Effects of long-term cyclic iloprost therapy in systemic sclerosis with Raynaud's phenomenon. A randomized, controlled study

OBJECTIVE: Iloprost is a stable prostacyclin analogue which has been shown to be effective in the short-term symptomatic treatment of Raynaud's phenomenon (RP) secondary to systemic sclerosis (SSc). The aim of this study was to evaluate the effects of long-term cyclic therapy with iloprost in comparison with nifedipine on the skin score, pulmonary function and Raynaud's severity score in patients with SSc and RP. METHODS: We conducted a 12-month prospective, randomised, parallel-group, blind-observer trial to compare the effects of intravenously infused iloprost (2 ng/kg/min on 5 consecutive days over a period of 8 hours/day and subsequently for 8 hours on one day every 6 weeks) with those of conventional vasodilating therapy with nifedipine (40 mg/day for os) in 46 patients with SSc and RP. RESULTS: At 12 months, iloprost but not nifedipine reduced the skin score (iloprost: from 13.26 +/- 2.05 to 9.26 +/- 1.32, p = 0.002; nifedipine: from 10.83 +/- 2.09 to 12.17 +/- 3.02, p = n.s.; iloprost vs nifedipine: p = 0.016) and the RP severity score (iloprost: from 2.17 +/- 0.2 to 1.22 +/- 0.13, p = 0.02 vs baseline; nifedipine: from 2.08 +/- 0.34 to 1.33 +/- 0.22, p = n.s.). Carbon monoxide diffusing capacity (DLCO), expressed as % of the predicted normal value, worsened significantly in the nifedipine group (from 69.6 +/- 7.4% to 61.5 +/- 6.5%, p = 0.044) and remained stable in patients treated with iloprost (from 53.2 +/- 4.8 to 56.0 +/- 4.6%, iloprost vs nifedipine: p = 0.026). CONCLUSION: In SSc patients, cyclic intravenous iloprost infusion is able to control vasospastic disease. Our results suggest that it might also act as a disease-modifying agent, as it seems to improve the course of the disease. Further studies principally focused on organ involvement and the natural history of the disease are needed to confirm our results.     

Disease-modifying effects of long-term cyclic iloprost therapy in systemic sclerosis. A retrospective analysis and comparison with a control group

OBJECTIVE: To evaluate the role of iloprost, a derivative of prostacyclin, as a possible disease-modifying agent for systemic sclerosis (SSc). METHODS: Fifty-six consecutive SSc patients treated for a median period of 4 years with cyclic infusions of iloprost for severe Raynaud's phenomenon and ischemic ulcers were compared with 56 control patients matched for age, sex, disease subset and duration. Control patients were also similar to the iloprost group with regard to autoantibody status, the presence of major disease-related organ manifestations at baseline, and the use of other treatments. The evolution of lung function test results, the frequency of major disease-specific complications and the survival of the cohorts were the objects of this analysis. RESULTS: No significant difference was observed between the two groups with regard to changes in lung function tests over time, or the number of patients who presented with the onset of active interstitial lung disease, pulmonary arterial hypertension or scleroderma renal crisis. Survival did not differ between the two groups. CONCLUSION: The evolution of lung function test results, the frequency of major disease-specific complications, and survival did not differ significantly between SSc patients treated with cyclic iloprost and a group of patients matched for sex, age, and disease subset and duration. However, no cases of severe pulmonary arterial hypertension were observed in the patients treated with iloprost, suggesting that studies focusing on the possible preventive action of iloprost on the progression of SSc- associated mild pulmonary arterial hypertension would be warranted.     

Isolated diffusing capacity reduction in systemic sclerosis.

