Prostanoids in scleroderma microangiopathy: clinical and pharmacoeconomic comparison between two intravenous regimens.

Objectives: Intravenous iloprost (ILO) has widely demonstrated its effectiveness and safety in systemic sclerosis (SSc) patients. Unfortunately, there is no clear consent about dosage, duration, frequency, and infusion modality. The aim of this study was to compare two different therapeutic schemes in the same cohort of consecutive SSc subjects, evaluating differences in terms of effectiveness [digital ulcer (DU) outcome], safety, and direct healthcare costs.Method: This was a retrospective observational study of 47 patients classified with SSc treated with intravenous ILO for severe Raynaud's phenomenon and/or DUs. Two regimens were compared: a continuous inpatient scheme and a daily outpatient scheme. Demographics and clinical data, concomitant therapies, adverse events, and data on resource use and costs were collected.Results: The number of DUs rose slightly with the switch from the continuous to the daily scheme (0.61 ± 1.2 vs 1.1 ± 1.7). Moreover, in the daily scheme there was an increase in the number of therapeutic cycles (2.4 ± 0.7 vs 4.71 ± 1.4, p < 0.001) and an increase in patients treated with other vasoactive drugs. There was a reduction in ILO tolerability and more than half of the patients suspended the treatment. Five patients required hospitalization for severe and refractory DUs in the daily scheme. Moreover, the costs of the two treatments were comparable [median 7174 (range 2748-18 524) EUR vs 6284 (3232-22 706) EUR, p = 0.712].Conclusion: Treatment with a daily scheme of ILO is characterized by worse tolerability and a higher dropout rate compared to a low-flow regimen, with similar costs. We suggest that a low-flow continuous therapeutic scheme is preferable in SSc patients.

The use of rituximab in idiopathic inflammatory myopathies: description of a monocentric cohort and review of the literature.

Rituximab (RTX), a chimeric monoclonal antibody targeted against CD20, has been used to treat refractory inflammatory myopathies (IIM). The primary objective of this study was to retrospectively assess the efficacy of RTX in reducing disease activity in patients with IIM refractory to conventional therapy. Secondary aim was the evaluation of adverse events (AE) during the treatment period. We examined 26 patients with a diagnosis of IIM, referred to our Rheumatology Unit and treated with RTX for active refractory disease. Patients were treated with RTX 1000 mg i.v., twice, with a 2-week interval. RTX treatment was associated with a significant reduction of creatine kinase (p=0.001) after six months compared to the baseline, an improved muscular strength measured with MMT8 (p<0.001) and a reduction of the extramuscular activity of the disease measured with MYOACT (p<0.001). In particular, RTX improved DM skin rash, arthritis and pulmonary manifestations. Autoantibody positivity (in particular antisynthetase, anti- SRP and antiRo/SSA), and a disease duration <36 months at the moment of the treatment are associated with a better response rate. Treatment with RTX was also associated with a reduction of the mean daily dose of steroids needed to control disease activity (p=0.002). Our results have confirmed that RTX is efficacious in the treatment of refractory IIM. Ad hoc controlled trials are needed to better clarify the specific subset of patients who may better respond to the treatment and the optimal therapeutic schedule.

Post-occlusive reactive hyperaemia (POHR) in systemic sclerosis: very early disease (VEDOSS) represents a separate entity compared to established disease.

OBJECTIVES: Vascular involvement is a key feature of systemic sclerosis (SSc). Vascular changes are central to the pathogenesis of the disease and the assessment of vascular involvement has a prognostic value. This assessment therefore has a pivotal role in the management of SSc patients. The aim of our study was to evaluate post-occlusive reactive hyperaemia (PORH) in consecutive SSc patients and to test whether a PORH test might be a useful tool for the early diagnosis of SSc. METHOD: Between April 2011 and April 2015, 60 consecutive SSc patients (mean age 56 ± 15 years, females:males = 18:1) were enrolled in the study. The patients were divided into those with full-blown SSc (n = 50) and those with very early diagnosis of SSc (VEDOSS) (n = 10) according to the literature. Laser speckle contrast analysis (LASCA) was used to assess PORH. RESULTS: A statistically significant difference was detected in the post-ischaemic hyperaemic peak flow between VEDOSS and established SSc (424% vs. 137%, p = 0.0011). PORH peak flow decreased according to the capillaroscopic pattern (early = 419%, active = 163%, late = 145%, p = 0.0027). Moreover, a correlation between capillary density and peak flow was revealed (rho = 0.33, p < 0.01). CONCLUSIONS: These data show a different pattern of vascular involvement in VEDOSS compared to established disease that mirrors capillaroscopic changes. Functional features of very early and established disease seem to be the physiological counterpart of abnormalities detected by capillaroscopy. The POHR test might be a useful aid for further characterization of vascular involvement in SSc. In particular, blunted POHR might prove a tool to separate pre-clinical from full-blown SSc.

