Comparison of humeral blood flow during rewarming and recooling of the hand in normal subjects or presenting Raynaud's phenomenon

Vascular reactivity to heat and cold was studied in 11 normal subjects without vascular disease and in 23 patients with Raynaud's phenomenon (etiologies: Raynaud's disease, scleroderma, thoracic outlet syndrome). The study of hand and digital temperatures and brachial artery blood flow was performed in ambiant conditions (room temperature 23.5 +/- 1 degree C) and after thermal (cold or warm exposure: 10, 33 and 40 degrees C), mechanical and metabolic modifications (with a wrist tourniquet). In these conditions, blood flow was studied at each temperature, before, during and after 3 minutes ischemia of the hand. Analysis of results showed that vasomotricity possibilities were preserved but that responses were not identical. Patients with primary Raynaud's phenomenon, and even more those with scleroderma as well, had reduced brachial artery blood flow after cooling (10 degrees C). After ischemia, maximal blood flow was also reduced. The microcirculatory disease existing in Raynaud's phenomenon limits the vasodilator capacity of hand vessels, but probably more in tissues with vascular lesions. Vasodilation seems to be limited during exposure to low well as high temperatures, but vasoconstriction capacity is not disturbed.     

Finger plethysmography for studying the blood rheological and hemodynamic components of an acrosyndrome

Digital plethysmography allows investigation of maximum digital pulse (M.D.P.) after immersion of hands at 45 degrees C over three minutes. It is correlated with digital arterial blood flow. Reactivity to cold is determined from the ratio M.D.P./digital pulse after local and body cooling over 3 minutes. Tests were performed on 65 controls, 69 patients with idiopathic Raynaud's syndrome, 12 with scleroderma, 10 with digital arteritis and 15 with Raynaud's phenomenon secondary to hemorheologic affections. Maximum digital pulse was significantly decreased in patients with digital arteritis and scleroderma. The M.D.P. was normal in controls and patients with idiopathic Raynaud's syndrome, and was significantly increased in patients with a rheologic Raynaud's phenomenon. Digital artery reactivity differentiates the populations studied: it was maximum in patients with scleroderma, moderate in controls and patients with isolated digital arteritis and marked in patients with idiopathic Raynaud's disease and those with rheologic Raynaud's phenomena.     

Occlusive digital artery disease in patients with Raynaud's phenomenon

In order to assess the relationship of occlusive digital artery disease to the presence or subsequent appearance of systemic illness in patients with Raynaud's phenomenon, the records of 147 patients with Raynaud's phenomenon, subdivided on the basis of quantitative finger plethysmographic results into those with and without occlusive digital artery disease, were reviewed. Patients with definite scleroderma were excluded from the study. Occlusive digital artery disease was detected in 62 percent of the 147 cases. A cause for Raynaud's phenomenon was found at initial evaluation in 34 percent of patients with occlusive digital artery disease and 24.9 percent of patients without it. Follow-up status was ascertained in 56 patients with no cause for Raynaud's phenomenon discovered at initial evaluation. During a follow-up period averaging five and a half years, systemic illness became apparent in 43.8 percent of those with occlusive digital artery disease and only 16.7 percent of those without it. Connective tissue diseases, primarily scleroderma, dominated in both categories, but carcinoma was also a problem and appeared only in patients with occlusive digital artery disease. The presence of occlusive digital artery disease in patients with Raynaud's phenomenon of no apparent cause warrants greater concern and closer follow-up for the development of cancer or connective tissue disease. Digital plethysmography for the detection of occlusive digital artery disease is an important part of the evaluation of patients with Raynaud's phenomenon.     

Toxic oil syndrome: a syndrome with features overlapping those of various forms of scleroderma

Thirty-two toxic oil syndrome (TOS) patients were selected because they presented with scleroderma-like changes and were observed during the first 36 months of evolution of the disease. Initially, these patients presented with a noncardiogenic pulmonary edema, eosinophilia, arthralgia/arthritis, peripheral edema, and myositis. Histologic investigations showed a widespread chronic interstitial infiltrate with lymphocytic vasculitis. They subsequently developed peripheral neuropathy, joint contractures, scleroderma-like changes, Raynaud phenomenon, pulmonary hypertension, sicca syndrome, and liver disease. Biopsy studies during this stage showed fibrosis and obliterating arteriopathy. Late features of TOS are musculoskeletal pain, cramps, livedo reticularis, carpal tunnel syndrome, and digital tuft changes. TOS is a new chemically induced scleroderma-like syndrome with features overlapping those of eosinophilic fasciitis, systemic sclerosis, and forms of localized scleroderma.     