OBJECTIVE. To determine the long-term outcome of patients with systemic sclerosis (SSc) and an isolated reduction in the diffusing capacity for carbon monoxide (DLCO) at the time of initial evaluation. METHODS. Patients with an isolated reduction in DLCO (i.e., normal forced vital capacity [FVC] and normal ratio of the forced expiratory volume in one second [FEV1] to the FVC) on initial evaluation were identified from among 815 patients with SSc who were carefully followed up throughout their illness. We requested that patients have repeat pulmonary function testing (PFT), and the outcomes of these tests, as well as cardiopulmonary and survival outcomes, were determined. RESULTS. An isolated reduction in DLCO, with a normal FVC was detected in 152 (19%) of the 815 patients. A subset of those with an isolated reduction in DLCO (11%) developed isolated pulmonary hypertension and had severely reduced survival rates. Pulmonary hypertension was strongly associated with an initial DLCO of less than 55% of predicted normal and a FVC (% predicted)/DLCO (% predicted) ratio of greater than 1.4. Among all patients in whom this ratio was greater than 1.4, 22% developed isolated pulmonary hypertension, compared with only 2% of those whose ratio was less than 1.4 (P less than 0.01). Of the 152 patients with isolated DLCO reduction, 73 (48%) underwent PFTs a mean of 5.4 years (range 2.0-13.2) after the initial PFT. Only 6 (8%) of these 73 patients ever had serious pulmonary disease: 5 had isolated pulmonary hypertension, and 1 had severe pulmonary fibrosis. Half of the patients with a low initial DLCO demonstrated a significant improvement (greater than 20%) at followup testing that could not be explained by the demographic, clinical, or laboratory findings at the first visit. CONCLUSION. Isolated reduction in DLCO is a frequent abnormality in SSc. Overall, it is associated with a good prognosis for survival and for pulmonary morbidity. A small subset of patients (11%) who have a very low DLCO (less than 55% of predicted) have developed isolated pulmonary hypertension, all of whom had limited scleroderma.     

Low versus high-dose iloprost therapy over 21 days in patients with secondary Raynaud's phenomenon and systemic sclerosis: a randomized, open, single-center study

OBJECTIVE: We compared the efficacy of different dosages of longterm iloprost treatment on Raynaud's phenomenon (RP), ulcer healing, skin thickening, and progression of internal organ sclerosis in patients with systemic sclerosis (SSc). METHODS: Fifty patients with SSc were randomized 1:1 for the maximally tolerated dose up to 2 ng/kg body weight per minute or low-dose (0.5 ng/kg bw per min) intravenous iloprost administration, applied for 6 hours daily over 21 days. Effects on RP, ulcer healing, skin thickness, esophageal function, and lung involvement assessed by forced vital capacity (FVC) and DLCO were measured, as well as side effects. RESULTS: Both regimens yielded 70% reduction of digital ulcers, 40% reduction in frequency of RP, and 30% reduction in duration of RP. One year after therapy, the modified Rodnan skin score appeared to be unchanged. FVC and DLCO-SB were stable in 87% and 74% of the patients, respectively. The effect of iloprost on skin thickness and lung function was sustained in a subgroup of patients receiving several courses of iloprost. As assessed by a patient questionnaire, 12% of all patients did not respond to iloprost therapy, but 78% experienced a longlasting effect. Mild side effects were common in both groups, but did not lead to discontinuation of therapy. CONCLUSION: Low-dose iloprost was shown to be equally effective as high-dose iloprost in longterm treatment and was very effective in therapy of digital ulcers. Registered in www.ClinicalTrials.gov (registration no. NCT00622687).     

Prevalence of exercise pulmonary arterial hypertension in scleroderma

Pulmonary arterial hypertension (PAH) is a complication of scleroderma (systemic sclerosis, SSc); as soon as PAH develops, the patient's prognosis deteriorates rapidly. Early detection of PAH ensures timely treatment. We investigated the prevalence of exercise-induced PAH in a cohort of patients with SSc, and examined the relation between exercise-induced PAH and clinical characteristics and biochemical markers. METHODS: Patients with SSc and normal resting systolic pulmonary arterial pressure (sPAP) were studied. Eligible patients were asked to perform cycloergometer exercise until exhaustion, and exercise sPAP was measured. All patients had their pulmonary function tested and underwent echocardiography at rest. Brain natriuretic peptide (BNP) was also determined. RESULTS: Forty-one patients with SSc were studied. Mean sPAP at rest was 29.7 mm Hg, rising to a mean of 41.4 mm Hg on exercise. Eleven of 41 patients (26.8%) had sPAP post-exercise > 50 mm Hg and 8/41 (19.5%) > 55 mm Hg. A significant correlation was found between exercise sPAP and DLCO (p = 0.008) and between sPAP and BNP levels (p = 0.04). Pre-existing severe Raynaud's phenomenon was more prevalent (50% vs 20%), DLCO levels lower (78.9 vs 92.7 % predicted), and BNP levels higher (72.6 vs 42.1 pmol/ml) in patients with exercise sPAP > 55 mm Hg. CONCLUSION: The prevalence of exercise-induced PAH in patients with scleroderma is high. Patients with lower DLCO and higher levels of BNP are at higher risk of developing higher sPAP. Studies with longterm followup are required to evaluate the risk of developing resting PAH in these patients.     

