expression of circulating miR-146a-5p and miR-150-5p, and reduced the angiogenic potential as was manifested by the lower number of tube-like structures that were formed by EaHy926 endothelial cell line. In vitro, the accumulation in the supernatants of the pro-angiogenic factors EMMPRIN, VEGF and MMP-9 was increased by co-culturing the HT1080 fibroblasts and the U937 monocytes, while the accumulation of the anti-angiogenic factor thrombospondin-1 (Tsp-1) and the expression levels of miR-146a-5p were reduced. Transfection of HT1080 cells with the miR-146a-5p mimic, decreased the accumulation of EMMPRIN, VEGF and MMP-9. When we neutralized EMMPRIN with a blocking antibody, the supernatants derived from these co-cultures displayed reduced migration, proliferation and tube formation in the functional assays. Conclusions: Our findings implicate miR-146a-5p in the regulation of EMMPRIN and propose that TCZ affects angiogenesis through its effects on EMMPRIN and miR-146a-5p.

Autologous Hematological Stem Cell Transplantation for Systemic Sclerosis in Israel.

BACKGROUND: Autologous hematological stem cell transplantation (HSCT) is a novel therapy for systemic sclerosis (SSc) that has been validated in three randomized controlled trials. OBJECTIVES: To report the first Israeli experience with HSCT for progressive SSc and review the current literature. METHODS: 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. RESULTS: 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. CONCLUSIONS: HSCT is an important step in the treatment of progressive SSc in Israel. Careful patient selection reduces treatment related morbidity and mortality.

Crowned dens syndrome, yet another rheumatic disease imposter.

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

Infliximab for the treatment of refractory polyarteritis nodosa.

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.

Lysyl oxidase-a possible role in systemic sclerosis-associated pulmonary hypertension: a multicentre study.

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.

[THE ROLE OF SEMAPHORIN 7A IN SYSTEMIC SCLEROSIS].

INTRODUCTION: Semaphorins are a large group of membrane bound and secreted proteins. The semaphorins were first recognized for their important role in neurodevelopment and specifically their repulsive axonal growth guidance during embryonic development. Recently, semaphorins have also been found to have an important role in the regulation of the immune system, thus denoted as "immune semaphorins". Semaphorin 7A is a membrane bound protein which mediated its effect by two receptors: the ß1 integrin subunit and plexin C1. Interactions between semaphorin 7A and its receptors contribute to inflammation and immunity by the stimulation of macrophage chemotaxis and cytokine production, regulation of dendritic cell migration and modulation of T cell function. Recently, semaphorin 7A has been found to have a role in the induction of fibrosis by tumor growth factor ß1 (TGF ß1). TGFß1 activates semaphorin 7A and its receptors plexin C1 and ß1 integrin subunit and induces proliferation of fibroblasts, lung fibrosis and remodeling in mice. A small study of 4 patients with systemic sclerosis (SSc) has recently demonstrated increased expression of semaphorin 7A mRNA on fibroblasts and B lymphocytes in peripheral blood. AIMS: To evaluate the expression of semaphorin 7A on regulatory T cells and B cells from peripheral blood of patients with SSc compared to healthy controls and to try and correlate the expression of semaphorin 7A with pulmonary fibrosis, skin fibrosis and other clinical characteristics of SSc patients. METHODS: Twenty six SSc patients were compared to 10 healthy controls. The expression of semaphorin 7A was evaluated by flow cytometry analysis of B cells using monoclonal antibodies to CD 108 and CD 19 and on peripheral regulatory T cells using monoclonal antibodies to CD 3 and CD 108. The analysis was conducted using flow-cytometry. Demographic, clinical and laboratory data were prospectively collected. Further data collection included: Systolic pulmonary artery pressure as assessed by echocardiography, lung function tests including diffusing capacity, nailfold video capillaroscopy pattern, modified Rodnan skin score (MRSS), Valentini activity index and Medsger severity score. Pulmonary involvement was determined by high resolution CT scan if it was suspected, according to impaired lung functions or auscultatory findings. RESULTS: Ten patients with diffused SSC (8 of whom suffered from pulmonary fibrosis) and 16 patients with limited disease were compared with 10 healthy controls. There was no difference between the groups with regard to age, gender, BMI or smoking habits. Semaphorin 7A expression on regulatory T cells was not different between SSc patients and healthy controls 4.2±6.5 % vs. 2.3±1.1 % (p< 0.35) nor was a difference found between SSC patients with diffuse disease compared to limited disease 2.5±8 % vs. 5.1±14 % (p< 0.3). Comparing the expression of semaphorin 7A on B cells did not reveal a difference between SSc patients and healthy controls as well 9.7±9.4 % vs. 4.9±1.7% (p< 0.12). No correlation was found between skin score, activity score or severity score and levels of expression of sempahorin 7A on B cells or regulatory T cells. CONCLUSIONS: In this small scale study we were not able to validate the role of semaphorin 7A as a mediator of fibrosis in SSc, as was suggested by a previous pilot study. Larger scale studies and investigation of semaphorin 7A on other peripheral cells and in tissues are needed in order to delineate the exact role of semaphorin as a mediator of fibrosis in SSc.

