Calcium-channel blockers for Raynaud's phenomenon in systemic sclerosis

OBJECTIVE: Most patients with systemic sclerosis (SSc) have Raynaud's phenomenon (RP), which is often more severe than idiopathic RP. This study was a meta-analysis to determine the efficacy of calcium-channel blockers for the treatment of RP in SSc. The primary outcome measures were frequency and severity of ischemic attacks, digital skin temperature, patient and physician global assessments, and digital ulcers. METHODS: The Cochrane search strategy was used to ascertain all trials in all languages. Primary data sources included Medline, Current Contents, and the Cochrane Controlled Trials Register. Studies that met the inclusion criteria were randomized controlled trials of >2 days' duration with a dropout rate of <35%. Twenty-nine studies were found, of which 8 randomized controlled trials were eligible for inclusion. The total number of patients included was small (n = 109). Most trials included primary and secondary RP, and the main reasons for trial exclusion were inability to extract subset data on SSc patients (18 trials), data published previously (2 trials), and lack of a control group (1 trial). Data were abstracted independently by 2 reviewers, and either a weighted mean difference (WMD) or a standardized mean difference (SMD) was calculated for all continuous outcomes; however, information was not available for all outcomes within trials. RESULTS: The WMD of all calcium-channel blockers versus placebo (6 trials) and of nifedipine alone versus placebo (5 trials) for the reduction in the frequency of ischemic attacks over a 2-week period was -8.31 (95% confidence interval [95% CI] -15.71, -0.91) and -10.21 (95% CI -20.09, -0.34), respectively. The SMD of all calcium-channel blockers versus placebo (3 trials) and of nifedipine alone versus placebo (2 trials) for the reduction in the severity of ischemic attacks was -0.69 (95% CI -1.21, -0.17) and -0.99 (95% CI -1.74, -0.24), respectively. CONCLUSION: Calcium-channel blockers for RP in SSc have been tested in several small clinical trials and appear to lead to significant clinical improvement in both the frequency and the severity of ischemic attacks. Most trials were crossover trials in which order effect was not studied. This could have introduced bias. The results of this study suggest that the efficacy of calcium-channel blockers in reducing the severity and frequency of ischemic attacks in RP secondary to SSc is moderate at best (mean reduction of 8.3 attacks in 2 weeks and 35% less severity), and a further large, randomized controlled trial needs to be conducted.     

Lymphocyte-endothelium interaction in systemic sclerosis and Raynaud's phenomenon.

OBJECTIVE: To investigate interactions of immune cells with vascular endothelium in patients with systemic sclerosis (SSc) and in patients with idiopathic or autoimmune Raynaud's phenomenon (RP). METHODS: Lymphocytes obtained from 11 patients with SSc, 9 with RP and 14 control subjects were pre-stimulated in vitro with alloantigens and cultured together with human umbilical vein endothelial cells (HUVECs). Lymphocyte adhesion and induction of endothelial HLA-class 11 molecules were measured by flow cytometry. Lymphocyte cytotoxicity against HUVECs was also evaluated. In some cases cells were cultured under experimental conditions of hypoxia and reoxygenation. RESULTS: Lymphocyte adhesion and induction of endothelial cell expression of HLA-DR molecules were similar in controls and SSc patients, but significantly lower in RP (p < 0.05 and p < 0.03, respectively). Cytotoxic activity of lymphoblasts against endothelial cells was negligible in all patient groups. Under experimental conditions of hypoxia and reoxygenation lymphocyte adhesion was significantly greater than in normoxic conditions in SSc patients, while it was similar to normoxia in control subjects and RP patients. CONCLUSION: These results suggest that in RP patients there may be regulatory mechanisms of lymphocyte response able to control the processes that lead to lymphocyte adhesion and endothelial HLA-DR molecule induction. These mechanisms could play an important role in RP, and might possibly be lost in clinically evident SSc.     

Increased circulating platelet-leucocyte complexes in patients with primary Raynaud's phenomenon and Raynaud's phenomenon secondary to systemic sclerosis: a comparative study.