INCREASE OF PULMONARY DIFFUSING CAPACITY IN SYSTEMIC SCLEROSIS

Pulmonary function tests and chest radiographs of 29 non-smokingsystemic sclerosis (SSc) patients were analysed, featuring anapparently paradoxic finding of an increased diffusing lungcapacity for carbon monoxide (DLCO). Twenty-one patients (72%)had abnormal pulmonary function, 11 of them had restrictivedisease (38%), six (21%) had isolated DLCO increase, four(14%)had isolated DLCO reduction, while two patients had obstructivedisease (7%). Chest X-ray revealed interstitial abnormalitiesconsistent with pulmonary fibrosis in all four patients withisolated DLCO reduction, in one obstructive patient and in sixrestrictive patients. Inpatients with DLCO increased steroidtreatment significantly reduced DLCO (P<0.05) and membraneDLCO component (Dm) (P<0.05). Hitherto unobserved findingof DLCO increase in SSc patients was associated with shorterduration of SSc (P<0.05), normal lungmechanics and roentgenogram(P<0.05) and absence of pulmonary symptoms (P<0.05). Thefindings that in some SSc patients DLCO increases suggest thatDLCO might prove to be an early and sensitive indicator of acutepulmonary involvement. KEY WORDS: Scleroderma, Pulmonary function tests, Pulmonary diffusing capacity, Memebrane diffusing capacity, Pulmonary capillary blood volume, Corticosteroids     

Bronchoalveolar lavage fluid cells in mixed connective tissue disease

OBJECTIVE: Patients with mixed connective tissue disease (MCTD) exhibit clinical features of systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and polymyositis and dermatomyositis (PM-DM). The objective of this study was to clarify differences in BAL findings and immunophenotypes of BAL fluid (BALF) cells of patients with interstitial lung disease associated with these diseases. METHODOLOGY: We were unable to recruit a sufficient number of SLE patients with lung disease. We compared immunophenotypes of lymphocytes and alveolar macrophages (AM) in BALF of 20 MCTD patients with those of 21 SSc and 27 PM-DM patients and tested the relationships between immunophenotypes and pulmonary function in MCTD. RESULTS: MCTD patients had a significantly higher CD4/CD8 ratio with more CD4 positive lymphocytes than PM-DM patients (P = 0.025). In AM phenotypes, MCTD patients had a significantly lower percentage of CD71 positive AM compared with SSc patients (P = 0.023). DLCO was negatively related to absolute numbers of CD8 positive lymphocytes (R = -0.517, P= 0.033). CONCLUSIONS: CD4 positive lymphocytes in BALF were increased in MCTD compared to PM-DM patients, while CD71 positive AM were decreased in MCTD compared to SSc patients. CD8 positive lymphocytes correlated negatively with DLCO measurements in MCTD patients.     

Intravenous cyclophosphamide pulse therapy in interstitial lung disease associated with systemic sclerosis in a retrospective open-label study: influence of the extent of inflammation on pulmonary function

Interstitial lung disease (ILD) is the primary cause of death in patients with systemic sclerosis (SSc). It is thought that chronic inflammation is a key component in SSc-ILD. Treatment, such as cyclophosphamide (CYC), targets this inflammation. We hypothesized that treatment with CYC might be more effective in the inflammatory phase. Therefore, we analyzed whether the extent of inflammation, as assessed by the proportion of ground glass compared to fibrosis, SSc disease duration, the extent of ILD, or baseline diffusion capacity of the lungs (DLCO) <?60%, modifies the effect of intravenous CYC pulse therapy (750 mg/m²) on pulmonary function (as measured by FVC, DLCO) in SSc-ILD patients, after 12, 24, and 36 months. Consecutive patients with SSc-ILD receiving CYC pulses between 2003 and 2015 were included. Pulmonary function tests were performed at 0, 6, 12, 24, and 36 months. There were 75 patients included. Forced vital capacity (FVC) (86% of predicted) and DLCO (42% of predicted) were stable after 12, 24 and 36 months of follow-up (p?>?0.05). Forty-four patients completed 12 cycles of CYC. For the extent of ILD, proportion of ground glass compared to fibrosis, SSc disease duration, and baseline DLCO, there were no differences (all p?>?0.05) in the course of FVC and DLCO. Treatment with CYC followed by maintenance therapy stabilizes pulmonary function in patients with SSc-ILD over a 3-year period. The extent of ILD, proportion of ground glass, SSc disease duration, and baseline DLCO <?60% did not influence the effect of CYC on pulmonary function.     

