Annals of the Rheumatic Diseases 1991; 50: 839-845

Raynaud's phenomenon: its relevance toscleroderma

Jill J F Belch

It is now over 125 years since Maurice Raynaudfirst described his clinical syndrome. ' Bydefinition, it is episodic digital ischaemiaprovoked by cold and emotion. It is classicallymanifest by pallor of the affected part followedby cyanosis and rubor. The pallor reflectsvasospasm, the cyanosis results from removal ofoxygen from the static venous blood, and ruboris caused by reactive hyperaemia followingreturn of flow. Raynaud's phenomenon has anoverall prevalence of about 10%,2 though it mayaffect as many as 20-30% of younger women.3Although it can be a benign condition (primaryRaynaud's disease), it may be associated with anunderlying disorder (Raynaud's syndrome). Itis particularly associated with the connectivetissue diseases (table 1). Raynaud's syndromeoccurs in between 90 and 98% of patients withsystemic sclerosis,4 and more importantlyproves to be the first symptom in 700/o ofpatients with this disease4 5 and may precede itsdevelopment by up to 20 years.6

In this review it is proposed to evaluate therelevance ofRaynaud's phenomenon to systemicsclerosis in two ways. Firstly, by reporting the

Department of Medicine, evidence supporting Raynaud's phenomenon asNineweils Hospital, a precursor of systemic sclerosis and, secondly,

indee DD1 9SY by discussing its importance as a complicatingJ J F Belch symptom in fully established systemic sclerosis.

Table I Conditions associated with Raynaud's phenomenon

Immunological disorders Obstructive vasular diseaseSystemic sclerosis Thoracic outlet syndrome (eg cervical rib)Systemic lupus erythematosus Atherosclerosis (especially Beurger's disease)Mixed connective tissue diseaseDermatomyositis DrugsRheumatoid arthritis ErgotaminesCryoglobulinaemia i BlockersSj6gren's syndrome Cytotoxic drugs

OccupationalVinyl chloride disease OthersVibration induced white finger MalignancyNitrate workers (outside work) Endocrine disorders (eg hypothyroidism)Frozen food packers Uraemia

Table 2 Features associated with progression ofRaynaud's disease to Raynaud's syndrome

a Clinical symptoms and signs c Detection of antibodiesAny features of connective tissue disease AntinuclearAsymmetry of vasospastic attacks AnticentromereDigital ulceration Scleroderma 70Return of chilblains in older age group Type IV collagenOlder age at onset of Raynaud's phenomenon LamininVery young children

d Blood coagulationb Abnormal nailfold vessels Raised factor VIII von Willebrand

factor antigenRaised ,3 thromboglobulin

Raynaud's phenomenon as a precursor ofsystemic sclerosisBased on various studies,7 the prevalence ofsystemic sclerosis ranges from 0-1 to 13-8 per100 000 population. This is far lower than theprevalence of Raynaud's phenomenon, and thusonly a proportion of patients presenting withRaynaud's phenomenon will progress to systemicsclerosis. One of the earliest studies of diseaseprogression was carried out by Gifford andHines,8 In a study of629 female patients over 28years of age they found progression to aconnective tissue disease in 24%. Another earlystudy suggested a figure of 50%.6 Both thesestudies, however, were published before 1970and since then there has been an increasingawareness that Raynaud's syndrome may bemuch more common than previously thought.At the present time the frequency with whichsecondary conditions are recognised varieswidely in reported studies and may depend inpart on doctors' referral patterns, duration ofRaynaud's phenomenon at the time seen, andthe thoroughness with which a search for anassociated disorder is undertaken.9 '0 Moreover,the development of more sophisticated labora-tory tests has produced a shrinkage in the groupwith Raynaud's disease and an expansion in thenumbers of patients with Raynaud's phenom-enon and one or more features of systemicsclerosis. These patients are sometimes referredto as suspected secondary Raynaud's syndrome.It should be noted, however, that the aboveapplies to patients referred to hospital becauseof their Raynaud's phenomenon and should notbe applied to patients with Raynaud's phenom-enon in the general population. This is clearlyshown by the low incidence or absence ofconnective tissue disease in a group of patientswith Raynaud's phenomenon in the generalpopulation followed up by questionnaire."1Both from a clinical and prognostic point ofview, however, it is important to be able todetect, ifpossible, those patients with Raynaud'sphenomenon who will develop a connectivetissue disease. Furthermore, the study of thepathophysiology of systemic sclerosis might beenhanced by identifying patients at risk or thosepresenting early in the disease. This earlydetection of a connective tissue disease inpatients with Raynaud's phenomenon can bedifficult, but, recently, more clearly definedabnormalities have been detected which have astrong link with disease progression (table 2).These are: (a) certain clinical features; (b)abnormal nailfold vessels; (c) some immuno-logical tests; and (d) test of blood coagulationand rheology. Each will be dealt with in turn.

