Reduction of fat free mass index and phase angle is a risk factor for development digital ulcers in systemic sclerosis patients

Clinical Rheumatology - This study aims to evaluate the role of fat free mass index (FFMI) and phase angle (PhA) as markers to predict occurrence of new digital ulcers in systemic sclerosis (SSc)...     

系统性硬化病患者指溃疡的关联因素分析:来自中国欧洲抗风湿病联盟硬皮病试验研究组数据库的资料

目的 了解出现指溃疡的系统性硬化病( SSc)患者的临床特点及危险因素,以便早期预防及治疗,提高生活质量.方法 北京协和医院欧洲抗风湿病联盟硬皮病试验研究组数据库中,在2009年2月至2010年8月间前瞻性地收集SSc患者共166例,均满足1980年美国风湿病学会SSc分类(诊断)标准.对出现指溃疡的患者的临床表现、实验室检查与未出现者进行对比分析.计量资料采用-x±s表示,采用t检验,计数资料采用X2检验进行对比;采用Logistic回归进行危险因素分析.结果 ①166例患者中,共49例患者(29.5％)出现指溃疡,出现指溃疡的年龄(36±12)岁,全部患者存在雷诺现象.②有指溃疡患者的年龄(40±12)岁,雷诺现象发病年龄(33±12)岁,从雷诺现象到出现其他临床表现的时间(18±15)个月,与无指溃疡的SSc患者[分别为(46±12)岁,P=O.005;(39±13)岁,P=0.005;(115±307)个月,P=0.002]相比差异均有统计学意义.③与没有指溃疡的患者相比,有指溃疡的患者男性比例升高,以弥漫型SSc更常见,食管受累多(P＜0.05).结论 SSc患者中指溃疡并不少见,尤其在男性以及弥漫型SSc患者中更常见,有指溃疡者,其出现雷诺现象的年龄偏小,该组患者更易合并食管受累.     

Cigarette smoking as a significant risk factor for digital vascular disease in patients with systemic sclerosis

OBJECTIVE: Patients with systemic sclerosis (SSc) are at high risk for digital vascular complications, including amputation and gangrene. Cigarette smoking is an important risk factor for vascular disease in the general population. We investigated the influence of cigarette smoking on digital ischemia in patients with SSc. METHODS: We studied 101 patients with SSc (87 women and 14 men, median age 53 years, median disease duration 13 years). Smoking history was defined in terms of current smoking status and total number of pack-years. Digital ischemic events were classified as debridement, hospital admission for intravenous (IV) administration of vasodilators, and digital amputation. The influence of smoking on digital ischemic events was examined using logistic regression, adjusting for age, sex, and disease duration. Results are expressed as the odds ratio (OR) and 95% confidence interval (95% CI). RESULTS: Of the 101 patients, 21 (21%) were current smokers, 37 (37%) were ex-smokers, and 43 (43%) had never smoked. After adjusting for age, sex, and disease duration, current smokers were significantly more likely than never-smokers to have had debridement (OR 4.5, 95% CI 1.1-18.3) or admission for IV vasodilators (OR 3.8, 95% CI 1.1-12.9). Patients smoking at higher intensity were more likely to require admission for IV vasodilators. CONCLUSION: Among patients with SSc, current smokers are 3-4 times more likely than never-smokers to incur digital vascular complications. Resources should be directed to supporting smoking cessation in patients with SSc.     