Pulmonary hypertension is associated with impaired exercise performance in patients with systemic sclerosis

OBJECTIVE: The aim of this study was to evaluate the exercise tolerance by expired gas analysis during stress test in patients with Systemic Sclerosis (SSc). METHODS: Eighteen women (mean age 48.56+/-12.48 years) affected by SSc were studied. A complete echocardiographic examination including pulmonary artery systolic pressure estimation, pulmonary function tests, diffusion lung capacity for carbon monoxide (DLCO), and exercise test were performed. During exercise, breath-by-breath expired gas analysis was performed. RESULTS: Seven patients (39%) had baseline pulmonary systolic hypertension (group A) and 11 patients (61%) did not (group B). Six patients had reduced DLCO values. Both maximal oxygen consumption (VO2max) and anaerobic threshold (VO2AT) values were markedly decreased compared to the predicted values. Seven of 18 patients were unable to complete a maximal exercise (5 of whom affected by pulmonary systolic hypertension). Group A patients showed reduced VO2max, VO2AT, and O2 pulse compared with patients with group B patients (p=0.004, 0.017, and 0.013, respectively); VO2max, VO2AT and O2 pulse were significantly correlated to baseline pulmonary artery systolic pressure. CONCLUSIONS: An exercise intolerance in patients affected by SSc is present. Impairment of exercise performance is associated with pulmonary hypertension.     

Bronchiectasis in systemic sclerosis. A study using high resolution computed tomography

OBJECTIVE: To detect noninvasively the presence of bronchiectasis in patients with systemic sclerosis (SSc), through the use of high resolution chest computed tomography (HRCT). METHODS: Twenty two patients with SSc, of whom 13 with diffuse and 9 with limited disease, besides a complete history, physical and routine laboratory and immunologic profile, were evaluated by pulmonary function testing and HRCT. The chi square test with Yates' correction, the Fisher's exact test, the Fisher's test (F test) and the "t" test were used for statistical analysis of the results. RESULTS: Eleven patients (50.0%) had decreased carbon monoxide diffusing lung capacity (DLCO) and, out of these, four had restrictive lung disease, based on a combined decrease of forced vital capacity (FVC) and total lung capacity (TLC). Another two patients exhibited this pattern without DLCO impairment. HRCT revealed a ground glass picture in 15 patients (68.2%), fibrosis in 9 (40.9%) (of which 5 with ground glass as well), and cylindrical bronchiectasis in 13 (59.1%). Bronchiectasis was more common in diffuse than in limited SSc, and the difference approached but did not reach the level of statistical significance. On the other hand, it was not correlated with either decreased DLCO, presence of ground glass and fibrosis, or with patients' age and disease duration. CONCLUSION: Although the number of patients included in our study is relatively small, our data, for the first time in the literature, indicate a significant association between scleroderma and bronchiectasis. Bronchiectasis should be included in the list of pulmonary manifestations of SSc, and SSc in the list of conditions causing bronchiectasis.     

Pulmonary survival study in 91 patients with systemic sclerosis

In systemic sclerosis (SSc), major determinant of morbidity and mortality is pulmonary complication including pulmonary interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH). In this study, the natural course of pulmonary involvement in SSc patients was investigated. This was a historical cohort study of SSc patients at a referral center for SSc in Iran between February 1998 and December 2007. Patients had a standardized initial evaluation, and interstitial pulmonary involvement was established by high-resolution CT scan (HRCT). Pulmonary hypertension was assessed by tricuspid gradient on echocardiography. Development of abnormal FVC or DLCO was considered as secondary outcome. Analysis of pulmonary survival was performed for primary and secondary outcomes. Ninety-one SSc patients were included in the study with the mean age of 44.1 (14.8). Among these, 65 (71.4%) patients were classified as limited subtype (lcSSc) and 84 (93.3%) were women. PAH was investigated in 8 (8.2%) patients, 1 (6.7%) in dcSSc and 7 (15.9%) in lcSSc subtype of disease. ILD had developed after a median of 107 (SE = 24.4) months after the first symptom of SSc, and 29 patients (31.9%) developed pulmonary fibrosis. Alveolitis and fibrosis had developed after a median of 129.0 (22.9) and 259.0 (74.2) months, respectively. There was a significant difference in Alveolitis-free pulmonary survival between two subgroups of the disease, which showed pulmonary alveolitis developed later in limited SSc (P = 0.03). The difference was not significant in two subtypes when Cox regression model was used to identify the effect of other prognostic factors on pulmonary survival in patients. In the present study, clinical manifestations of two subtypes of disease were divergent at first; however they became convergent in late stages, and this was the same as results in previous studies. Echocardiography for evaluation of pulmonary hypertension and pulmonary function tests for early detection of ILD and PAH is recommended for SSc patients to detect early stages of pulmonary involvement before significant vascular and fibrotic changes occur.     

