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This review of the literature highlights the results of the recent randomized controlled trials about the management of systemic sclerosis (SSc) and its complications. The latest randomized studies have failed to demonstrate the utility against placebo of the injections of botulinum toxin A to achieve a better control of Raynaud's phenomenon and the efficacy of the adipose-derived cell transplantation for the treatment of hand dysfunction. Rituximab allows a significant improvement of cutaneous induration. The injections of mesenchymal stromal cells are well tolerated and should encourage future randomized trials to evaluate their efficacy. Finally, nintedanib and tocilizumab allow a reduction in the rate of decline of lung function, as well as a possible stabilization with tocilizumab., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Introduction: Pharmaceutical prescription in systemic sclerosis is guided by national and international recommendations. This study's primary objective was to describe and analyze these prescriptions among patients of our cohort. We also aimed to assess drug compliance among our patients., Methods: This is a monocentric observational study on two cohorts of patients with systemic sclerosis; a primary cohort comprising ambulatory patients, who were prospectively included, with exhaustive prescription's data collection; and a secondary cohort included patients asked to fill in a self-questionnaire on treatment compliance., Results: The main cohort included 157 patients, including 31 cases of diffuse systemic sclerosis. A vasodilator drug for Raynaud's phenomenon was prescribed in 75 patients (47.9%) and a specific treatment for pulmonary arterial hypertension in 10 patients (6.4%). Immuno-modulators/immunosuppressants was prescribed in 62 patients (39.5%), who received prednisone (n=37, 23.6%), mycophenolate mofetil (n=14, 8.9%), hydroxychloroquine (n=12, 7.6%) and colchicine (n=22, 14%). Treatment for "gastro-intestinal tract involvement" was prescribed for 106 patients (67.5%) and treatment of a scleroderma renal crisis with an angiotensin-converting enzyme inhibitor for 6 patients (3.8%). Among the 42 patients in the secondary cohort, 21.4% reported a good compliance, mostly older patients (P=0.045) or those who had not experienced adverse events (P=0.009)., Conclusion: This study provides original real-life data illustrating the heterogeneity of prescription habits in systemic sclerosis. As previously reported, treatment compliance was insufficient., (Copyright © 2020 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Raynaud's phenomenon (RP) is characterised by transient ischaemia in the extremities in response to cold or emotions. It can be primary (idiopathic) or secondary to an underlying disease. The pathophysiology of RP is multifactorial and complex. Microvascular impairment is a hallmark of the disease. The objective of this work is to review the different pharmacological treatments currently used in the management of RP, from their mechanism of action to the available evidence regarding their efficacy. We also propose to discuss potential pharmacological targets such as the potentiation of the nitric oxide pathway, or the inhibition of the RhoA-Rho kinase pathway. The last part of this review deals with drug-induced RP. Among various medications, beta-blockers, interferons, tyrosine-kinase inhibitors or cytotoxic agents such as bleomycin are involved., (© 2014 Société Française de Pharmacologie et de Thérapeutique.)

Aims: Raynaud's phenomenon is a vasospastic disorder of the extremities that can lead, in the hands, to pain, disability, ischemic ulcers and digital chronic ischemia. Medical and surgical current treatments are not fully effective while causing side effects. Recent studies have emphasized the value of botulinum toxin type A (BTX A) in the management of primary Raynaud's phenomenon. The originality of Raynaud's syndrome secondary to systemic sclerosis is to combine both arterial vasospasm and sclerosis of the arterial wall, what is supposed to reduce BTX A effects. The purpose of this work is to evaluate BTX A efficiency in patients with Raynaud's phenomenon secondary to systemic sclerosis., Patients and Method: We performed a prospective study for 12 months. Patients with severe Raynaud's phenomenon due to systemic sclerosis were injected with BTX A in the two hands. Evolution of ischemic ulcers, QuickDASH Score, O2 partial pressure, pain were measured before and 30 days after injection., Results: We treated 18 patients. Thirty days after injection, we noticed a complete healing of ulcers, QuickDASH Score was improved from 39.4 to 20, as the O2 partial pressure from 16 to 42 mmHg and the pain from VNS from 6/10 to 2/10., Conclusion: BTX A appears to improve significantly Raynaud's phenomenon symptomatology in patients with systemic sclerosis despite the component of arterial sclerosis., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Raynaud's phenomenon is a transient paroxysmal vasomotor phenomenon affecting the extremities including manifestations of ischemia. It is a common phenomenon in the general population. In a routine clinical situation, the first step is to differentiate Raynaud's disease from a secondary Raynaud's phenomenon, the latter requiring complementary investigations. We report here the case of an 80-year-old woman who presented a secondary Raynaud's phenomenon. First-line investigations remained negative. A mammography was performed and revealed breast cancer. Raynaud's phenomenon disappeared after treatment of the breast carcinoma and did not recur during the 2-year follow-up., (Copyright 2009 Elsevier Masson SAS. All rights reserved.)