Analysis of the prevalence of cataracts and glaucoma in systemic lupus erythematosus and evaluation of the rheumatologists' practice for the monitoring of glucocorticoid eye toxicity.

Chronic glucocorticoid (GC) therapy is associated with an increased risk of developing cataracts and glaucoma, and recommendations have been developed for monitoring these side effects in patients with rheumatic diseases. The aim of this study was to assess the prevalence of cataracts and glaucoma and the adherence to the existing recommendations for monitoring eye toxicity of chronic GC therapy among systemic lupus erythematosus (SLE) patients in routine clinical practice. Clinical charts of 170 patients were examined, and 34 (20%) of them never underwent an eye assessment. The remaining 136 underwent an eye assessment with an interval of 75 ± 61.7 months. Only 45 (33%) had received an evaluation during the previous 12 months. All these 170 patients were taking chronic CG therapy at a mean daily dose of 5.4 ± 2.4 mg prednisone and a mean cumulative dose of 27.6 ± 20.5 g. Out of the 136 patients with at least one eye assessment, cataracts were observed in 39 patients (29%) and glaucoma in 4 patients (3%). Cataracts were diagnosed at a mean age of 46.5 ± 10 years; the development of cataracts was associated with age, disease duration, and cumulative GC dose. Glaucoma was diagnosed at a mean age of 40.5 ± 16 years; due to the small number of patients, no correlations were made. The prevalence of cataracts and glaucoma is higher than in the general population, and these conditions occur early in the life of SLE patients. An association between GC and cataracts is confirmed. The adherence to recommendations is suboptimal as only 33% of patients underwent an eye assessment over the previous 12 months. These data reinforce the need to improve adherence to recommendations for eye monitoring among SLE patients under chronic therapy with GC.

Behçet's disease: features of neurological involvement in a dedicated centre in Italy.

OBJECTIVES: The aim of the present study was to retrospectively assess the prevalence of neurological involvement and the clinical patterns of presentation in a monocentric cohort of patients with BD, who have been followed in the last twenty years at our centre. METHODS: One hundred and seventeen patients were retrospectively studied. The male/female ratio was 1.6:1, with a mean disease duration of 11±5 years. Their mean age was 42±9 years (min:18, max:77), while the mean age at disease onset was 25±4 years (min:10, max:58). The mean ± SD duration of follow-up at our centre was 7±2 (min:1, max:11) years. RESULTS: Neurological involvement was observed in 38% (44 patients, 36 males and 8 females; mean age at onset 25±4 years). Organic brain involvement, demonstrated by MRI was due to ischaemic pons-mesencephalon lesions in 19 patients and to meningoencephalitis with brainstem involvement in 16. Peripheral nervous system involvement was confirmed by electroneuromyographic study in 4 patients, and consisted of peripheral neuropathy prominent in the lower extremities in all cases; we have also observed only 2 cases of endocranial hypertension and 3 BD patients suffering from pulsatile, severe headache, without abnormal neurological examination, responding only to medium-high doses of steroids. Excluding peripheral neuropathy and isolated headache, the onset of CNS involvement (total prevalence: 32% of the cohort) was observed in 2 patients within the first year from the onset of BD, in 4 cases between the first and the third year, in 24 between the third and the fifth year, 7 between the fifth and the tenth year; none presented a CNS involvement after the first 10 years of disease. CONCLUSIONS: Neuro-BD is more frequent in young males and it never represents a presenting feature of the disease. The most frequent time of onset of neurological involvement seems to be within the first 10 years of disease. Since neurological involvement may result in severe functional disability or be a life-threatening disease, a careful follow-up during the first years after onset is recommended.