Clinical associations of anticentromere antibodies and antibodies to topoisomerase I. A study of 355 patients

Anticentromere antibodies (ACA) and anti-topoisomerase I (anti-topo I) were assayed in serum samples from 355 patients: 89 with proximal scleroderma; 54 with CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias), without proximal scleroderma; 154 with primary and secondary Raynaud's disease; and 58 with other rheumatic diseases, without Raynaud's disease. Sera from healthy control subjects were also assayed. Using immunoblotting techniques, anti-topo I was detected in 28% of the patients with proximal scleroderma; using immunodiffusion techniques, this antibody was found in only 20% of the same group of patients. Anti-topo I and ACA were found primarily in patients with scleroderma, CREST syndrome, and Raynaud's phenomenon. ACA identified patients with less severe disease, whereas anti-topo I identified patients with skin and cardiac involvement and patients with malignancies.     

Esophageal manometric findings in autoimmune rheumatic diseases: is scleroderma esophagus a specific entity?

Summary In order to assess whether distal esophageal hypomotility in scleroderma is unique to this disease or not, we studied 25 normal volunteers and 109 patients with autoimmune rheumatic diseases (27 with primary Sjögren's syndrome, 25 with idiopathic Raynaud's phenomenon, 25 with rheumatoid arthritis, 19 with scleroderma, 5 with undifferentiated connective tissue disease, 3 with systemic lupus erythematosus, 2 with mixed connective tissue disease, 2 with sclerodermatomyositis, and one with morphea). Esophageal dysfunction typical of scleroderma was present in 17 patients (15.6%), of whom 13 had scleroderma (68%) and one each primary Sjögren's syndrome, rheumatoid arthritis, undifferentiated connective tissue disease, and mixed connective tissue disease. Twenty-two percent of all patients had nonspecific esophageal motility changes, clustered among primary Sjögren's syndrome, idiopathic Raynaud's phenomenon, and rheumatoid arthritis. We conclude that lower esophageal hypomotility, although most frequent in scleroderma, is not unique to this disease and can be encountered in several other autoimmune rheumatic diseases.     

Fine structure of digital vascular lesions in Raynaud's phenomenon and disease.

The ultrastructural changes in the vessels of the fingertips of patients with Raynaud's phenomenon or disease, with or without scleroderma, are described for the first time. Fingertip specimens were taken by punch biopsy. The light microscopic changes, including segmental vasculitis, fibrinoid degeneration of capillaries, and involuntary regression of glomus bodies explain the reduced digital blood flow associated with Raynaud's disease and phenomenon. The moment-to-moment digital blood flow, recorded rheoplethysmographically, was low when the patient was in a comfortable environment and was increased in a hot environment. This result substantiates the therapeutic importance of reflex vasodilatation. These findings correlate well with the ultrastructural changes in capillaries, including multiple cytoplasmic folds in endothelial cells, abundant intracytoplasmic filaments, and unusual incorporation of collagen fibrils in the basement membrane. These changes must influence nutritional and thermoregulatory function of the digital blood vessels.     

Digital blood flow measurement by venous occlusion plethysmography in Raynaud's phenomenon. Value of the rewarming test

The fingertip blood flow measured by mercury strain gauge plethysmography with venous occlusion, at 22 degrees C room temperature, had significantly lower mean values in 190 patients with Raynaud's phenomenon (55 men aged 49 yrs +/- 16, 135 women aged 48 yrs +/- 16) than in 40 age and sex matched controls: 18 ml/100 ml/minute +/- 14.6 versus 35 ml/100 ml/minute +/- 15 at level p less than 0.01. The mean fingertip blood flow was significantly lower (p less than 0.01) in 31 cases of scleroderma and 32 cases of pulpar necrosis (respectively 13 ml +/- 13 and 11 ml +/- 8) than in 55 cases of primary Raynaud's disease (no detectable etiology and normal capillaroscopy 5 years after onset) or in 34 cases of mild Raynaud's phenomenon (respectively 21.6 +/- 16 and 24.4 +/- 18). A warming test (both hands in water at 45 degrees C during 3 minutes) was performed in 50 cases with low basal fingertip blood flow. It induced a "normalized" flow in 22 cases (mostly primary or mild Raynaud), a partly improved flow in 20 cases (mostly secondary Raynaud) and no improvement in 8 cases (scleroderma). The warming test appears to be clinically useful to assess the vasospasm and the vasodilating capabilities.     