An imbalance between prostacyclin (PGI2) and thromboxane A2 is observed in patients with scleroderma. Iloprost is a stable analogue of PGI2 with a plasma half-life of 20-30 min. Intravenous iloprost is effective in the treatment of Raynaud's phenomenon related to scleroderma, decreasing the frequency and severity of attacks. It also appears useful for the treatment of digital ulcers. Inhaled iloprost is an effective treatment for NYHA class III pulmonary arterial hypertension, either idiopathic primary or associated with a particular condition, such as scleroderma. Intravenous iloprost improves kidney vasospasm in patients with scleroderma. The possible benefits of sequential intravenous iloprost on the natural course of scleroderma require further investigation.

We are going over therapeutic acquisitions in a club-journal including relevant publications in different fields: mecanism of action, therapeutic perspectives in a near future, and side effects.

Raynaud's phenomenon has been described more than 140 years ago, its prevalence in the general population is high, and yet the underlying pathological mechanisms are only partly understood. In children, female preponderance has been reported, as it is also the case in adults, and the disease usually starts after the age of 10. Diagnosis and differential diagnosis, in particular with erythromelalgia, are usually made through patient's or parent's interrogatory. It is important to distinguish primary Raynaud's phenomenon, which is usually benign, from Raynaud's phenomenon secondary to connective tissue disease. To this regard, nailfold capillaroscopy is of great help, as may be more recently introduced techniques such as thermography and digital blood pressure response to cooling. Primary Raynaud's phenomenon usually only requires simple physical measures (avoidance of exposure to coldness, gloves in winter, ...) plus sometimes oral calcium blockers. By contrast, Raynaud's phenomenon secondary to connective tissue disease requires systemic investigations, assessment and treatment of the underlying disease and, in some cases, more aggressive treatments such as intravenous carboprostacyclin (Iloprost).

Raynaud's phenomenon is a paroxysmal vasospasm affecting the extremities, particularly the fingers. The idiopathic type is the most frequently encountered and the secondary types have multiple origins. The mainstay of treatment relies on hygieno-dietetic measures. When they fail, calcium antagonists, sustained-release transdermal glyceryl trinitrate and a few other vasoactive drugs may prove to be effective. However, side effects may limit their prescription.

The severity of the acute intoxication from buflomedil, a vasodilator with papaverinic and alpha-adrenolytic effects, remains generally underestimated. We report the case of a 18-year-old girl who ingested a high amount of buflomedil. Two hours later, she developed seizures and ventricular arrhythmias. On admission to the ICU, she was in circulatory arrest followed by deep coma with mydriasis (GCS = 3). Buflomedil blood concentration, 2 hours after admission, was 97.3 mg.L-1. Toxicological screening for other drugs was negative. Therapy included external chest compressions tracheal intubation, mechanical ventilation, epinephrine and gastric lavage. The haemodynamic status improved within the first 24 h, although she remained comatose until the fifth day. She was discharged the eight day after her admission. This observation demonstrates that the potential severity of buflomedil poisoning is mainly due to early cardiac complications. Treatment remains purely supportive.

The role of the endothelium in vascular tone is well established. New physiopathological concepts were brought about by the discovery of endothelium derived vasoactive substances such as the vasodilators prostacyclin and endothelium-derived relaxing factor (EDRF) or the vasocontrictors endothelin and other putative endothelium-derived contracting factors (EDCF). Their discovery led to new therapeutic concepts in vascular, respiratory and infectious diseases. Prostacyclin is a prostaglandin derived from arachidonic acid which has an inhibitor effect on platelet aggregation. It also has a vasodilator effect on vascular smooth muscles cells. Prostacyclin analogues are choice vasculoactive pharmacological agents for patients with thromboangiitis obliterans or severe peripheral vascular disease, whether arteriosclerotic or not. The effect of EDRF is vascular dilatation, predominately in the arteries but also in the veins, including vessels in grafted tissues. EDRF also inhibits platelet aggregation and adhesion. Inversely, the endothelium can also release EDCF which has a vasoconstrictor effect. Endothelin, a recently identified 2429 kD EDCF is active in both arteries and veins and is implicated in physiologic regulation of vasomotricity.