Q Fever Risk in Patients Treated with Chronic Antitumor Necrosis Factor-Alpha Therapy.

Q fever is a zoonotic bacterial disease caused by Coxiella 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-α medications are at risk for developing chronic Q fever. We present two patients who developed Q fever while being treated with anti-TNF-α agents and discuss the significance of timely diagnosis of C. burnetii infection in these patients.

Autoinflammatory associated vasculitis.

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

Tocilizumab Efficacy in a Patient with Positive Anti-CCP Chronic Lyme Arthritis.

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.

Acute sacroiliitis.

The purpose of this study was to review the data on the etiology, risk factors, clinical presentations, and diagnosis of acute sacroiliitis. A Pubmed search utilizing the indexing term "acute sacroiliitis" 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. The diagnosis of acute sacroiliitis is often challenging because of both the relative rarity of this presentation and diverse character of acute sacroiliac pain, frequently mimicking other, more prevalent disorders. Technetium bone scintigraphy can localize the disease process to the sacroiliac joint, while computed tomography or magnetic resonance imaging can be used for the detailed characterization and the extent of the disease as well as the diagnosis of complications. Pyogenic sacroiliitis is by far the most common cause of acute sacroiliitis. Brucellosis, acute sacroiliitis in the course of reactive arthritis, and crystalline-induced sacroiliitis frequently imitate pyogenic sacroiliitis. Acute sacroiliitis can rarely be also related to hematological malignancies or treatment with isotretinoin. Awareness to the possibility of acute sacroiliitis and a thorough physical examination are the necessary prerequisites to its timely diagnosis, while the appropriate laboratory and imaging studies should confirm the precise diagnosis and direct the appropriate treatment strategy.

Etanercept treatment-related c-ANCA-associated large vessel vasculitis.

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.

Brief report: lysyl oxidase is a potential biomarker of fibrosis in systemic sclerosis.

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.

Higher expression of latency-associated peptide on the surface of peripheral blood monocytes in patients with rheumatoid arthritis may be protective against articular erosions.

Latency-associated peptide (LAP) forms small latent complexes with transforming growth factor beta 1 (TGF-ß1). TGF-ß-LAP complexes can be detected on the surfaces of immune cells and have been recently shown to play a role in immune regulation through TGF-ß1-mediated functions. A study was undertaken to investigate the correlation of LAP expression on the surface of immune cells and presence of articular erosions in patients with rheumatoid arthritis (RA). Venous blood was obtained from patients with severe RA as well as from healthy control subjects. Surface expression of LAP on peripheral blood mononuclear cells was analyzed by flow cytometry, measured as flow cytometric intensity separately on CD14(+) and CD14(-) cells, and compared between RA patients and healthy subjects. Patients with RA demonstrated higher surface expression of LAP on both CD14(+) and CD14(-) mononuclear cells than healthy individuals. Patients with erosive RA had significantly reduced intensity of anti-LAP staining on the CD14(+) cells when compared to RA patients without erosions (p = 0.01). The intensity of anti-LAP staining on CD14(-) cells was not different between groups of RA patients. Higher expression of LAP on the surface of the cells of monocyte lineage may be protective of formation of articular erosions in RA. Further studies are needed to elaborate the mechanism of this phenomenon.

Tocilizumab - a novel therapy for non-organ-specific autoimmune diseases.

In the past decade, tocilizumab, an anti interleukin-6 agent, has been successfully developed as a therapeutic agent for the treatment of rheumatoid arthritis and systemic onset juvenile idiopathic arthritis. In addition to countering inflammation, tocilizumab is also known affect B cell as well as T cell function, thus modulating immune function, and impact osteoclasts, as well as vascular endothelial growth factor. As such, its efficacy is currently being explored in a large number of autoiommune conditions including a number of vasculitides, systemic lupus erythematosus, systemic sclerosis, polymyositis, graft versus host disease, relapsing polychondritis, as well as Behcet's syndrome, spondyloarthropathies, and tumor necrosis factor receptor associated periodic syndrome.