Serum concentration of surfactant protein D in patients with systemic sclerosis: The potential marker of the interstitial lung disease severity

Pulmonary involvement is a severe manifestation of systemic sclerosis (SSc). The study was designed to determine the serum level of surfactant protein D (SP-D) in patients with SSc in relation to clinical and laboratory parameters as well as to analyze dynamics of changes of these indices within one year of observation.SP-D was assayed in 41 patients with SSc and 15 healthy controls. Additionally, pulmonary function tests, chest high-resolution computed tomography (HRCT), and inflammatory markers were assessed. All tests were performed twice: at entry and repeated after one year of observation.The serum level of SP-D was significantly higher in patients with SSc than in healthy controls. Serum concentration of SP-D was significantly higher in patients with systemic sclerosis-related interstitial lung disease (SSc-ILD) than in those without SSc-ILD. SP-D was found to correlate with lung involvement evaluated with the Medsger score (diffusing capacity of the lung for carbon monoxide (DLCO), forced vital capacity, radiological changes, and estimated pressure in the pulmonary artery in echocardiography). SP-D correlated with the honeycombing and/or reticular pattern in HRCT and ground glass opacification pattern. Serum concentration of SP-D was elevated in patients with a decreased DLCO. Furthermore, SP-D was higher in patients with diffuse cutaneous type (dcSSc) of the disease than in those with SSc limited type (lcSSc). Because of the small size of the group, it was not possible to perform a statistical analysis for patients who had different results in HRCT, VC, and Medsger score between the first and the second evaluation.SP-D seems to be an index for assessing lung involvement. It reflects the state of pulmonary fibrosis but not the dynamics of the pulmonary fibrosis progression. Further studies are needed to evaluate clinical application of the index, and currently, there is no evidence for the recommendation of the application of SP-D in routine evaluation of patients with SSc.     

Pulmonary arterial hypertension in systemic sclerosis: the need for early detection and treatment

Pulmonary arterial hypertension (PAH) is an important cause of mortality in systemic sclerosis (SSc). The symptoms are non-specific and can be ascribed to other features of the disease, so it is often underrecognized until the late stages. Earlier treatment with new agents is associated with better treatment outcomes. The aim of this article is to develop evidence-based guidelines for screening for PAH and interstitial lung disease (ILD) in SSc. PAH occurs in up to 27% of patients with SSc. Abnormal pulmonary function, particularly a disproportionate fall in carbon monoxide diffusing capacity (DLCO), can identify patients in the early stages of PAH, prompting further investigation in high-risk patients (limited SSc of >10 years' duration, symptoms and/or signs of PAH, DLCO <50% predicted, a rapid or large fall in DLCO without evidence of ILD and/or estimated systolic pulmonary artery pressure >45 mmHg on echocardiography). Right heart catheter remains the diagnostic gold standard. An algorithm for screening with regular pulmonary function tests for the early detection of PAH and ILD in SSc is proposed.     