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Clinical features associated with connectivetissue disease developmentThe American Rheumatism Association (ARA)criteria for systemic sclerosis'2 have a highspecificity but low sensitivity for the disease.Thus patients who quite clearly have a sclero-derma spectrum disorder presenting with iso-lated features such as sclerodactyly, or pittingscars and digital ulceration do not fulfil theARA criteria. It is reasonable to suspect onclinical grounds that the disease in such patientswill evolve with time into fully establishedsystemic sclerosis, and indeed this impression issupported by prospective clinical studies.'3"Thus isolated features of connective tissuedisease occurring in association with Raynaud'sphenomenon should alert clinical suspicion.The age of onset of Raynaud's phenomenon

may also be important. As stated, Raynaud'sphenomenon is common in young women andmost of these patients probably have primaryRaynaud's disease. When Raynaud's phenom-enon develops in older subjects the likelihood ofan underlying connective tissue disease isincreased. Kallenberg reports a study of 90patients, in whom the median age of onset ofvasospastic symptoms in Raynaud's disease was14 years, and 36 years in patients with a definiteconnective tissue disease.'" Eighty per cent ofpatients presenting with onset of Raynaud'sphenomenon at the age of 60 years or above willhave an associated condition,'6 but the incidenceof connective tissue disease remains the same asin the general population. The higher numberof secondary cases reflects a larger proportion ofpatients with atherosclerosis (29% v 5% in thetotal Raynaud's population) and to a lesserextent, hyperviscosity syndromes secondary to amalignancy. Conversely, Raynaud's phenom-enon occurring in very young children, thoughrare, is usually due to an underlying connectivetissue disease.'7

Other suspicious but, as yet, unvalidatedsymptoms which perhaps should alert theclinician are those such as the presence of digitalulceration. Digital ulceration does not occur inRaynaud's disease. The reoccurrence of chil-

Nailfold capillaroscopy showing enlargement ofall three parts ofthe capillary loop and lossofcapillaries. (This picture is courtesy ofDr Francis Lefford, department ofanatomy anddevelopmental biology, University College, University ofLondon.)

blains in an adult may also raise suspicions, asshould the occurrence of severe attacks persist-ing throughout the summer.'8 Furthermore,asymmetrical colour change with few digitsaffected suggests Raynaud's syndrome ratherthan Raynaud's disease.'9 It is also of interestthat those patients who do develop systemicsclerosis are much more likely to developlimited cutaneous systemic sclerosis (CREST(calcinosis, Raynaud's phenomenon, oeso-phageal dysmotility, sclerodactyly, telangiec-tasia)) if the history of the preceding Raynaud'sphenomenon is over many years or decades.Those presenting with systemic sclerosis withinone year of onset of Raynaud's phenomenontend to have diffuse systemic sclerosis (progres-sive systemic sclerosis). 20The above clinical symptoms, however, can

only act as a guide to the clinician as age andsymptomatology vary widely at presentation. Amore reliable guide is the finding of abnormalnailfold vessels on capillary microscopy.