Nutritional risk in patients with systemic sclerosis

Clinical Rheumatology -     

Mortality and prognostic factors in Spanish patients with systemic sclerosis

OBJECTIVE: To determine survival and mortality in a cohort of Spanish patients with scleroderma (systemic sclerosis, SSc) and to analyse whether survival is influenced by demographic, clinical or immunological variables or the extent of skin involvement. METHODS: The study included 79 patients diagnosed with SSc and taking part in a study to determine the extent of sclerosis, visceral involvement and immunological alterations. We studied the number of observed and expected deaths (the expected number being based on age- and sex-specific rates in the background population) and derived standardized mortality ratios with their 95% confidence intervals (CI). Cumulative survival after onset of the first symptom was estimated according to the Kaplan-Meier method. The Cox method was used to identify the prognostic factors. RESULTS: The mortality rate was 0.0249 deaths per person-year. Survival at 15 yr was 0.62 (95% CI 0.410-0.778). The standardized mortality ratio was 429.4% (95% CI 222-750). On crude analysis, lung involvement [forced vital capacity (FVC) <70%, pulmonary hypertension], SSc renal crisis, an active capillaroscopic pattern, pericardial effusion and age over 60 yr at diagnosis were associated with shorter survival. On multivariate analysis, only age at diagnosis over 60 yr, FVC <70% and SSc renal crisis were independent prognostic factors. CONCLUSIONS: The mortality rate associated with SSc showed a four-fold increase compared with the background population. Lung involvement and sclerodermal renal crisis were found to be independently associated with reduced survival.     

A prognostic risk index for long-term mortality in patients with peripheral arterial disease

BACKGROUND: Prognostic information in peripheral arterial disease (PAD) may provide the basis for optimal management strategies at an early stage. This study aimed to develop a prognostic risk index for long-term mortality in patients with PAD. METHODS: In a single-center observational cohort study, 2642 patients with an ankle-brachial index of 0.90 or lower were randomly divided into derivation (n = 1332) and validation (n = 1310) cohorts. Cox regression analysis with stepwise backward elimination identified predictors of 1-year, 5-year, and 10-year mortality in the derivation cohort. Weighted points were assigned to each predictor. Index discrimination was determined in both the derivation and validation cohorts. RESULTS: During 10 years of follow-up, 42.2% and 40.4% of patients died in the derivation and validation cohorts, respectively. The risk index for 10-year mortality (+ points) included renal dysfunction (+12), heart failure (+7), ST-segment changes (+5), age greater than 65 years (+5), hypercholesterolemia (+5), ankle-brachial index lower than 0.60 (+4), Q-waves (+4), diabetes (+3), cerebrovascular disease (+3), and pulmonary disease (+3). Statins (-6), aspirin (-4), and beta-blockers (-4) were associated with reduced 10-year mortality. Patients were stratified into low (<0 points), low-intermediate (0-5 points), high-intermediate (6-9 points), and high (>9 points) risk categories, according to risk score. Ten-year mortality rates were 22.1%, 32.2%, 45.8%, and 70.4%, respectively (P < .001) and comparable to mortality in the validation cohort. C statistics demonstrated good discrimination in both the derivation (0.72) and validation cohorts (0.73). CONCLUSIONS: A prognostic risk index for long-term mortality stratified patients with PAD into different risk categories. This may be useful for risk stratification, patient counseling, and medical decision making.     

Evidence of 5‐lipoxygenase overexpression in the skin of patients with systemic sclerosis: A newly identified pathway to skin inflammation in systemic sclerosis

Objective

Leukotrienes are a family of arachidonic acid derivatives with potent proinflammatory and profibrotic properties, and 5‐lipoxygenase (5‐LOX) catalyzes two key steps in the leukotriene biosynthetic pathway. Since inflammatory cell infiltrates and excessive fibrosis are hallmarks of systemic sclerosis (SSc) skin lesions, we undertook the present study to investigate the expression of 5‐LOX in skin biopsy specimens from patients with SSc.

Methods

Expression of 5‐LOX in skin sections from 10 SSc patients and 8 healthy controls was examined by in situ hybridization with specific riboprobes and by immunohistochemistry analysis with 5‐LOX monoclonal antibodies. Synthesis of 5‐LOX by cultured dermal fibroblasts from 7 patients with SSc and 4 controls was measured by fluorescence‐activated cell sorter analysis. In addition, concentrations of leukotriene B₄ (LTB₄) and LTE₄ in fibroblast supernatants after stimulation were determined using enzyme immunoassays.