Long-term cyclic intravenous iloprost in systemic sclerosis: clinical experience from a single center.

The aim of the present study was to retrospectively evaluate response to therapy in 73 patients affected by systemic sclerosis (SSc) who underwent long-term cyclic treatment with intravenous iloprost for peripheral vascular involvement (average duration of treatment 54.12±41.04 months). Seventy-three SSc patients were enrolled. Data were collected by reviewing clinical records and by phone or direct interview. Patients underwent a thorough physical examination at the end of follow up. The incidence of severe vascular manifestations was also assessed. Statistical analysis was performed by Wilcoxon's signed rank test and descriptive statistics using Statview software. In this study cohort, 55 of 73 (75.2%) patients had a history of ischemic digital ulcers (DUs); 28 patients (38.4%) had active DUs at the beginning of treatment. Skin ulcers healed completely in 25 of 28 patients (89.3%) at the end of the first treatment. However, 40 of 55 patients (72.6%) relapsed after an average of 24 months. There was a significant correlation between relapse rate and/or number of ulcers and clinical factors (diffuse subset, changes in results of Allen's test, NT-pro BNP levels). The annual incidence of pulmonary arterial hypertension (PAH) was 2.34 (95%CI: 0.94-4.83) per 100 person years, the rate of gangrene was 2.7%, and no cases of scleroderma renal crisis were recorded. The incidence of PAH and of digital gangrene was higher than that observed in unselected SSc case series. These data suggest that our patients treated with iloprost have a higher vascular involvement than large case series of unselected SSc patients. A number of clinical factors are correlated to the severity of vascular involvement and could have an impact on the response to therapy. The clinical significance of these findings requires clarification and further investigation is needed.

Long-term prospective study of osteoporotic patients treated with percutaneous vertebroplasty after fragility fractures.

SUMMARY: This paper presents a prospective study on factors that could influence fracture risk after percutaneous vertebroplasty (PVP) in 115 osteoporotic patients. The mean follow-up was 39 months. The incidence of new fractures after PVP was 27.8%. Low body mass index (BMI), bone mineral density (BMD), and vitamin D are factors associated with increased risk of new fractures. INTRODUCTION: The purpose of this study was to evaluate factors that could increase the occurrence of new vertebral fractures (VFx) after PVP. METHODS: In our prospective study, we included patients of both sexes with osteoporosis (OP) and at least one painful VFx. We performed a baseline biochemical evaluation (including vitamin D plasma levels) and collected demographic, BMD, and clinical data. One hundred fifteen patients were treated with PVP and assigned to oral bisphosphonates plus Ca and vitamin D. The patients returned to control visits after 1, 3, and 6 months and every 6 months thereafter. X-rays film of the dorsolumbar spine was repeated every 12 months, or in case of pain that would suggest VFx occurrence. RESULTS: The mean follow-up was 39 ± 16 months (range, 15-79). Thirty-two patients (27.8%) had new fragility VFx, all symptomatic. All the fractured patients agreed to undergo a new PVP. We compared the patients who had new VFx to those who had not, and we found significantly lower BMI, total hip, and femoral neck T-scores in the group with new VFx. Furthermore, baseline plasma levels of 25(OH) vitamin D (25(OH)D) were significantly lower in this group. Upon analyzing plasma levels of 25(OH)D 12 months after PVP, we found that a significant difference still persisted: 22 ± 12 (group with new VFx) vs. 41 ± 22 ng/ml (group with no VFx; p < 0.01). CONCLUSION: We found that in patients with OP treated with PVP, the incidence of new VFx was 27.8% after 39 months; low BMI, BMD, and vitamin D are factors associated with increased risk of new VFx in patients treated with PVP.