Nailfold capillary microscopyA more reliable indication of systemic sclerosisis the microvascular involvement by the disease,which results in characteristic patterns of capil-lary abnormalities in the skin of the fingers,especially at the nail fold, that can be seen by invivo microscopy." Direct observations of capil-laries in human skin date back to 1912, but thebest known early description ofnailfold capillaryabnormalities in systemic sclerosis was publishedby Brown and O'Leary in 1926.22 Recentrefinements have permitted photographicrecordings of the row of horizontal capillaryloops at the nail fold just proximal to the cuticle,but less sophisticated apparatus allows a clinicianto examine the nailfold vessels as part of his orher routine clinical procedure.

Nailfold capillary abnormalities have beenseen in many diseases, but their most character-istic pattern is found in the sclerodermaspectrum disorders; systemic sclerosis, mixedconnective tissue disease, overlap syndromes,and dermatomyositis.2' They are also seen inpatients with Raynaud's phenomenon at risk ofdeveloping systemic sclerosis.23 24 Fitzgerald etal in a prospective study showed that anabnormal nailfold capillary pattern was stronglyassociated with the subsequent development ofsystemic sclerosis both limited and diffuse.'0This is true both for children presenting withRaynaud's phenomenon'7 and for adults. Themain characteristics of vessel abnormalities are:(a) enlargement of all three parts of the capillaryloop: arterial, apical, and venular and (b) theloss of capillaries either diffusely or in localisedareas (figure). Those with limited systemicsclerosis (CREST) tend to develop only enlarge-ment of vessels, whereas in those patients withdiffuse systemic sclerosis (progressive systemicsclerosis) both patterns are seen.

Immunological factorsImprovements in the techniques of antinuclearantibody determination have substantiallyincreased the usefulness of this approach in

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Raynaud's phenomenon: its relevance to scleroderma

systemic sclerosis. In particular, the change mnuclear substrate to that of rapidly dividinghuman cells has produced an increase in theproportion of patients with systemic sclerosiswith detectable serum antinuclear antibodiesfrom 33% to better than 95%.20 Recent attentionhas focused particularly on the anticentromereantibody and the scleroderma 70 antibody (Scl70). Anticentromere antibody is found inpatients with limited systemic sclerosis(CREST). 13 In contrast, Scl 70 is found inpatients with diffuse systemic sclerosis. Workby Cruz et al25 and by Goldman26 has shownanticentromere antibody and Scl 70 in the bloodof some patients with Raynaud's disease alone.Both groups suggested that such patients may

be the ones who progress to systemic sclerosis.Kallenberg et al investigated this possibilityfurther by following up 85 patients withRaynaud's phenomenon for six years. 3 In thosepresenting with Raynaud's disease alone anti-centromere antibody had a predictive value forthe development of limited systemic sclerosis(sensitivity 60%, specificity 98%) and Scl 70 fordiffuse systemic sclerosis (sensitivity 38%,specificity 100%). Interestingly, Steen et allooked at antinuclear antibodies as a predictorof severity within the group with systemicsclerosis and found that antinuclear antibodypositivity did not relate to survival or to thedevelopment ofpulmonary hypertension.27 Thusit seems that the presence of antinuclear anti-bodies, particularly anticentromere antibodyand Scl 70, in patients with apparent Raynaud'sdiseasemay indicate later progression to systemicsclerosis. Once the clinical syndrome is estab-lished, however, the antinuclear antibodies losetheir prognostic value.Of interest, is recent work by Gabrielli et al,28

who investigated antibodies against type IVcollagen and laminin. Most patients withsystemic sclerosis were found to have one or

other of the antibodies in their blood. Addition-ally, about 25% of serum samples from patientswith clinical Raynaud's disease were also posi-tive. Of these, 800/o later developed additionalserological or clinical manifestations of systemicsclerosis. As the incidence of antinuclear anti-bodies and abnormal nailfold vessels is notstated in the group who progressed, however, itis not possible to assess the importance of theabove findings.