Efficacy evaluation of prostaglandin E1 against placebo in patients with progressive systemic sclerosis and significant Raynaud's phenomenon.

BACKGROUND: Raynaud's phenomenon, due to connective tissue diseases, is difficult to treat successfully. Symptomatic improvement has been reported using nifedipine or iloprost, but adverse side effects may limit their use. The purpose of this study was to examine the effects of PGE1 (Alprostadil) in patients with scleroderma and severe Raynaud's disease. METHODS: Twelve females, aged 50-67 years, were included in the study with six of them receiving a 3-hour infusion of alprostadil at the standard dosage of 60 micrograms in 250 cc of physiological infusion for six consecutive days and the remaining six receiving placebo (250 cc of physiological infusion administered in the same manner). RESULTS: After infusion, blood flow, digitally measured by telethermography was increased only in patients treated with alprostadil. The number, frequency and severity of attacks recorded were reduced only in patients treated with alprostadil. No side effects were recorded during and after the infusion. CONCLUSION: In conclusion, alprostadil is effective in the management of Raynaud's phenomenon, due to scleroderma.     

Blood hyperviscosity with reduced skin blood flow in scleroderma

The vascular complications of scleroderma have previously been attributed to the progressive obliteration of small vessels. Our study was carried out to determine whether abnormalities of blood viscosity occur in this disease, thereby contributing to the ischaemic process. Blood viscosity was measured in 20 patients using a rotational viscometer. At a high rate of shear, blood hyperviscosity was found in 35% of the patients and at a low rate of shear, in 70%. In addition there was a significant increase in the plasma viscosity which implicates changes in plasma proteins (fibrinogen, immunoglobulins) as causing the hyperviscosity. Measurement of the hand blood flow by venous occlusion plethysmography showed reduced flow at 32 degrees , 27 degrees , and 20 degrees C. A unique finding was a delayed recovery of the blood flow after cooling. These observations suggest that the increased resistance to blood flow in skin affected by scleroderma may be caused by an interaction between the occlusive vascular lesion and blood hyperviscosity. In addition, blood flow patterns and hyperviscosity could help distinguish scleroderma from primary Raynaud's disease.     

Raynaud's phenomenon: pathophysiologic features and treatment with calcium-channel blockers

Raynaud's phenomenon may be associated with severe pain, functional disability and digital infarction, particularly in patients with underlying vascular disease. The pathophysiologic features of Raynaud's phenomenon are complex although vasospasm contributes to the production of digital ischemia in most cases. Calcium-channel blockers have been shown to produce arteriolar vasodilation and an increase in peripheral blood flow. They have been used to treat patients with Raynaud's phenomenon in several prospective, randomized, double-blind, placebo-controlled trials. Low doses of verapamil were ineffective but both diltiazem and nifedipine produced subjective improvement in 60 to 90% of cases. Objective measures of digital blood flow were not improved. Patients without underlying vascular disease responded more readily to therapy than patients with scleroderma. Adverse effects were uncommon and seldom necessitated discontinuation of therapy. These data suggest that nifedipine and diltiazem provide effective short-term improvement in symptoms for most patients with Raynaud's phenomenon.     

Changes in regional cerebral blood flow after a cold hand test in systemic lupus erythematosus patients with Raynaud's syndrome

The appearance of vasospastic features in the central nervous system (CNS) after a cold stressor test was Investigated through single photon emission computed tomography (SPECT) of regional cerebral blood flow in patients with systemic lupus erythematosus, with and without Raynaud's syndrome, and in scleroderma patients. We have shown that Raynaud's syndrome may occur in the CNS and that anticardiolipin or lupus anticoagulant positivity may favour perfusion defects.     

Antinuclear antibodies in patients with Raynaud''s phenomenon: clinical significance of anticentromere antibodies.