[Long term outcome of treatment of diffuse proliferative glomerulonephritis with pulse steroids and short course pulse cyclophosphamide]. / Outcome a lungo termine di pazienti con glomerulonefrite lupica proliferativa diffusa trattati con boli di steroidi e un breve ciclo di ciclofosfamide.

OBJECTIVES: To evaluate the long- term outcome of a group of systemic lupus erythematosus (SLE) patients with diffuse proliferative glomerulonephritis (DPGN) treated with pulse steroids and a short course of pulse cyclophosphamide (Cyc) in order to find out baseline predictor variables of disease outcome at the end of the follow-up. METHODS: Female SLE patients fulfilling ACR criteria with active DPGN treated with pulse steroids and pulse Cyc were enrolled in the study and retrospectively analyzed with particular interest to renal flares and poor renal outcome at the end of follow- up as outcome measures. RESULTS: 30 female patients with DPGN were included, of these 20 (66,7%) patients are actually in follow-up at our unit, 4 (13.3%) died and 6 (20%) were lost during the follow-up. Fourteen patients (46.6%) presented at least one renal flare (RF) during the follow up for a total of 21 flares. At our last observation, 18 (60%) presented a good renal outcome while 12 (40%) had a poor outcome. Lower age at kidney biopsy resulted an important prognostic factor for the occurrence of both RF and poor long- term renal outcome; additionally, a poor renal outcome resulted significantly correlated with an inadequate response at the end of the protocol and with the number of renal flares after remission. CONCLUSIONS: These data suggest that, in general, a short course therapy with Cyc might be effective in controlling disease activity but demonstrated high rate of RF and poor renal outcome over time; however, this protocol might represent an effective therapeutic strategy in a subgroup of patients with specific epidemiological and clinical characteristics and suggest the possibility of tailoring immunosuppressive therapy on the basis of prognostic factor at baseline.

Mortality rate and outcome factors in mixed cryoglobulinaemia: the impact of hepatitis C virus.

OBJECTIVES: Mixed cryoglobulinaemia (MC) is a chronic small-vessel vasculitis. Shortly after the discovery of hepatitis C virus (HCV) in 1989, an association between HCV infection and MC was being increasingly reported, suggesting the potential pathogenetic implication of HCV in most of the cases that had been previously diagnosed as essential MC. A number of studies have pointed out prognostic factors linked to mortality in this disorder. None of them, however, have clarified the impact of HCV discovery on the natural history of the disease. The aim of the present study was to evaluate mortality in MC after the discovery of HCV infection. METHODS: We retrospectively collected clinical and serological data in 70 unselected HCV-positive patients being followed up at our unit from 1990. Clinical and prognostic factors linked to poor outcome were evaluated. RESULTS: Chronic hepatitis, renal involvement, and intestinal vasculitis were the most frequent causes of death. CONCLUSION: Compared to other series, the outcome in our MC seemed to be better. Factors linked to a poor outcome were renal involvement, widespread vasculitis, male sex, and cryocrit.

[Churg-Strauss syndrome: outcome and long-term follow-up of 38 patients from a single Italian centre]. / Caratteristiche clinico-sierologiche e dati di out come di una casistica monocentrica di pazienti affetti da sindrome di Churg-Strauss.

OBJECTIVE: This study was aimed at verifying any potential correlation between anti-myeloperoxidase antineutrophil cytoplasmic antibodies (ANCA-MPO) and clinical features and outcome indices in Churg-Strauss Syndrome (CSS). METHODS: Thirty-eight Churg-Strauss syndrome patients were selected from the medical records of all vasculitis patients attending the Rheumatology and Immunology Unit at the Department of Internal Medicine of the University of Pisa in the decades between 1989 and 2008. Data were analysed retrospectively. Statistical analyses of the results were carried out using the Mann-Whitney test to determine the correlations between the clinical and serological parameters. Qualitative variables were compared using contingency table analysis and Fisher's exact test. RESULTS: ANCA-MPO were detected in15/38 (39%) patients. Positive ANCA status was associated with peripheral neuropathy (p=0.0006), whereas negative ANCA status was associated with lung involvement (p=0.002). Relapses were strongly associated with positive ANCA status (p=0.01) and with an increase in- or a reappearance of ANCA-MPO levels (p=0.006). Finally, ANCA-MPO were significantly associated with neurological damage (p=0.003). CONCLUSIONS: The presence or absence of ANCA-MPO identify different clinical subsets in CSS. Overall, ANCA-MPO appears as a useful tool in the monitoring of CSS and in particular a good predictor of CSS relapses.