Epidemiologic studies indicate that episodic vasospasm of arterioles (Raynaud's phenomenon) is a common finding in the general population. The prevalence has been estimated at approximately 10%. Raynaud's phenomenon follows a benign course in most cases and may improve or even disappear in time. Occasionally, Raynaud's phenomenon may be induced by some drugs (beta-blockers, ergot, vinblastine...) or some occupations (pneumatic hammer operators, hand-arm vibration syndrome...) or may be a sign of connective tissue disease (systemic sclerosis, systemic lupus erythematosus, Sjögren's syndrome...). Several different physiologic mechanisms may be responsible for vasospasm: hyperactivity of the sympathetic nervous system and abnormal adrenergic receptor function appear to be most important. Calcium channel blockers have been studied extensively for the treatment of primary and secondary Raynaud's phenomenon. There have been shown to be particularly effective for inhibiting vascular responses evoked by alpha 2-adrenoceptor activity. Calcium channel blockers have been mostly effective in Raynaud's phenomenon.

A testicular tumour could be diagnosed by the occurrence of a Raynaud's phenomenon complicated by severe digital arteritis. The arteritis rapidly regressed under prostacyclin therapy. Such vascular manifestations are frequent in testicular carcinoma, but they usually develop after chemotherapy. To our knowledge, this is the first case where they preceded the diagnosis and specific treatment of a tumour of the testis.

We report on a case of Sharp syndrome which was diagnosed late in on 11-year old boy. After 5 years of corticosteroid treatment, he presented with myopericardic aggravation, glomerular disease, and seizures with delirium, which responded to high-dose steroid therapy with early switch using synthetic antimalarial drugs. Six years later the results are still satisfactory.

Raynaud's phenomenon is usually a benign acrosyndrome which few of the currently available therapies improve significantly. This makes the evaluation of the efficacy of vasodilators very difficult, especially as there are no standardised complementary investigations to quantify their effects. Assessment is based essentially on careful interrogation and the use of an analogical scale remains the method of reference. The multiplicity of factors inducing the acrosyndrome necessitates cross-over trials versus placebo over sufficiently long periods of observation (if possible, one month). As regards follow-up and objective evaluation, reactivity to cold is a promising method providing the tests can be standardised with respect to methodology and expression of results.

Twenty-seven patients with systemic scleroderma and Raynaud's phenomenon underwent a randomised double blind therapeutic trial: monotherapy with Ketanserine (80 mg/day for 6 months) against Placebo. The secondary effects were comparable in both groups as were the withdrawals from the trial for aggravation of Raynaud's phenomenon (one in each group). No significant difference was observed between the two groups as regards the evolution of the Raynaud's phenomenon or skin changes. Dysphagia was improved in the Ketanserine group (p less than 0.05) but not in the Placebo group. Some patients in the Ketanserine group experienced an improvement in the Raynaud's phenomenon at the end of the trial period; there were no improvements in the Placebo group. Three haemorrheological parameters (total blood viscosity, plasma viscosity and thixotropism) were abnormal at the beginning of the trial and did not improve by the end in the Ketanserine group. The K infinity coefficient of Quemada's law was normal at the start of the trial and increased after treatment (p less than 0.05).

In 20 patients with Raynaud's phenomenon affecting the upper or lower limbs (1974-1976), 4 methods of conservative therapy were used, in combinations according to the case: 1) Intraarterial injections of xylocaine-priscol-pronestyl. 2) Nitroglycerine ointment. 3) More rarely, paraphalangeal injections of 1% quinine-urea. 4) The hypertensive regime of Lassen and Larsen (mineralocorticoids by mouth). The age was in general between 45 and 75 years, and a vascular context, either arterial or venous, was frequent. Signs of scleroderma were absent. Disc disorders with radicular signs were not rare (6 cases). The most frequent combination, intraarterial injections and nitroglycerine ointment, generally had a remarkable effect. On only 3 occasions was recourse had to other methods. No patient had to undergo sympathectomy.

The authors review the drug treatment of Raynaud's disease. Many substances have been used including nitrate derivatives, calcium antagonists, alpha blockers, angiotensin converting enzyme inhibitors, prostaglandin E1, E2 and I2, and ketanserin. The efficacy of these drugs is often partial and variable. The indications are discussed with respect to the clinical course and etiology of the Raynaud's phenomenon.