Natural history of mild-moderate pulmonary hypertension and the risk factors for severe pulmonary hypertension in scleroderma

OBJECTIVE: To determine risk factors for developing pulmonary hypertension (PH) in patients with scleroderma (SSc, systemic sclerosis). METHODS: We used a cohort of 1136 SSc patients using severe PH as the primary outcome in a natural history study. RESULTS: Among 361 individuals with no initial echocardiographic PH, 92 (26.0%) developed mild-moderate PH and 48 (13.6%) severe PH. Patients developing severe PH had lower initial DLCO (48.8% of predicted) than those who did not develop PH (56.8% of predicted). Patients with mild-moderate PH had a 17% probability of progressing to severe PH, and 15.6% probability of regressing to no PH. Individuals with limited disease, mild-moderate PH, and age > or= 47 years at diagnosis had a 27.3% probability of developing severe PH, compared to 8.5% in individuals with diffuse disease, no evidence of PH, and age < 47 years at diagnosis. Longitudinal regression models estimated that individuals with limited disease, mild-moderate PH, and DLCO < 50% predicted had an age-adjusted odds ratio of 8.6 of developing severe PH within 2 years compared to individuals without these risk factors. CONCLUSION: Development of severe PH is uncommon in certain subgroups of SSc patients. Risk factors for progression of PH include older age, limited skin disease, and elevated pulmonary artery pressures at the time of initial evaluation.     

High‐dose prednisolone and bolus cyclophosphamide in interstitial lung disease associated with systemic sclerosis: a prospective open study

Aim: Currently, therapy for interstitial lung disease in patients with systemic sclerosis is unsatisfactory. A prospective open label study was conducted in a North Indian tertiary Institute to assess the efficacy of intermittent pulse cyclophosphamide (CYC) and high‐dose prednisolone in systemic sclerosis (SSc)‐related interstitial lung disease (ILD). Methods: Consecutive patients with SSc and ILD, diagnosed on spirometry, carbon monoxide diffusing capacity (DLCO) and high‐resolution computed tomography (HRCT) scan were treated. Pulmonary function tests were carried out at baseline and after 6 months. Patients received oral prednisolone 1 mg/kg body weight initially, with tapering to a dose of 7.5 mg/day was reached. Monthly CYC pulses were given for 6 months followed by 3‐monthly maintenance pulses. CYC was discontinued in patients with declining pulmonary function, adverse effects or static disease after 6 months. Results: Average disease duration of 36 patients was 59.78 ± 63.22 months. Seven patients improved (forced vital capacity [FVC] increase 10% or DLCO increase 15%), five deteriorated (FVC decline 10% or DLCO decline 15%) and 24 had stable disease. Thus, 31 out of 36 patients either improved or had static lung disease. Mean FVC (% of predicted) improved by 4.16% over 6 months (P = 0.069). Mean DLCO (% of predicted) improved by 5.66% (P = 0.27). Average % of predicted DLCO at baseline was 39%. Conclusion: High‐dose prednisolone with pulse CYC can either improve or stabilize lung functions in patients with severe systemic sclerosis lung disease irrespective of presence of ground glass appearance on HRCT.     

Prevalence and characteristics of moderate to severe pulmonary hypertension in systemic sclerosis with and without interstitial lung disease

OBJECTIVE: To determine the prevalence and characteristics of moderate to severe pulmonary hypertension (PH) in patients with systemic sclerosis (SSc) with and without interstitial lung disease (ILD). METHODS: We retrospectively studied clinical and functional characteristics of 197 consecutive patients with SSc who had undergone a screening echocardiography to detect PH. RESULTS: Moderate to severe PH was suspected in 36 patients (18.3%) and confirmed in 32 who underwent right heart catheterization. The prevalence of PH did not differ between patients with limited and patients with diffuse cutaneous SSc. PH was detected in 12/67 (17.9%) patients without ILD vs 24/110 (21.8%) patients with ILD (p not significant). In patients with ILD, a lower PaO2 appeared as the unique independent factor significantly associated with PH, regardless of the extent of fibrosis. In 3 patients out of 9 (33.3%) with ILD and significantly restrictive disease, PH was out of proportion to the degree of fibrosis. In patients with no ILD, a higher grade of dyspnea appeared as the unique independent factor associated with PH. In patients with no ILD, altered DLCO was the sole indicator of the pulmonary function tests associated with PH (best cutoff value 72%). DLCO correlated with systolic pulmonary arterial pressure only in patients with no ILD. CONCLUSION: Prevalence of moderate to severe PH was similar in SSc patients with and those without ILD. In patients with ILD, a lower PaO2 was the unique independent indicator associated with PH. In some patients with severe ILD, PH was out of proportion to the degree of fibrosis. A linear correlation between DLCO and systolic pulmonary arterial pressure was observed only in patients without ILD. All these indicators should assist identification of patients with or without ILD requiring diagnostic procedures for PH before annual screening.     