Genetic polymorphisms of thiopurine S-methyltransferase in a cohort of patients with systemic autoimmune diseases.

OBJECTIVES: Azathioprine (AZA) is a purine antimetabolite, prodrug widely used as a disease modifying drug in several rheumatic conditions. The aim of the present study was to evaluate the prevalence of TPMT genetic polymorphisms in a cohort of Italian Caucasian patients affected by rheumatic diseases and treated with AZA, and to establish correlations with the tolerability of AZA treatment. RESULTS: Seventy-eight Caucasian patients, 16 males and 62 females, median age 41 years (min-max: 24-76) were enrolled. At the time of evaluation, the median duration of treatment with AZA was 8 months (min-max: 2-150 months); the median dose of AZA per kg of body weight was 1.42 mg (min-max: 0.5-2). Among the 78 patients evaluated, 76 presented a wild type genotype (TPMT *1), while polymorphic alleles were identified in 2 patients (2.6%). Twenty-five patients (32%) experienced different types of adverse events (AE) under AZA treatment. Eighteen patients (23.1%) discontinued AZA because of AE. No correlation was observed between polymorphic TPMT alleles and the development of AE. CONCLUSIONS: Our analysis supports the view that TPMT genotyping alone is not sufficient to adequately personalize the AZA dosage in rheumatic patients. Further studies based on phenotypic analysis of TPMT enzyme and assay of AZA metabolite appear to be required.

[Ultrasound lung comets: new echographic sign of lung interstitial fibrosis in systemic sclerosis]. / Le comete ultrasoniche polmonari (ULC): un nuovo segno ecografico di fibrosi polmonare nella sclerodermia.

OBJECTIVE: Interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) are common complications of systemic sclerosis (SSc). Echocardiography evaluates PAH, and chest sonography detects even mild ILC as ultrasound lung comets (ULC), i.e. multiple comet-tails fanning out from the lung surface and originating from subpleural interlobular septa thickened by fibrosis. AIM: to assess ILaD and PAH by integrated cardiac and chest ultrasound in SSc. METHODS: We enrolled 30 consecutive SSc patients (age= 54+/-13 years, 23 females) in the Rheumatology Clinic of Pisa University. In all, we assessed systolic pulmonary arterial pressure (SPAP), from maximal velocity of tricuspid regurgitation flow, and ULC score with chest sonography (summing the number of ULC from each scanning space of anterior and posterior right and left chest, from second to fifth intercostal space). All patients underwent plasma assay for anti-topoisomerase antibodies (anti-Scl70), and antiicentromere associated with development of pulmonary involvement. Twenty-eight patients also underwent high resolution computed tomography, HRCT (from 0= no fibrosis to 3= honey combing). RESULTS: ULC number - but not SPAP - was correlated to HRCT fibrosis and presence Scl-70 antibodies. ULC number was similar in localized or diffuse forms (16+/-20 vs 21+/-19, p=ns) and was unrelated to SPAP (r=0.216, p=ns). CONCLUSIONS: Chest sonography assessment and ULC allow a complete, simple, radiation-free characterization of interstitial lung involvement in SSc - all in one setting and with the same instrument, same transducer and the same sonographer. In particular, ULC number is associated with HRCT evidence of lung fibrosis and presence of Scl-70 antibodies.

[Churg-Strauss vasculitis and idiopathic hypereosinophyl syndrome: role of molecular biology in the differential diagnosis of hypereosinophyl syndrome]. / Vasculite di Churg-Strauss e sindrome ipereosinofila idiopatica: ruolo della biologia molecolare nella diagnosi differenziale delle sindromi ipereosinofile.