Digital arterial circulation before and after administration of a vasodilator orally was explored by mercury gauge pulsed plethysmography and photoplethysmography in 12 patients with primary Raynaud's phenomenon and results compared with those of 10 healthy volunteers. The amplification factor F, ratio of amplitude in reactive hyperemia over amplitude at rest was determined in the index before and after 8 mg daily of dihydroergokryptine over 4 weeks. Before treatment, for each of the two plethysmographic technics, a significant increase in mean factor F values was noted in the patients with Raynaud's phenomenon when compared with healthy controls. This is due to a decline in digital arterial flow at rest. Using the mercury gauge plethysmograph, a significant reduction in factor F was observed after vasodilator treatment corresponding to an increase in digital flow at rest without increase in flow during hyperemia. Using photoplethysmography, no significant variation in factor F was noted after treatment. Mercury gauge plethysmography, which measures global digital blood flow appears to be a more sensitive method than photoplethysmography, which measures dermal and hypodermal blood flow, for follow-up of effects of vasodilator treatment on Raynaud's phenomenon.

Raynaud's phenomenon, either idiopathic or secondary is often severe. It is due to a vasospasm in response to cold, and an increase in sympathetic tone, hyperviscosity and sometimes hyperactivation of platelets and erythrocytes have been reported. New drugs have been developed such as ketanserin, which is a specific inhibitor of serotonin S2 receptors, and has led to a positive response in 38%-80% of patients. The prostaglandins PGE1 and PGI2 were given i.v. in refractory patients and led to a beneficial effect in 50%-70% of cases. These data seem to justify the development of prostaglandin analogues.

A block Bier technique using a one milligram Reserpine injection has been applied to ten patients with severe Raynaud's phenomenon (six of them had digital gangrene). Six patients have been improved and three have completely healed. This method must only be applied to severe cases and may be used as a pretherapeutic test in upper sympathectomy.

Vascular acrosyndromes are mainly subjective clinical phenomena that are difficult to classify, are related to the patient's background, and require a particularly strict protocol for the evaluation of their therapy. An essential criterion is the homogeneity of groups treated, the Raynaud's phenomenon having to be separated into idiopathic Raynaud's disease, digital arteritis and scleroderma. Functional subjective disturbances have to be rated by the patients themselves, while taking into account the conditions of daily life and of climate. Clinical trials must be double-blind against placebo after a pre-inclusion study. They must be conducted entirely during cold spells for Raynaud's phenomena. Static measurements are of limited value amongst functional exploratory techniques, dynamic tests (vascular reactivity to cold) providing more valid data on the action of medication.

Many studies have been done to try to define new therapeutic uses for calcium antagonists, in diseases in which calcium plays a role. Positive results have been obtained in the prevention of acute attacks of idiopathic Raynaud's disease and migraine, and in effort-induced asthma. Some activity could be demonstrated in selected groups of patients with pulmonary hypertension, manic-depressive illness, untractable epilepsy, various functional gynecological or digestive disorders, and in drug-induced nephrotoxicity. A possible effect on the prevention of resistance to anti-cancer drugs could be of major interest. Their antiplatelet effect, and their possible effect against atherosclerosis, which remains to be confirmed, their lack of side-effects in asthmatics and of interference with glucose regulation increase their usefulness in patients with hypertension or ischemic heart disease, especially when other diseases are present.

In each of the 16 patients included in our first study [6 idiopathic Raynaud's phenomenon (I), 4 associated with systemic lupus erythematosus (SLE) and 6 with progressive systemic sclerosis (PSS)] digital vasospasm could be reproduced by immersion of both hands in cold water (4 degree C). Each patient received in a double-blind manner and random order on two consecutive days, the calcium-channel blocking agent nifedipine (20 mg) and placebo. Nifedipine protection against vasospasm provoked by cold water (4 degrees C) was considered good or excellent in 14 of the 16 patients (p less than 0.001 versus placebo). In the second study, 30 patients [12 I, 10 PSS, 5 SLE and 3 rheumatoid arthritis (RA)] received in a double blind manner and random order, on two consecutive weeks, nifedipine (20 mg 3 time daily) and placebo. The improvement with nifedipine (in percentage of the decrease of the number of vasospastic attacks) was 90.95 in the 1 group, 78.63 SLE and RA and 64.02 in PSS (p less than 0.01). An open study during 3 months has confirmed the effectiveness of nifedipine (10 mg 3 times daily). The improvement was 88.92 in the 1 group, 76.33 in SLE and RA and 59.16 in PSS, 7 out of 30 patients stopped the treatment because of side effects (headache, flush, nausea, oedema of the ankles). Thus nifedipine appears to be extremely useful in the treatment of Raynaud's phenomenon.