Platelet activation and circulating platelet-leucocyte complexes increase in vascular ischemic events and autoimmune inflammatory diseases. Platelet activation markers and platelet-leucocyte complexes were evaluated in primary Raynaud's phenomenon (RP) and in RP secondary to systemic sclerosis (SSc). Whole-blood flow cytometry was utilized to quantify CD62P, platelet microparticles (PMP), platelet-monocyte complexes (PMC) and platelet-neutrophil complexes (PNC) in primary RP and in SSc patients with secondary RP. SSc patients with secondary RP had significantly higher platelet CD62P expression than primary RP patients and controls (P = 0.017 and 0.004, respectively). Primary and secondary RP patients had higher mean PMC and PNC levels than controls (all P < or = 0.001). PMP level in SSc patients with pulmonary hypertension was significantly higher than in others (P = 0.048). All parameters were similar in SSc patients with and without digital ulcers, aspirin-users and nonusers (P > 0.05). CD62P level decreased significantly after iloprost administration in four patients with digital ulcers (16.1 +/- 17.4 vs 7.4 +/- 3.8%, P = 0.03). Our results suggest there is platelet-leucocyte complex formation in RP, and, despite antithrombotic therapy, platelet activation and platelet-leucocyte interaction are ongoing in SSc. This is important as it might have potential therapeutic implications with respect to using antiplatelet drugs in SSc.     

Pulmonary vascular response during Raynaud's phenomenon in progressive systemic sclerosis

Progressive systemic sclerosis and Raynaud's phenomenon are associated with a distinctly vascular form of pulmonary involvement and pulmonary hypertension. To investigate a possible underlying vasospastic predisposition in these patients, the pulmonary vascular response to Raynaud's phenomenon induced by cold-water hand immersion was examined in nine patients. Four patients had pulmonary fibrosis and four patients had the CREST syndrome; no patient had pre-existing pulmonary hypertension. During Raynaud's phenomenon, there was no significant rise in mean pulmonary artery pressure (15 +/- 3 versus 15 +/- 2 mm Hg, p = NS) or pulmonary vascular resistance (112 +/- 38 versus 118 +/- 50 dynes X second X cm-5, p = NS) over baseline, despite a significant rise in mean aortic pressure (104 +/- 14 versus 92 +/- 11 mm Hg, p less than 0.01) and systemic vascular resistance (1,700 +/- 450 versus 1,500 +/- 470 dynes X second X cm-5, p less than 0.01). It is concluded that pulmonary vasospasm with transient pulmonary hypertension does not occur in patients with progressive systemic sclerosis and Raynaud's phenomenon during episodes of Raynaud's phenomenon. Abnormal pulmonary vasospasm in these patients in response to other stimuli, however, is not excluded.     

Quantitation of microcirculatory abnormalities in patients with primary Raynaud's phenomenon and systemic sclerosis by video capillaroscopy

OBJECTIVE.: To assess nailfold capillary density and dimensions in patients with primary Raynaud's phenomenon (PRP), limited cutaneous systemic sclerosis (LSSc) and diffuse cutaneous SSc (DSSc), and healthy control subjects. METHODS.: Using the technique of nailfold video capillaroscopy, capillary density and dimensions were averaged from all visible capillaries in a 3 mm length of the nailfold from right and left ring fingers of each subject. Twenty healthy control subjects, 15 patients with PRP, 13 patients with DSSc and 21 patients with LSSc were examined. Intra-observer and inter-observer variability were calculated in 18 and 23 patients, respectively. RESULTS.: There were significant trends for capillary density to fall and for all dimensions to rise across the four groups (P < 0. 0001 for density and all dimensions, order healthy controls, PRP, DSSc and LSSc). Intra- and inter-observer reproducibility studies showed that although there was good correlation between and within observers, the limits of agreement were between +/-25-50% indicating lack of reproducibility. CONCLUSIONS.: Microcirculatory abnormalities can be quantified using the technique of video capillaroscopy and were most marked in patients with LSSc.     

Seasonal variation of Raynaud's phenomenon secondary to systemic sclerosis.