Antinuclear antibodies (ANA) were detected in the sera of 73 out of 138 patients (53%) referred to us because of Raynaud's phenomenon. When ANA were found, systemic manifestations were likely to be present. The use of human fibroblast monolayers as a nuclear substrate allowed differentiation of several fluorescence patterns, including the discrete speckled variety produced by anticentromere antibodies. These antibodies were detected in the sera of 7 out of 10 patients with CRST syndrome (70%), in 7 out of 40 patients with scleroderma (18%), all without kidney-involvement, in one patient with Sjögren's syndrome and severe Raynaud's phenomenon, and in 7 patients with Raynaud's phenomenon associated with a few symptoms of a connective tissue disease (especially scleroderma). ANA testing on tissue culture monolayers in Raynaud's phenomenon appears to be of value in predicting systemic disease manifestations and the presence or possible future development of distinct clinical patterns, especially the CRST syndrome.     

Low plasma protein nitrotyrosine levels distinguish primary Raynaud's phenomenon from scleroderma

OBJECTIVE: To investigate the hypothesis that increased formation of reactive nitrogen species may contribute to the vascular pathology that develops in patients with connective tissue disease such as scleroderma. PATIENTS AND METHODS: The level of protein-bound nitrotyrosine in plasma was measured by stable isotope dilution gas chromatography/negative ion chemical ionisation mass spectrometry in 11 patients with primary Raynaud's phenomenon, 37 with scleroderma, 13 with chronic renal impairment, and in 23 healthy controls. RESULTS: Plasma protein-bound nitrotyrosine was markedly decreased in patients with primary Raynaud's phenomenon (mean (SEM) 0.60 (0.06) ng/mg dry protein) compared with patients with scleroderma (1.78 (0.21) ng/mg protein), chronic renal impairment (1.42 (0.17) ng/mg protein) or healthy controls (1.63+/-0.15 ng/mg protein, ANOVA p<0.001). CONCLUSION: These data suggest that there is decreased nitration of plasma proteins, or increased degradation of nitrated proteins from the circulation of patients with primary but not secondary Raynaud's phenomenon.     

Arteriolar resistance and hemorheological disorders related to Raynaud's phenomenon

The functional condition of resistance arteries in human hands was monitored with a noninvasive test. Blood flow velocity changes (Doppler flow meter) were monitored in the radial artery before and after a 1-min stop flow in the hand under conditions of stable systemic arterial pressure. In addition, the most significant parameter of hemorheological disorders in microcirculation, RBC aggregability, was investigated in the same patients' blood samples. The muscular tone of the resistance arteries was found to be a mean of 35% higher during Raynaud's phenomenon than in the healthy controls tested. The raised vascular tone was not related to the patients' age and had a pronounced tendency to rise with disease duration. RBC aggregability was a mean of 4% higher in the patients than in the healthy controls, and the difference was not reliable. We concluded that, among principal pathogenic factors which might cause deficiency of the blood supply to fingers, it is the enhanced tone of resistance arteries that is primarily responsible for the development of Raynaud's phenomenon, while hemorheological disorders are not, or are considerably less, involved in the development of the principal symptom of the disease, deficient blood supply to the fingers.     

Large vessel occlusive disease associated with CREST syndrome and scleroderma.

OBJECTIVES--To report the cases of three patients with CREST syndrome and one patient with diffuse scleroderma who had severe macrovascular disease and only minimal vascular risk factors. METHODS--The medical histories, physical examinations, and results of clinical investigations were reviewed in four patients. RESULTS--These four patients had severe morbidity from macrovascular disease of the arms and legs in the presence of minimal underlying vascular risk factors. These patients represent 11% of the women with scleroderma seen at our hospital since 1974. This is a greater than threefold increase above the expected proportion of symptomatic vascular disease seen in population studies. In the patients with CREST syndrome, large vessel disease was first seen more than 10 years after the onset of Raynaud's phenomenon, which was the first manifestation of the disease. A pathological specimen of the ulnar artery from one patient showed severe luminal narrowing by an acellular material with no evidence of atheroma. CONCLUSIONS--These cases suggest an association of both the CREST syndrome and scleroderma with macrovascular disease.     

Raynaud's features in childhood. Clinical, immunological and capillaroscopic study.