The efficacy of the calcium-channel blocker nicardipine in the treatment of Raynaud's phenomenon was assessed in a double-blind, randomised, crossover trial in 20 patients. Each patient received 2 weeks of nicardipine 20 mg three times daily and 2 weeks of placebo. Nicardipine significantly improved the frequency and severity of Raynaud's phenomenon. An open study during 2 months in 30 patients confirmed the effectiveness of nicardipine (20-40 mg 3 times daily). Side effects (headache, flushing, ankle oedema) were frequent but usually mild. We conclude that nicardipine is effective in the treatment of Raynaud's phenomenon.

The discovery of thromboxanes and prostacycline has opened up a new therapeutic approach to vascular and thrombotic diseases. Aspirin is no longer considered to be an antiaggregant drug, but an inhibitor of cyclooxygenase which, depending on the dose, may have an effect on platelets and the vessel. Thromboxane synthetase inhibitors and thromboxane receptor blockers represent a new mode of inhibition of platelet activation. Therapeutic trials of the vasodilator and antiaggregant prostacycline have been carried out in obliterative arterial disease and Raynaud' syndrome with a certain degree of success. The production of a stable analogue of prostacycline and the manipulation of the leukotrienes are the therapeutic hopes for the future.

The viscosity of normal and pathological blood samples is determined using a Couette viscometer (5.10-2s-1 less than or equal to shear rate less than to equal to 125 s-1). In different pathological cases, the rheograms show an abnormal behaviour. The viscosity curves exhibits a break between 0.1 and 1 s-1. This work shows the results obtained in the case of a patient suffering from Raynaud's disease. During therapy with lysine acetylsalycilate one observed the gradual shift of the breack to low shaer values, then, the return to a normal rheogram. In the same time, acroyanosis has completely disappeared, recovering normal nail growth.

Purpose of the Study: To determine the effects of Nifedipine on cold stress reactive hyperemia in patients with Raynaud's phenomenon., Design: Open trial comprising an observation period without treatment and a treatment period with Nifedipine., Setting: Referral-based angiology department in a university hospital., Patients: 26 patients with definite Raynaud's phenomenon were included; 6 patients were withdrawn (3 for side effects, 1 for pregnancy, 2 for protocol inobservance). INTERVENTIONS took place after one week of observation and one week of treatment with Nifedipine per os 20 mg 3 times daily. At day 0, 7 and 14, cold stress was performed to measure cold reactive post-ischemic hyperemia., Main Results: During the Nifedipine period, the number of attacks, their intensity and resulting total disability decreased significantly, and hyperemia increased significantly., Conclusions: Our study confirms improvement in Raynaud's phenomenon with Nifedipine. This calcium-channel inhibitory drug also improves cold reactive hyperemia. This new cold test is inexpensive and easy to perform and appears to be suitable for assessing hemodynamic objective improvement in drug trials concerning Raynaud's phenomenon.

Severe forms of Raynaud's phenomenon are very disabling. In a randomized, single-blind trial, we have evaluated the effects of PGI2, a natural compound with strong vasodilator and anti-platelet activities, in 14 patients presenting with Raynaud's phenomenon. The patients received a 24-hour infusion of either PGI2 in doses of 10 mg/kg.min, or only the solvent (glycine buffer). All patients recorded the frequency and severity of the attacks before and after treatment, and 7 of the 8 patients who received the solvent benefited from a PGI2 infusion 30 to 60 days later. Among the 14 patients (6 men, 8 women), 10 had underlying collagen disease. The number of attacks per week was initially 15.9 +/- 5.3 (mean +/- s.e.). The resulting impairment was pronounced (+ + on a + to + + + scale). Radioimmunoassays of prostaglandins showed a strong increase in 6-keto PGF1 alpha levels during the infusion, without changes in thromboxane levels. A significant (p less than 0.05) reduction was observed in the number of attacks (2.6 +/- 2.5 per week) and in impairment (+ on average after PGI2 but not after the buffer). Improvement after PGI2 lasted from 0.5 to 12 months, and all but one patient regarded the treatment as effective in long-term, despite undesirable side-effects (flush, hypotension) which occurred regularly during PGI2 infusion. In all patients with ulcerations of the finger tips, these healed more rapidly after PGI2. It is concluded that in spite of immediate discomfort, PGI2 in 24-hour infusions seems to be of value in the treatment of severe Raynaud's phenomenon.