T cell polarization identifies distinct clinical phenotypes in scleroderma lung disease

OBJECTIVE: Lung involvement is the leading cause of morbidity and mortality in systemic sclerosis (SSc; scleroderma), and interstitial lung disease (ILD) is the most common pulmonary manifestation. An abnormal profibrotic Th2/Tc2-polarized T cell response is postulated to mediate tissue damage and fibrosis. The aim of this study was to investigate whether a polarized T cell phenotype in SSc is associated with lung disease or other clinical manifestations of SSc. METHODS: Circulating T cells were characterized by flow cytometry in 62 patients with SSc and 36 healthy control subjects, using antibodies against CD3, CD4, CD8, chemokine receptor CCR5 (Th1/Tc1-specific), and prostaglandin D2 receptor CRTH2 (Th2/Tc2-specific). The ratio between CCR5 and CRTH2 T cell frequencies was used to quantify type 1 (high-ratio) or type 2 (low-ratio) immune polarization. RESULTS: Patients with SSc exhibited lower CCR5/CRTH2 T cell ratios than those exhibited by control subjects (P<0.0001), indicating a Th2/Tc2-polarized phenotype. Markedly reduced CCR5/CRTH2 T cell ratios were observed in SSc patients with ILD compared with SSc patients without ILD (P<0.0001), particularly in patients with active ILD (P<0.0001) compared with those with stable lung function. Lower CCR5/CRTH2 ratios were strongly associated with a lower value for the percent predicted forced vital capacity (P<0.0001). In patients with an estimated right ventricular systolic pressure>35 mm Hg, suggestive of pulmonary vascular disease, a lower value for the percent predicted diffusing capacity (DLCO) was associated with higher CCR5/CRTH2 T cell ratios (Th1/Tc1) (P=0.009), while in those with right ventricular systolic pressure<35 mm Hg, a lower value for the percent predicted DLCO correlated with lower ratios (Th2/Tc2) (P<0.0001), as observed for ILD. CONCLUSION: T cell polarization in SSc is strongly associated with specific manifestations of lung disease. Measurement of T cell polarization may represent a valuable tool to monitor disease activity and predict clinical outcomes in SSc patients with lung disease.     

Influence of clinical features, serum antinuclear antibodies, and lung function on survival of patients with systemic sclerosis.

OBJECTIVE: To evaluate the independent contribution of several clinical and laboratory variables to the mortality of a cohort of Danish patients with systemic sclerosis (SSc). METHODS: A cohort of 174 patients with incident SSc was retrospectively identified using clinical charts and study records of all new patients with SSc. Disease onset was defined as the time of onset of cutaneous sclerosis. Vital status and causes of death were determined at the end of the observation period. Data on clinical status and pulmonary function were obtained. Antitopoisomerase I (anti-topo I), anticentromere, anti-U1-RNP, anti-U3-RNP, anti-Th-RNP, and anti-RNA polymerase (anti-RNAP) antibodies were determined by means of double immunodiffusion, immunofluorescence, hemagglutination technique, radioactively labelled antisense riboprobes, and ELISA, respectively. RESULTS: Patients were followed for a mean period of 13.3 yrs; 16 died of an SSc related condition and 50 of other causes. Pulmonary fibrosis, DLCO reduction < 40% of the expected, diffuse cutaneous involvement, SSc nephropathy, cardiac disease, and anti-topo I and anti-RNAP antibody were related to decreased survival due to SSc. Variables that entered a Cox regression model of SSc related mortality were right heart failure (RR 12.4, 95% CI 2.5-60), diffuse SSc (RR 7.8, 95% CI 1.8-35), SSc nephropathy (RR 6.1, 95% CI 1.8-21), and DLCO < 40% (RR 4.8, 95% CI 1.1-20). The relative risk of developing right heart failure and diffuse SSc given the presence of anti-RNAP antibody was 14 (p = 0.0001) and 1.9 (p = 0.01), respectively. The corresponding figures for anti-topo I antibody were 4.6 (p = 0.02) and 2.0 (p = 0.01). CONCLUSION: SSc related mortality was associated with right heart failure and diffuse SSc, both of which were also associated with the presence of anti-topo I and anti-RNAP antibody. The prognostic value of these autoantibodies may lie in the early course of the disease when specific morbidity has not yet evolved.     