OBJECTIVE: Patients with systemic sclerosis (SSc) were assessed for 12 months to quantify the seasonal variation in Raynaud's phenomenon (RP) in patients with an underlying connective tissue disease. METHODS: Eighteen patients with SSc (17 limited, 1 diffuse type) were studied. Raynaud's attacks were recorded in a daily diary for four 2-week periods at 3 month intervals. Daily number and duration of attacks and overall severity of RP were calculated for each 2-week period. Mean daily temperatures, measured and perceived, were obtained for each period. RESULTS: In winter, patients had a mean of 2.9 attacks/day (SD +/-1.1), daily duration 70 minutes (SD +/-48) and a severity of score of 4.1 (SD +/-2.0) out of 10. All 3 variables correlated with ambient outdoor temperature and varied significantly over the 12 months (p<0.001) with mean reductions of 48, 50, and 56% respectively from winter to summer. Only 3 of 18 patients reported no attacks during the summer period. The mean measured and perceived outdoor temperatures increased from winter to summer by 10.6 and 14.3 degrees C, respectively. CONCLUSION: For patients with SSc, RP is a problem throughout the year. Symptoms may be reduced by about 50% in the summer months, but few patients experience complete relief.     

Homocysteine levels in patients with Raynaud's phenomenon

BACKGROUND: Patients with Raynaud's phenomenon (RP) have vasomotor dysregulation, mainly cause by dysfunction of the endothelium. Since homocysteine has been found to be damaging to endothelial cells, we investigated the concentrations of plasma homocysteine, folate and vitamin B12 in patients with primary or secondary RP compared to healthy individuals. PATIENTS AND METHODS: We measured the concentrations of plasma fasting homocysteine, folate and vitamin B12 in a group of healthy individuals (n = 45) and in patients with primary (n = 26) or secondary RP (n = 42). RESULTS: Median homocysteine levels in healthy controls and in patients with primary RP, secondary RP were 7.9 (IQR 4.1 to 11.8) 9.8 (IQR 5.1 to 14.4), and 10.6 (6.0 to 15.3) mumol/L, respectively. Patients with primary and secondary RP had significantly higher homocysteine concentration compared to healthy controls (Kruskal Wallis p = 0.01). After matching for age and sex, patients with either primary or secondary RP showed significantly higher homocysteine levels (Wilcoxon p < 0.0001). No significant differences between the three groups were found concerning serum levels of vitamin B12 (p = 0.9) and serum folate levels (p = 0.2). CONCLUSION: These data demonstrate that patients with RP have higher plasma levels of homocysteine. No significant differences in folate and vitamin B12 levels were found between patients with primary RP, secondary RP, and healthy individuals. These data suggest that homocysteine may play a role in RP and may provide new clues in understanding of the vasomotor dysregulation.     

Pathophysiology and clinical consequences of Raynaud's phenomenon related to systemic sclerosis

According to the so-called vascular hypothesis, Raynaud's phenomenon (RP) is one initial event in the pathophysiological cascade leading to sclerosis in systemic sclerosis (SSc). It is characterized by recurrent, reversible spasms of small arterioles and digital arteries, usually triggered by cold and emotional stress. Clinical signs of RP are a sudden pallor of single digits of fingers followed by reactive hyperaemia and in severe cases also by cyanosis. Besides imbalances between vasoconstrictive and vasodilatory processes, structural alterations of the involved vessels are fundamental to secondary RP in SSc. The latter is the reason why secondary RP in SSc, in contrast to primary RP, often leads to ischaemia and re-perfusion injuries. New insights into the pathophysiology of RP feature a special role for alpha2c-adrenoreceptors, Rho-kinase signalling pathways and soluble mediators. They have resulted in promising therapeutic options, including antagonism of endothelin receptors, inhibition of phosphodiesterases or selective blockade of alpha2c-adrenoreceptors. They should also have a positive impact on the course of SSc in general.     

Calcium‐channel blockers for Raynaud's phenomenon in systemic sclerosis

Objective

Most patients with systemic sclerosis (SSc) have Raynaud's phenomenon (RP), which is often more severe than idiopathic RP. This study was a meta‐analysis to determine the efficacy of calcium‐channel blockers for the treatment of RP in SSc. The primary outcome measures were frequency and severity of ischemic attacks, digital skin temperature, patient and physician global assessments, and digital ulcers.