Blood coagulation and rheologyBlood flow in the microcirculation dependsdirecdy on the properties of the cellular ele-ments of both blood and plasma. Hard erythro-cytes, activated platelets, and leucocytes haveall been reported in Raynaud's phenomenon,29as have increased plasma viscosity and decreasedfibrinolysis.30 Most of these abnormalities are

best seen in patients with established systemicsclerosis. This is also true of the endothelial cell

injury that may contribute to the Raynaud'ssyndrome in systemic sclerosis. The exceptionsto this are plasma thromboglobulin concentra-tions and factor VIII von Willebrand factorantigen (vWFAg).

Platelet activation either primary or as a

result of endothelial damage may contribute tostructural changes in the blood vessel by therelease of factors such as serotonin and plateletderived growth factor.3' ( Thromboglobulin isa further protein released by activated plateletsand this can be measured in plasma by asensitive radioimmunoassay. Raised concentra-tions of (3 thromboglobulin have been detectedin systemic sclerosis and also in some studies ofRaynaud's disease, though not in others.32 33 Inthe later study33 concentrations of (3 thrombo-globulin were raised in patients with Raynaud'sphenomenon with minor symptoms of systemicsclerosis, suggesting that raised concentrationsmight help predict those who will develop fullyestablished systemic sclerosis.

Factor VIII vWFAg is made and released byvascular endothelium, and various noxiousphysical and chemical stimuli will increase itsproduction. It seems to be a marker for vasculardamage and through its action on platelets andin the coagulation cascade has a prothromboticeffect. Kahaleh et al reported raised concen-trations of factor VIII vWFAg in systemicsclerosis,34 and later work showed raisedconcentrations in both Raynaud's disease andRaynaud's syndrome which seemed to predicttransformation from Raynaud's disease toRaynaud's syndrome.35 These data on both (3thromboglobulin and factor VIII vWFAgneed to be confirmed in large prospectivestudies.

Extent of vasospasmIt has been suggested that the severity of thevasospasm may be useful as a guide to thosewho later develop systemic sclerosis. It wouldseem possible, therefore, that the extent ofvasospasm might also be a useful marker.Raynaud's phenomenon is recognised clinicallyby the characteristic vasospasm induced colourchanges in the fingers and toes. Similar findingsare also observed in the ear lobes, tip of thenose, and other extremities. Cold inducedvasospasm has also been detected in the brain(migraine headaches),36 heart,37 lung,38 andoesophagus39 of patients with Raynaud'sphenomenon. What is of interest, however, isthat this vasospasm is not limited to thosepatients with systemic sclerosis, and patientswith Raynaud's disease can also have migraine,lung and oesophageal vasospasm. At the presenttime, therefore, it seems unlikely that thepresence of systemic vasospasm will be helpfulin separating Raynaud's disease from earlyRaynaud's syndrome.

Connective tissue diseases such as systemicsclerosis often have an insidious onset withRaynaud's phenomenon being the first symptomin most cases, preceding the disease by manyyears. Raynaud's phenomenon is common,however, particularly in young women, but willprogress to systemic sclerosis in only a minority.For prognostic and possibly therapeutic reasonsit is important to know which patients haveRaynaud's disease which will develop, or isalready evolving, into systemic sclerosis. Theabove clinical and laboratory factors may beuseful in determining which patients with

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Raynaud's disease will progress to Raynaud'ssyndrome. Indeed, it has been suggested thatnailfold capillary microscopy and serum anti-nuclear antibody determinations can detectmore than 90% of patients destined to havesystemic sclerosis.20 Abnormal nailfold vesselsand the presence of antinuclear antibodies in theblood, combined with other clinical guides,such as age of onset and vasospasm severity,should provide helpful guidelines for the diag-nosis of Raynaud's syndrome associated withsystemic sclerosis.