OBJECTIVE: Hypereosinophilic syndromes are a heterogeneous group of uncommon disorders characterized by the presence of marked peripheral blood eosinophilia, tissue eosinophilia, or both, resulting in a wide variety of clinical manifestations, often without an identifiable cause. Churg-Strauss syndrome is a systemic vasculitis characterized by prominent peripheral eosinophilia, asthma and systemic involvement. The presence of mild to severe eosinophilia and systemic involvement raise the search of many trigger factor that need to be ruled out. Distinguishing CSS from idiopathic hypereosinophilic syndrome may be particularly challenging, especially in ANCA negative patients. METHODS: The aim of the present study was to present a small case series of patients referred to a Rheumatology Unit for mild to severe eosinophilia and signs and symptoms of systemic involvement and to outline the clinical significance of molecular biology in the work-up of hypereosinophilia. RESULTS: Eleven patients with moderate to severe peripheral eosinophylia, were referred to our Unit from 1996 to 2007. Female to male ratio was 7/4, mean age 40.54 (range 22-75). Three out of eleven patients resulted positive for molecular biology. The diagnosis of idiopathic hypereosinophylia was confirmed in one out of three on the basis of the clinical picture and bone marrow biopsy. CONCLUSIONS: Molecular biology may be useful in the screening and in the follow-up of a new hypereosinophylic patient.

[Chronic inflammation and endothelial dysfunction: analysis of a cohort of patients with SLE and UCTD]. / Flogosi cronica e disfunzione endoteliale: analisi di una coorte di pazienti affetti da LES e UCTD.

OBJECTIVE: Cardiovascular complications, mainly caused by an accelerated atherosclerosis, are one of the leading causes of death and disability in patients with systemic autoimmune diseases. Endothelial dysfunction is considered the earliest and reversible step of atherogenesis. Aim of the present study is to investigate endothelial function (EF) in patients with systemic lupus erythematosus (SLE), undifferentiated connective tissue diseases (UCTD) and correlate the results with clinical and laboratory variables. METHODS: EF was assessed on the peripheral microcirculation by the perfused forearm technique that can estimate both endothelium- dependent and endothelium- independent vasodilatation. The same evaluation has been repeated in two patients after the administration of 20 mg of 6-metilprednisolone. RESULTS: Twenty-three female patients with SLE or UCTD, with a follow up of at least 1 year have been studied and compared with 8 healthy controls matched for epidemiological variables and traditional risk factors for cardiovascular disease. A significant reduction both in endothelium dependent than endothelium independent vasodilatation was observed in both patients groups compared with controls. In addition, UCTD patients demonstrated a significant reduction in the nitric oxide pathway compared with controls and SLE patients. Finally, steroid administration induced an improvement of vascular reactivity. CONCLUSIONS: Despite the well documented side effects of chronic corticosteroid therapy, our data might suggest a role for antinflammatory and immunosuppressive therapy in the prevention of premature atherosclerosis in patients with systemic autoimmune diseases.

Functional and isokinetic assessment of muscle strength in patients with idiopathic inflammatory myopathies.

OBJECTIVE: To assess muscle strength in patients with idiopathic inflammatory myopathies (IIM) using neuromuscular scales and isokinetic testing. METHODS: Muscle function was evaluated in 27 IIM patients being followed at the Rheumatology Unit of the University of Pisa using: (i) a modified version of the grading system used to assess Duchenne dystrophy, (ii) the four-stage grading system of Henriksson and Sandstedt, (iii) an isokinetic muscle strength test (Kin Com, Chatanooga) and (iv) the Health Assessment Questionnaire (HAQ). RESULTS: The neuromuscular scales showed normal or only mildly impaired muscle strength in 60% (Duchenne scale) and 80% (Henriksson and Sandstedt scale) of the patients, respectively, whereas isokinetic testing detected moderate to severe reductions in muscle strength in almost 70% of the patients. No correlations were observed between muscle strength and disease activity, therapy, age at evaluation and disease duration. There was a correlation between the results of the HAQ and neuromuscular testing, but not the isokinetic test. CONCLUSIONS: Although less easy and more expensive to administer, isokinetic testing appears to be a more sensitive instrument than the standard neuromuscular tests for assessing muscle function in IIM patients. In particular, it can detect small reductions in muscle strength.