Methods

The Cochrane search strategy was used to ascertain all trials in all languages. Primary data sources included Medline, Current Contents, and the Cochrane Controlled Trials Register. Studies that met the inclusion criteria were randomized controlled trials of >2 days' duration with a dropout rate of <35%. Twenty‐nine studies were found, of which 8 randomized controlled trials were eligible for inclusion. The total number of patients included was small (n = 109). Most trials included primary and secondary RP, and the main reasons for trial exclusion were inability to extract subset data on SSc patients (18 trials), data published previously (2 trials), and lack of a control group (1 trial). Data were abstracted independently by 2 reviewers, and either a weighted mean difference (WMD) or a standardized mean difference (SMD) was calculated for all continuous outcomes; however, information was not available for all outcomes within trials.

Results

The WMD of all calcium‐channel blockers versus placebo (6 trials) and of nifedipine alone versus placebo (5 trials) for the reduction in the frequency of ischemic attacks over a 2‐week period was −8.31 (95% confidence interval [95% CI] −15.71, −0.91) and −10.21 (95% CI −20.09, −0.34), respectively. The SMD of all calcium‐channel blockers versus placebo (3 trials) and of nifedipine alone versus placebo (2 trials) for the reduction in the severity of ischemic attacks was −0.69 (95% CI −1.21, −0.17) and −0.99 (95% CI −1.74, −0.24), respectively.

Conclusion

Calcium‐channel blockers for RP in SSc have been tested in several small clinical trials and appear to lead to significant clinical improvement in both the frequency and the severity of ischemic attacks. Most trials were crossover trials in which order effect was not studied. This could have introduced bias. The results of this study suggest that the efficacy of calcium‐channel blockers in reducing the severity and frequency of ischemic attacks in RP secondary to SSc is moderate at best (mean reduction of 8.3 attacks in 2 weeks and 35% less severity), and a further large, randomized controlled trial needs to be conducted.

     

Spontaneous chromosome damage (micronuclei) in systemic sclerosis and Raynaud's phenomenon

OBJECTIVE: To evaluate the prevalence of spontaneous chromosome damage in cultured peripheral lymphocytes of patients with systemic sclerosis (SSc), idiopathic Raynaud's phenomenon (RP), and suspected secondary RP, by means of molecular cytogenetic analysis. METHODS: We studied 43 patients with SSc, 13 with idiopathic RP, and 16 with suspected secondary RP and 25 healthy controls. As a marker of chromosome alteration we used the micronucleus (MN) assay. All subjects were also classified for antinuclear antibodies, anticentromere antibodies (ACA), or Scl70. To identify the mechanism of MN formation, we also performed MN fluorescence in situ hybridization (FISH) analysis using a pancentromeric DNA probe. RESULTS: Patients with SSc and subjects with RP showed significantly higher MN frequencies than controls (25.9 +/- 1.7 and 19.1 +/- 2.15, respectively, vs 9.4 +/- 2.2; p < 0.001). Subjects with suspected secondary RP displayed MN frequency (23.5 +/- 2.7) comparable to that of SSc patients, while spontaneous MN level in idiopathic RP subjects (13.6 +/- 3.0) did not differ significantly from controls (9.4 +/- 2.2). ACA positive subjects showed the highest MN frequencies (32.8 +/- 1.7) compared to subjects with a different antibody pattern (18.3 +/- 1.6). CONCLUSION: Our results show the presence of higher levels of micronuclei in circulating lymphocytes of patients with SSc and subjects with suspected secondary RP. They also suggest a possible role of ACA in determining cytogenetic anomalies. FISH analysis indicated that both aneuploidogenic and clastogenic events contributed to the formation of MN observed in SSc patients and subjects with suspected secondary RP.     