Raynaud's syndrome in systemic sclerosisThere are two important aspects in the study ofRaynaud's syndrome as part of the manifesta-tions of systemic sclerosis: (a) the possible roleof the vasospasm/abnormal vasculature in theactual pathogenesis of systemic sclerosis and (b)the management of the troublesome symptomsproduced by a combination of the Raynaud'ssyndrome, blood abnormalities, and skinthickening.

Vascular factors and the pathogenesis ofsystemic sclerosisAlthough the pathophysiology of systemicsclerosis is not fully clarified, microvascularchanges and the process of fibrosis are boththought to be involved. As Raynaud's phenom-enon can result from simple injury to thevasculature, as is seen in cold, vibration, andtraumatic injury, it is possible that theRaynaud's phenomenon seen early in systemicsclerosis is a manifestation of early vasculardamage. A serum factor cytotoxic for endothelialcells has been described in systemic sclerosis40and is dealt with later in this issue. As thiscytotoxic factor has also been detected in theserum of patients with Raynaud's disease thereis a possibility that vasospasm itself combinedwith vascular damage and viscous blood mayallow progression of the disease. The diffusenature of the vasospasm and microvasculardestruction in systemic sclerosis leads to a stateof underperfusion and chronic ischaemia ofvarious organs. Data show that human fibro-blasts exhibit prolonged growth and extendedlife span at decreased oxygen concentra-tions.4 An increase in skin thickness second-ary to hypoxia may underlie the sclerodermaprocess in systemic sclerosis.43 Such a hypothesiscan, however, only be examined when effectiveenough treatments for vasospasm are used over

Table 3 Blood and vessel wallfactors which contribute to poorflow in the microcirculationof patients zwuth systemic sclerosisPlatelet PlasmaIncreased aggregation Increased fibrinogenIncreased K thromboglobulin Increased viscosityIncreased serotonin Increased lipid peroxides

Circulating aggegatesIncreased thromboxane A2

Red blood cell Vessel wallDecreased red cell deformability Increased factor VIII von WillebrandIncreased superoxide dismutase factor antigen

Decreased fibrinolysisDecreased prostacyclin production (later stages)Endothelial cytotoxic factor

the longer term. If prevention of disease pro-gression occurs with such treatments it wouldbe a useful pointer to the pathogenesis ofsystemic sclerosis.

Treatment of Raynaud's syndromeIn Raynaud's syndrome associated with systemicsclerosis the symptomatology can be severe,with skin nutritional changes, digital ulcers,and even gangrene. Although the vasospasmcontributes to these symptoms, other factorscombine to produce what is for many patientsthe worst feature of their disease-continualdigital ischaemia. It has long been recognisedthat structural changes can be seen in the smallvessels throughout the body in systemicsclerosis.' Eighty per cent of digital arteriesstudied showed luminal narrowing of 75% ormore.45 Furthermore, whether the hard redcells, activated platelets, and abnormalities offibrinolysis30 are a cause or consequence of thedamaged endothelium, they contribute furtherto decreased blood flow in the microcirculation(table 3). The combination of vasospasm,narrowed vessels, and blood abnormalitiesproduces a significant clinical problem, whichrequires urgent management.

MILD DISEASEAlthough most patients with systemic sclerosishave severe disease, some patients with mildRaynaud's disease can benefit from simplemeasures. Many patients are apprehensiveabout their disease, reassurance is often re-quired, and information about the self helpgroup, the Raynaud's Association, is oftengratefully received. * If the use of tobacco isstopped, this can produce immediate benefit, ascan a change in occupation. Withdrawal ofdrugs known to be associated with Raynaud'sphenomenon can also be useful. Although thecontraceptive pill has been linked anecdotallywith the development of Raynaud's disease, thishas never been clearly proved in epidemiologicalstudies. It is current practice to stop thecontraceptive pill only if there is a clear linkwith the time of onset of the disease.