Results

Expression of 5‐LOX was found in all skin sections from SSc patients as well as from controls. However, the number and percentage of 5‐LOX–positive cells were significantly higher in SSc skin sections compared with control sections. Expression of 5‐LOX was seen in cells within perivascular inflammatory infiltrates as well as in fibroblasts throughout the skin. The experiments with cultured skin fibroblasts revealed that 5‐LOX was constitutively expressed in these cells, which resulted in the production of leukotrienes after cell stimulation. Whereas no difference was found for LTE₄, SSc fibroblasts produced significantly higher amounts of LTB₄ after stimulation, compared with healthy control fibroblasts.

Conclusion

The results of this study suggest that the 5‐LOX pathway may be of significance in the pathogenesis of SSc and may represent a target for new treatment strategies.

     

A score of risk factors associated with ischemic digital ulcers in patients affected by systemic sclerosis treated with iloprost

A single series of patients affected by systemic sclerosis (SSc) and cyclically treated with iloprost was reviewed in order to evaluate the incidence of digital ulcers (DUs) and to compare the characteristics between the patients with and without this painful and disabling vascular complication. The record charts of 85 SSc patients were revised. Ischemic DUs and scleroderma contracture ulcers were separately considered. Twenty-nine subjects developed ischemic DUs during the course of the disease; whereas, scleroderma contracture ulcers occurred in six subjects. Ischemic DUs were associated with younger age at scleroderma onset, a longer disease duration, a longer time delay from scleroderma diagnosis to iloprost therapy, a bigger skin involvement, the presence of joint contractures, a videocapillaroscopic late pattern, a history of smoking, and of corticosteroids therapy. After the exclusion of four subjects with concomitant peripheral arterial disease, a forward-stepwise logistic regression analysis showed that only four variables, i.e., age at scleroderma onset, delay in beginning iloprost therapy, history of smoking, and presence of joint contractures remained significantly associated with ischemic DUs. In a score reflecting the sum of these four risk factors, the prevalence of ischemic DUs increased progressively from the lowest to the highest value of the score. The predictivity of this model was evaluated by the receiver-operating characteristics curve, with an estimated area under the curve of 0.836 with 95% confidence interval from 0.736 to 0.937. All the patients with scleroderma contracture ulcers were characterized by both diffuse pattern of disease and positivity for anti-Scl70 antibody. In this retrospective study, scleroderma patients with ischemic DUs are characterized by early disease onset, delay in beginning iloprost therapy, smoking habit, and presence of joint contraction. A score reflecting the sum of these factors may be useful to predict the risk of developing ischemic DUs.     

Evidence of 5-lipoxygenase overexpression in the skin of patients with systemic sclerosis: a newly identified pathway to skin inflammation in systemic sclerosis

OBJECTIVE: Leukotrienes are a family of arachidonic acid derivatives with potent proinflammatory and profibrotic properties, and 5-lipoxygenase (5-LOX) catalyzes two key steps in the leukotriene biosynthetic pathway. Since inflammatory cell infiltrates and excessive fibrosis are hallmarks of systemic sclerosis (SSc) skin lesions, we undertook the present study to investigate the expression of 5-LOX in skin biopsy specimens from patients with SSc. METHODS: Expression of 5-LOX in skin sections from 10 SSc patients and 8 healthy controls was examined by in situ hybridization with specific riboprobes and by immunohistochemistry analysis with 5-LOX monoclonal antibodies. Synthesis of 5-LOX by cultured dermal fibroblasts from 7 patients with SSc and 4 controls was measured by fluorescence-activated cell sorter analysis. In addition, concentrations of leukotriene B4 (LTB4) and LTE4 in fibroblast supernatants after stimulation were determined using enzyme immunoassays. RESULTS: Expression of 5-LOX was found in all skin sections from SSc patients as well as from controls. However, the number and percentage of 5-LOX-positive cells were significantly higher in SSc skin sections compared with control sections. Expression of 5-LOX was seen in cells within perivascular inflammatory infiltrates as well as in fibroblasts throughout the skin. The experiments with cultured skin fibroblasts revealed that 5-LOX was constitutively expressed in these cells, which resulted in the production of leukotrienes after cell stimulation. Whereas no difference was found for LTE4, SSc fibroblasts produced significantly higher amounts of LTB4 after stimulation, compared with healthy control fibroblasts. CONCLUSION: The results of this study suggest that the 5-LOX pathway may be of significance in the pathogenesis of SSc and may represent a target for new treatment strategies.     