Role of videocapillaroscopy in early detection of transition from primary to secondary Raynaud's phenomenon in systemic sclerosis

Patients initially diagnosed as having primary Raynaud's phenomenon (PRP) may shift to secondary (SRP) during the follow-up. Nailfold videocapillaroscopy (NVC) is a tool that allows to distinguish between PRP and SRP through the identification of the "early" scleroderma-pattern of microangiopathy. The aim of this study was to evaluate the transition from PRP to SRP in an Italian cohort of patients during their follow-up. 129 patients with PRP were identified and followed-up for 2721 months. The diagnosis of PRP was achieved as suggested by LeRoy. The NVC diagnosis of scleroderma-pattern was based on the presence of specific "early" capillary abnormalities (i.e. giant capillaries, microhaemorrhages, and/or slight reduction of capillary density). Based on the identification of the "early" scleroderma-pattern by NVC, 14% of patients changed from PRP to SRP during the follow-up. Interestingly, 4.6% of these patients showed at baseline a fully normal NVC pattern (transition from normal to scleroderma NVC pattern in 3427 months), and 10% showed slight and not-specific nailfold capillary abnormalities (i.e. dystrophic capillaries and/or enlarged capillaries) at baseline (transition to scleroderma NVC pattern in 2515 months). Following a careful NVC analysis, we showed the progression from PRP to SRP in 14% of the analyzed patients. We suggest the capillaroscopic analysis twice a year in presence of PRP, in order to early detect the transition to SRP in patients showing at the beginning a normal pattern or not-specific nailfold capillary abnormalities, as assessed by NVC.     

Determination of fingertip lacticemy before and after cold stimulus in patients with primary Raynaud's phenomenon and systemic sclerosis

OBJECTIVE: Establishing a cold stimulus test based on the measurement of finger tip lacticemy (FTL) in Raynaud's phenomenon (RP). METHODS: Twenty-seven controls and 79 patients with RP [30 systemic sclerosis (SSc) and 49 isolated RP] were studied. The latter were further classified into probable primary RP (PPRP) and probable secondary RP (PSRP). FTL was determined before (pre-CS) and after (post-CS) a cold stimulus and the percentage difference was designated ACS-FTL. RESULTS: Pre-CS-FTL was marginally higher in SSc patients than in isolated RP and controls. Post-CS-FFL was significantly higher in SSc and PSRP than in PPRP and controls. SSc and PSRP patients had higher post-CS-FTL than pre-CS-FTL (positive ACS-FTL) while controls presented a negative ACS-FTL. Post-CS-FTL had a heterogeneous behavior in patients with PPRP. CONCLUSION: CS-FTL test was shown to be an easy method for evaluation of fingertip effective perfusion before and after a cold stimulus. Further studies are warranted to test its possible clinical application in discriminating between patients with SSc and controls, as well as between patients with PPRP and PSRP.     

Measurement of cold challenge responses in primary Raynaud''s phenomenon and Raynaud''s phenomenon associated with systemic sclerosis.

Using computed thermography continuous temperature recordings were made before and after cold challenge of the fingers of control subjects and patients with primary Raynaud's phenomenon and Raynaud's phenomenon associated with systemic sclerosis. Basal skin temperature measurements (Tpre) were significantly lower in patients with primary Raynaud's phenomenon and Raynaud's phenomenon associated with systemic sclerosis than in the controls. Temperatures immediately after cold challenge (T0) were significantly lower in patients with primary Raynaud's phenomenon and Raynaud's phenomenon associated with systemic sclerosis than in controls. The lag phase before the start of temperature recovery (Tlag) was significantly greater in patients with primary Raynaud's phenomenon and Raynaud's phenomenon associated with systemic sclerosis than in control subjects. The maximum recovery index (R%) was significantly less in patients with primary Raynaud's phenomenon and Raynaud's phenomenon associated with systemic sclerosis than in controls. The maximum rate of change of temperature during the rapid phase of rewarming (Gmax) was significantly greater in controls than in patients with primary Raynaud's phenomenon and Raynaud's phenomenon associated with systemic sclerosis. Discriminant analysis showed that the dynamic parameters of rewarming (Tlag, Gmax, and R%) showed greater variation between the patients with primary Raynaud's phenomenon and those with Raynaud's phenomenon associated with systemic sclerosis than did Tpre or T0. This method of analysis of cold challenge will be used in studies of the effects of treatment of Raynaud's phenomenon.