Protection from cold is very important. Toachieve this without subscribing to a hermit likeexistence is difficult, but there are practicalsolutions to the problem. Electrically heatedsocks and gloves are, for some, the idealsolution-a rechargeable battery worn roundthe waist provides up to three hours of warmth.The wires are concealed beneath the clothingproviding a normal appearance. Budget re-straints in some health board areas mean thatthese batteries can be difficult to obtain, butthey are very popular with patients, thoughoccasionally irritation of ulcers by the addedheat has been noted. Chemical hand warmersobtainable from local sports shops provide asatisfactory alternative source of heat. 'Comfortshoes' obtainable from surgical appliancedepartments can help the feet of patients with

*Raynaud's and Scieroderma Association Trust, 112 CreweRoad, Alsager, Cheshire ST7 2JA.

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Raynaud's disease-the padded soles relieve thepressure on the toes, which can result invasospasm, and also keep the feet warm.

SEVERE DISEASEDrug treatment of Raynaud's phenomenonremains symptomatic, directed towards thespasm itself or to blood constituents whichcontribute to decreased blood flow.

Vasodilators The use of vasodilators inRaynaud's syndrome remains controversial asmost studies have been uncontrolled. Someencouraging results have been obtained withthese compounds in patients with mild disease.'Patients with systemic sclerosis tend to havemore severe symptoms, and work with vaso-dilators in these patients has been disappointing,however, with side effects being the limitingfactor.

Nifedipine This calcium channel blocker iscurrently the recommended treatment forRaynaud's phenomenon,47 at a starting doseof 10 mg three times a day, which should beincreased gradually to 20 mg three times a day.Its mechanism of action in Raynaud's phenom-enon is predominantly vasodilatory, but it isalso an antiplatelet agent and may have otherpotential antithrombotic effects. The majorproblem with nifedipine is that to obtain asignificant therapeutic effect, intolerable vaso-dilatory side effects may be induced. In addition,it has been suggested that in systemic sclerosissuch profound vasodilatation can have a stealeffect, producing decreased digital blood flow.48Much of the recent research, therefore, hasconcentrated on attenuation of the side effects.Friedman et al recommended a maximum doseof 10 mg three times a day in elderly patientswith concomitant administration of aspirin forheadache relief. 6 As most side effects arerelated to the degree of acute vasodilatation,however, an approach designed to minimisesuch effects should be investigated. A slowrelease preparation is already used by mostclinicians, and Challenor et al demonstratedsignificant benefit in patients given both 10 and20 mg slow release nifedipine preparations(nifedipine retard) twice a day.49 The dose canbe increased to 20 mg of the retard preparationthree times a day.

Prostaglandin infusion The vasodilator anti-platelet prostaglandins, prostaglandin El50 andprostacyclin,5' may also be useful in themanagement of Raynaud's phenomenon. Thesedrugs have to be given by intravenous infusion(prostaglandin El by central line) and thereforerequire at least hospital attendance if notadmission. Side effects of both prostaglandin Eland prostacyclin are related to vasodilatation,but these disappear at the end of the infusion. Itis interesting that the vasodilator antiplateleteffects are short lived, but the duration ofresponse can be up to six weeks. This may beexplained by the beneficial effects of the prosta-glandins on fibrinolysis and white and red bloodcells.52 Unfortunately, these treatments do notcure the patient and repetition of the regimenis required. This means that in practice prosta-glandin treatment is usually reserved for

patients with intractable digital ulceration.More recently, stable prostacyclin analogueshave become available and a recent studyconfirmed the benefit of iloprost (Scheringchemicals) as a treatment for Raynaud's syn-drome complicated by systemic sclerosis.53 Theside effects seen were vasodilatory but occurredonly during the three day infusion. The goodtolerance of this drug prompted Rademaker etal to compare intravenous iloprost with oralnifedipine in Raynaud's syndrome secondary tosystemic sclerosis.54 Both drugs were found tobe effective, but the side effects seen withnifedipine were considered to be more trouble-some. Alternative approaches continue to beinvestigated, such as orally and transdermallyabsorbed stable prostaglandin analogues,55 andthis may allow more prolonged treatment. Thelong term effects of prostaglandins on boneand tumour growth must, however, first beestablished.As prostaglandins are endogenous local hor-

