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.

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.

Herpes zoster following BNT162b2 mRNA COVID-19 vaccination in patients with autoimmune inflammatory rheumatic diseases: a case series.

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.

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.

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.

Increased Prevalence of Metabolic Syndrome and Adipocytokine Levels in a Psoriatic Arthritis Cohort.

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

Ankylosing Spondylitis and Neck Pain: MRI Evidence for Joint and Entheses Inflammation at the Craniocervial Junction.

BACKGROUND: 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. OBJECTIVES: To describe the spectrum of active inflammatory lesions at the CCJ using MRI in a cohort of patients with AS and neck pain. METHODS: 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. RESULTS: 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. CONCLUSIONS: Active inflammation of both entheses and joints of the CCJ can be demonstrated by MRI in patients with AS.

[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.

Semaphorin 3A, a potential immune regulator in familial Mediterranean fever.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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 p<0.05). This decrease was specifically noted on regulatory B and T cells in FMF patients during attack and in smoldering disease and normalized in remission. CONCLUSIONS: 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.

[THROMBOANGIITIS OBLITERANS OVERLAPPING WITH ATHEROSCLEROTIC OCCLUSIVE ARTERIAL DISEASE: SMALL MESENTERIC ARTERY INVOLVEMENT BY THROMBOANGIITIS OBLITERANS].

INTRODUCTION: Thromboangiitis obliterans is an inflammatory occlusive vascular disease of young smokers that commonly involves the small and medium sized arteries and veins of the extremities. An important differential diagnosis of thromboangiitis obliterans is atherosclerotic arterial disease. An atypical presentation of thromboangiitis obliterans by involvement of mesenteric arteries has been described sporadically. CASE PRESENTATION: We report the case of a patient presenting with Raynaud's phenomenon, ischemia of the upper and lower extremities, as well as mesenteric ischemia. The dramatic course of the disease advanced to gangrene of the calves and intestinal infarction. In this patient, angiographic and histologic features were consistent with thromboangiitis obliterans associated with atherosclerotic arteriopathy. DISCUSSION: A review of the literature revealed 31 reported cases of mesenteric artery involvement by thromboangiitis obliterans. The overlap between thromboangiitis obliterans and atherosclerotic arteriopathy is rare but has recently focused attention in the literature. CONCLUSION: In the differential diagnosis of mesenteric ischemia, thromboangiitis obliterans is a rare but important diagnosis that should be considered. In view of shared features of thromboangiitis obliterans and peripheral artery disease, awareness of their possible coexistence is needed in order to make the right diagnosis and offer proper treatment.

Semaphorin 3A: an immunoregulator in systemic sclerosis.

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

Craniocervical junction involvement in ankylosing spondylitis.

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.