Elevated plasma adrenomedullin and vascular manifestations in patients with systemic sclerosis

OBJECTIVE: Adrenomedullin (ADM), a vasodilating peptide that possesses antiinflammatory properties, may have a regulatory role in the vascular manifestations of scleroderma (systemic sclerosis, SSc). We examined associations between ADM concentrations and vascular manifestations in a cohort of patients with SSc. METHODS: Patients were examined for manifestations of severe Raynaud's phenomenon (RP), defined as digital resorption, previous iloprost infusion, and sympathectomy. Doppler echocardiography and lung function tests were performed to detect elevation in pulmonary arterial pressure (PAP; > 35 mm Hg) and interstitial lung disease (ILD). Plasma ADM was measured by radioimmunoassay. RESULTS: Plasma ADM was measured in 62 SSc patients and 21 healthy controls. Elevated PAP was found in 15 (24.2%) SSc patients (mean PAP 46.5 +/- 11.2 mm Hg, range 37-74). ADM was not found to be related to age, sex, disease duration, or clinical subset. ADM level was significantly higher (median 13.9 pmol/l) in SSc patients with elevated PAP compared to those with lower PAP (median 7.2 pmol/l) (p = 0.01) and controls (median 7.9 pmol/l) (p = 0.04). ADM level was not different among patients who had elevated PAP with (n = 10) and without concomitant ILD (n = 5) (p = 0.21). SSc patients with severe RP (38.7%; median ADM 11.9 pmol/l) were found not to have different ADM levels compared to controls (p = 0.75). Patients who had both severe RP and elevated PAP were found to have significantly higher ADM levels (median 22.3 pmol/l) than patients who had neither manifestation (median 8.0 pmol/l) (p = 0.006) and those with severe RP alone (median 4.2 pmol/l) (p = 0.006). CONCLUSION: Elevated ADM was found in SSc patients with increased PAP regardless of concomitant ILD.     

Cyclophosphamide pulse regimen in the treatment of alveolitis in systemic sclerosis

OBJECTIVE: To evaluate, in a pilot study, the efficacy of a short term cyclophosphamide (CYC) pulse regimen on alveolitis in a cohort of patients with systemic sclerosis (SSc). METHODS: Twenty-three patients with SSc (17 diffuse SSc and 6 limited SSc) were selected in 5 centers in Italy, based on the findings of an abnormal bronchoalveolar lavage (BAL) cell analysis in association with altered pulmonary function tests (PFT) or recent deterioration in flow volume curve (FVC). Patients were also evaluated by skin score (Rodnan), esophageal manometry and barium swallow radiography, and electrocardiography and 2-mode echocardiography. The pre-enrolment pulmonary evaluation and after 6 months of therapy included evaluation of the clinical status, PFT (FVC, FEV1, DLCO), BAL. standard chest radiograph, and chest high resolution computed tomography. All patients received i.v. CYC (1000 mg/m2 of body surface monthly for 6 mo) and oral prednisone (25 mg daily for the first month and subsequently 5 mg daily of maintenance dosage for the remaining 5 mo). A complete blood count and urinalysis were obtained at monthly intervals. RESULTS: After 6 months of therapy the values for FVC did not change significantly. Individually, 8 of 23 patients showed an improvement (> 15% increase) in FVC after 6 months, while FVC in 13 cases remained stable. Only 2 patients had an important decline in FVC after 6 months of therapy (17 and 24% decrease). Improvement in DLCO was noted in 15 of 23 patients after 6 months of therapy. Four patients were stable and 4 patients had a worsened DLCO at the end of the study. After therapy the mean value of BAL fluid recovery did not change. There was a reduction in total cell number although this value did not reach statistical significance. The levels of neutrophils, eosinophils, lymphocytes, and macrophages did not change significantly. Scans for patients with grades 1, 2, and 3 did not differ significantly after 6 months of therapy, and 14 patients were stable. Changes in appearance, in relation to changes in extent of disease, were seen in 8 patients and consisted of an extension of reticular pattern and transformation from grade 1 to 2 (6/8 patients). All patients showed a ground-glass appearance indicating an acute alveolitis. Improvement in ground-glass was noted in 10 of 23 patients after 6 mo therapy. At the end of the study, 8 patients were stable and 5 patients had a diffusion of the ground-glass to other segments. No side effects were experienced during the treatment except for mild nausea in 4 patients; no patients discontinued therapy during the study. CONCLUSION: CYC pulse regimen seems to stabilize alveolitis in the majority of cases. The association of CYC pulsed modality with prednisone may be useful in SSc patients to control disease evolution in the lung.