mones, an attractive concept is to stimulateproduction of the body's own vasodilatorprostaglandins by giving the appropriate pre-cursor essential fatty acid. Evening primrose oilcontains the precursor of prostaglandin E1.Study results of evening primrose oil have beensomewhat disappointing, however, and althoughsome subjective improvement has been reported,no objective improvement of blood flow hasbeen shown.56 Further controlled work isrequired. Fish oil contains eicosapentaenoicacid, the precursor of the three series prosta-glandins. Fish oil has been shown to haveantiplatelet and viscosity lowering effects. Thestudy of fish oil by DiGiacomo et al, however,showed that although patients with Raynaud'sdisease apparently benefited from such treat-ment, patients with Raynaud's syndrome failedto improve.57

Ketanserin Ketanserin (Janssen Pharma-ceuticals), a serotonin antagonist with slight a,adrenergic antagonist effects, has been shownpossibly to be useful in the treatment ofRaynaud's phenomenon in a recent large multi-centre study.58 Jay et al showed that ketanserinsignificantly improved the subjective symptomsof patients with both primary and secondaryRaynaud's phenomenon.59 Unfortunately,owing to the multicentre nature of the study,objective tests of blood flow could not bemeasured.

Viscosity fibrinolysis and red cell deformabiliyAt the present time drugs such as low molecularweight dextran or ancrod, a defibrinating agent,have not been conclusively proved to be of usein Raynaud's syndrome. Moreover, they bothrequire parenteral admission and careful patientmonitoring. Stanozolol, an anabolic steroidwhich increases fibrinolysis, has been used inpatients with Raynaud's phenomenon, andearly work suggests some benefit when given ina dose of 5 mg twice a day.59 Side effects arethose usually associated with anabolic steroids,including virilisation of women and increasedactivity of liver enzymes. This treatment istherefore reserved for severely affected men andpostmenopausal women who have normal liverfunction. Results of a large study carried out in

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Others Transdermal application of drugs forRaynaud's phenomenon has proved popularwith patients. Local application of glyceryltrinitrate cream seemed useful, but side effectswere common.' A recent study showed thathexyl nicotinate lotion induced an increase incutaneous flow in patients with Raynaud'sphenomenon after single dosing,6' but no datayet exist about its efficacy in controllingRaynaud's symptoms. There have been a fewreports of uncontrolled studies of the vasodilatoreffects of captopril,62 and, recently, a study ofRaynaud's disease was published.63 Captopril iscontraindicated in renal disease, however, somay not be suitable for Raynaud's syndrome.

ConclusionConnective tissue diseases such as systemicsclerosis often have an insidious onset. Raynaud'sphenomenon may be the first symptom in mostcases. For reasons of prognosis and early diag-nosis and to obtain insight into the patho-physiology of systemic sclerosis it is importantto identify those patients with Raynaud'sphenomenon who will develop a connectivetissue disease. Some clinical information, suchas age of onset of Raynaud's phenomenon, canbe a useful guide as can some abnormalities ofplatelet and endothelial factors. Of most rele-vance, however, is the finding of abnormalnailfold vessels on capillary microscopy and thepresence of antinuclear antibodies in the blood.

Studies of patients with early systemicsclerosis have proved that microvascular changesare likely to play a part in the disease process.Work in this area progresses. The most signifi-cant advances in Raynaud's phenomenonresearch recently have been in its management.Treatments aimed at altering blood coagulationand rheology combined with vasodilator activityseem to achieve the best success, but side effectsremain a problem.

Jill J F Belch is in receipt of grants from the Raynaud'sAssociation and the Sir Jules Thorn Trust.

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