High frequency ultrasound assessment of skin in systemic sclerosis patients

Aim of the workTo evaluate the role of high frequency ultrasound (HFU) in assessing skin changes in terms of thickness and echogenicity in systemic sclerosis (SSc) patients with early and late changes.Patients and methodsTwenty-three SSc patients were enrolled along with 21 matched controls. Skin thickness was assessed using modified Rodnan skin score (mRSS) and HFU.ResultsPatients had mean age of 41.8 ± 9.1 years, 91.3% were females, mean disease duration 6.0 ± 4.6 years, 11 patients had early (<5 years) and 12 late (≥5 years) disease, 8 patients had limited (lcSSc) and 15 diffuse (dcSSc) cutaneous SSc. Antinuclear antibody was positive in 17 (73.9%) and antiscleroderma-17 in 18 (78.3%). Patients had significantly thicker skin between second and third metacarpophalangeal joint (L = 1.52 ± 0.35 mm vs 1.25 ± 0.35 mm; p = 0.017 and T = 1.48 ± 0.34 mm vs 1.26 ± 0.33 mm; p = 0.038 respectively). Patients with early disease had thicker skin than those with late disease. HFU dermal thickness showed no significant difference according to gender, subtypes, presence and absence of clinical manifestations or autoantibody positivity. There was significant higher dermal thickness in patients with reflux (p = 0.009) and was lower in patients with interstitial pulmonary fibrosis (p < 0.05). There was negative correlation between US dermal thickness and disease duration (p < 0.05). mRSS showed no correlation with HFU dermal thickness in all areas.ConclusionHFU is useful in assessing skin pathologic changes (even subclinical changes) in terms of thickness and echogenicity in SSc patients. Moreover, it could be a potential screening tool in differentiating normal from pathologic skin thickness.     

The treatment of skin ulcers in patients with systemic sclerosis

Systemic Sclerosis (Ssc) is a complex disease of the connective tissue, characterized by progressive thickening and fibrosis of the skin and the internal organs and by diffused damage of the microvascular system. The fibrosis ones of the skin associated to the characteristic vascular alterations lead to the genesis of ulcers, more or less extended, often multiple, peripheral localization, chronic course, painful, able to influence patient's quality of life. Indeed, immunity reactivity, the thinning and the loss of elasticity of the skin, the peripheral neurological damage and the eventual drug assumption that can reduce regenerative/reparative abilities, can easily make an ulcer chronic and become infected complicating still more the patient disease, rendering more difficult the cure often, ulcer evolves to gangrene, and in some cases, in amputation too. For all these reasons, we have begun to study ulcers therapy (local and systemic), considering this activity it leave integrating of the charitable distance of the sclerodermic patient, putting to point on strategy both diagnostic and therapeutic, but above all with the primary scope, if possible, is to prevent ulcers, in contrary case, to alleviate the pain and to render the quality of the life of the patient better.     

Lymphocytes in the skin of patients with progressive systemic sclerosis

Mononuclear cells (MNC) present in the dermis of the forearm and in the blood of patients with progressive systemic sclerosis (PSS) were quantified and analyzed for subsets using monoclonal antibodies. The findings were correlated with cutaneous and systemic features of the disease. Total T lymphocytes and their subsets, B cells, and macrophages were enumerated in the skin samples of 21 patients with PSS. The dermal MNC infiltrates consisted mostly of activated T lymphocytes with a mean T helper/T suppressor (T4/T8) ratio of 2.4 ± 1.3 SD. Few B1-positive or T6-positive cells (macrophages) were observed. There was no correlation between the skin or blood T4/T8 ratios and the degree of skin thickening. On histologic examination, 58 of 115 (50%) untreated patients with PSS had prominent dermal MNC infiltration. Significant correlations between the degree of MNC infiltration and both the degree (P < 0.05) and progression (P < 0.05) of skin thickening were observed. No correlations with other systemic disease features of PSS were noted. These results suggest that cutaneous T lymphocytes may play a role in mediating dermal sclerosis in PSS.