Raynaud's phenomenon, uncommon in childhood, often heralds connective tissue disorder. Since microvascular abnormalities can be detected at an early stage of the connective tissue disease, especially in scleroderma, a specific diagnosis can be made in patients presenting with Raynaud's phenomenon alone or Raynaud's phenomenon associated with symptoms suggestive of connective tissue disease. Raynaud's phenomenon was studied in 11 consecutive children, 10 girls and 1 boy, ages 6 to 15. One child had a definite diagnosis of cutaneous polyarteritis nodosa. In 6 others connective tissue disease was suspected: 4 had arthritis, 2 has telangiectasia, leg ulcers and antinuclear antibodies. Of the remaining 4, one had hemiplegia and 3 Raynaud's phenomenon only. Oscillometry of the radial artery was reduced in 7 of 9. Decreased capillary resistance was found in 2 of 6, while abrupt thinning in conjunctival vessels was seen in 3 of 7. On nailfold capillaroscopy, reduced vascularity was noted in 5 of 11, dilated capillaries in 4 of 11, tortuousity in 2 of 11, capillary thinning in 1 of 11, capillary spasm in 1 of 11 and normal pattern in 3 of 11. Two patients presenting with Raynaud's phenomenon were found to have "scleroderma-like pattern" on nailfold capillaroscopy. One of them died 2 years later of cardiopulmonary sclerosis, and another developed esophageal stricture and Barrett's esophagus. Neither has sclerodermatous skin. In childhood Raynaud's phenomenon, nailfold capillaroscopy is a non-invasive examination enabling early diagnosis of "systemic scleroderma sine scleroderma".     

Use of biofeedback training in treatment of Raynaud's disease and phenomenon

To assess biofeedback training in Raynaud's, we retrospectively reviewed 23 patients' records. Eleven had Raynaud's disease and 12 had Raynaud's phenomenon; 9 had recurrent digital ulcers. Patients demonstrated lower baseline digital temperatures than controls (p less than or equal to 0.001), patients with Raynaud's and scleroderma manifesting the lowest. After biofeedback training all patients elevated baseline temperatures. Patients with scleroderma and systemic lupus erythematosus had the greatest elevations. Improvement, both subjective (57%) and ulcers (44%), persisted one year after treatment. Four of 7 patients were capable of elevating digital temperatures within 5 min, 18 months after their last training session. These findings support biofeedback training as beneficial therapy in Raynaud's.     

Muscle involvement in the scleroderma syndromes

Muscle involvement was identified in 14 patients with scleroderma or a connective tissue disease overlap syndrome with predominant features of scleroderma. Patients presented with symmetrical proximal weakness indistinguishable from other inflammatory myopathies. Creatine kinase and electromyography were useful to demonstrate muscle involvement. Muscle histopathology demonstrated primarily the vasculopathy of scleroderma or polymyositis in similar numbers of patients. Scleroderma vasculopathy and polymyositis generally occur without specificity to diffuse scleroderma, the calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia syndrome, or an overlap syndrome with arthritis. Polymyositis also occurs when the vasculopathy of scleroderma involves other organ systems.     

Pathogenesis and treatment of Raynaud's phenomenon

Summary The pathogenetic theories and treatment of Raynaud's phenomenon are reviewed. In primary Raynaud's disease, most evidence supports a local defect at the digital artery level, with vasoconstriction or vasospasm of the digital arteries inducing the color changes. Normal sympathetic activity, low transmural arterial distending forces, and serotonin may be associated factors in the production of vasospastic attacks. In Raynaud's phenomenon, persistent vasoconstriction, thickened vessel walls, increased blood viscosity, and low digital artery blood pressure distal to obstructions may lead to vasospastic attacks with normal sympathetic nerve stimuli. Since the underlying cause of primary Raynaud's disease is unknown, treatment involves the use of agents to reduce sympathetic nerve activity or to prevent vascular smooth muscle contraction. Most patients will respond to conservative measures, but if they fail nifedipine is the drug of choice and alleviates the syndrome in about two thirds of patients. Reserpine and guanethidine may be as effective, but well-controlled studies have not been performed. The beneficial response to prazosin is moderate and dissipates with time. Side effects with these drugs prevent their use in many patients. Diltiazem and nitroglycerin ointments are of questionable value. Ketanserin, a serotonergic S₂-receptor antagonist, which has been shown to decrease the frequency of vasospastic attacks, and parenteral prostacyclin are among the new promising therapies.Part of this work was supported by grants from Janssen Pharmaceutica and the National Heart, Lung and Blood Institute, grant HL-26320.