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.

Giant Cell Arteritis: State of the Art in Diagnosis, Monitoring, and Treatment.

Giant cell arteritis (GCA) is the most prevalent subtype of vasculitis in adults. In recent years, there has been substantial improvement in the diagnosis and treatment of GCA, mainly attributed to the introduction of highly sensitive diagnostic tools, incorporation of modern imaging modalities for diagnosis and monitoring of large-vessel vasculitis, and introduction of highly effective novel biological therapies that have revolutionized the field of GCA. This article reviews state-of-the-art approaches for the diagnosis, monitoring, and treatment options of GCA.

Nailfold video capillaroscopy as a useful diagnostic tool in systemic vasculitis.

BACKGROUND: Nailfold video capillaroscopy (NVC) enables us a direct view of the microvasculature. Only several capillaroscopy studies in adult patients with vasculitis have been reported. AIM: To characterize NVC changes in vasculitis. METHODS: Vasculitis patients and healthy controls were evaluated by NVC. NVC changes associated with vasculitis were assessed retrospectively in a cohort of 100 patients with Raynaud's phenomenon (RP). RESULTS: 17 patients with active vasculitis and 8 patients with vasculitis in remission were compared to 25 age and sex-matched healthy controls. Active vasculitis patients demonstrated higher rates of neoangiogenesis and capillary loss in comparison to other groups. Two novel NVC abnormalities were observed in patients with vasculitis: "Rolling" (slow capillary flow) and "peri-capillary stippling" (PCS), small deposits that may represent capillary leak. PCS was observed exclusively in 5 of 17 patients with active vasculitis. Retrospectively, we were able to detect PCS also in 14 % of 100 patients that were evaluated for RP, of whom 64 % were diagnosed with scleroderma or a related disorder. CONCLUSIONS: Patients with active vasculitis demonstrate frequent capillary abnormalities. Although these abnormalities are non-specific, we suggest that their combination may aid the diagnosis of vasculitis. Future studies are needed to validate our findings.

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).

Ulcerative Colitis and Familial Mediterranean Fever: Can Anakinra Treat Both?

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.

Effects of Tocilizumab, an Anti-Interleukin-6 Receptor Antibody, on Serum Lipid and Adipokine Levels in Patients with Rheumatoid Arthritis.

Patients with rheumatoid arthritis (RA) are at increased risk of cardiovascular disease. Dyslipidemia is a known adverse effect of tocilizumab (TCZ), an anti-interleukin-6 receptor antibody used in RA treatment. We aimed to assess the effect of TCZ on lipid profile and adipokine levels in RA patients. Height, weight, disease activity scores, lipid profile and atherogenic indices (AI), leptin, adiponectin, resistin, interleukin-6, and high-sensitivity C-reactive protein (CRP) were measured before and four months after initiation of TCZ in 40 RA patients and 40 healthy controls. Following TCZ treatment, total cholesterol, high density lipoprotein (HDL), and triglycerides were significantly elevated, but no significant changes in weight, body mass index (BMI), low density lipoprotein (LDL), and AI were observed. Compared with controls, significantly higher adiponectin levels were measured in the RA group at baseline. Following TCZ treatment, resistin levels and the leptin-to-adiponectin ratio increased, adiponectin levels decreased, and leptin levels remained unchanged. No correlation was found between the change in adipokine serum levels and changes in the disease activity indices, nor the lipid profile. In conclusion, the changes observed suggest a protective role for TCZ on the metabolic and cardiovascular burden associated with RA, but does not provide a mechanistic explanation for this phenomenon.

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.

[SUSTAINABILITY OF RITUXIMAB IN CONCOMMITANT TREATMENT WITH METHOTREXATE OR LEFLUNOMIDE IN PATIENTS WITH RHEUMATOID ARTHRITIS].

INTRODUCTION: Rituximab is a biologic agent approved for the treatment of rheumatoid arthritis (RA) in combination with methotrexate (MTX) or leflunomide (LEF). However, limited data in the literature suggests that rituximab may have the same efficacy profile whether used in combination with MTX or as monotherapy. The aim of our study is to compare the sustainability of rituximab as monotherapy to combined therapy with MTX or LEF in Israeli patients with RA. METHODS: A total of 35 RA patients treated with rituximab combined with MTX or LEF were compared with 26 RA patients treated with rituximab monotherapy regarding sustainability of rituximab treatment and its relationship to some patient and disease-related factors. RESULTS: There was no difference in patient-related and disease-related parameters between patients treated with rituximab as monotherapy or combined with MTX/LEF. The survival of rituximab was similar in both groups (88.5% in the monotherapy group and 82.6% in the combined therapy group, p=NS), with similar percentages of patients discontinuing this biologic agent, whether due to inefficacy or side effects. CONCLUSIONS: Rituximab may be considered as a biologic monotherapy in RA patients. Further prospective studies, evaluating sustainability of rituximab as a monotherapy in patients with RA are warranted.

[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.