treatment of systemic sclerosis - annals of the rheumatic

Annals ofthe Rheumatic Diseases 1991; 50: 877-886

Treatment of systemic sclerosis

T A Medsger Jr

Similar to other members of the family ofconnective tissue diseases, systemic sclerosis(scleroderma) is a chronic, often disabling, anddisfiguring disease which represents a majorchallenge for both patient and doctor. Thepatient often must contend with fatigue, coldintolerance, pain, deformity and loss of handfunction, and change in facial appearance.These physical changes and limitations result inloss of self esteem and pessimism about thefuture. For these reasons a good relation withthe managing doctor and a strong family supportsystem are extremely important assets for thepatient with scleroderma. The doctor faces thespectre of an unusual and highly variabledisease with no widely recognised effectivetreatment and in which life threatening visceraldisease may appear quickly and withoutapparent warning. Even for the rheumatologist,predicting the natural history of disease in anindividual patient with scleroderma is difficult,and experience with certain complications isvery limited. Thus in many circumstancesconsultation with an expert having both aspecial interest and extensive experience in thedisease is useful.Many vitamins, hormones, pharmaceutical

drugs, and surgical procedures have beenreported to be successful in the treatment ofsystemic sclerosis. Almost all of these treat-ments have been received with great enthusiasmbut later abandoned after more rigorous andcritical scientific evaluation. Too often successhas been claimed solely on the basis of adiminution in subjective complaints-forexample, a reduction in frequency of Raynaud'sphenomenon, which may occur as a placeboeffect with virtually any new treatment, orpoorly documented 'softening' of the skin. Theinfluence of psychological factors on these andmany other symptoms is important. For thesereasons this review focuses only on methods oftreatment which have adequate rationale andmore than a few patients studied. Althoughsome agents may be promising, individualanecdotal reports about their effectiveness aretoo numerous to detail here.

Evaluation of the effectiveness of treatmenthas proved difficult for several reasons relatedto the disease itself.' Systemic sclerosis isvariable in its severity and in its rate ofprogression. Therefore, the classification ofpatients into recognised clinical-laboratorysubsets is important in the design of therapeutictrials. Conversely, interpretation of the resultsof studies in which this precaution was nottaken is facilitated by this knowledge. Forexample, patients with late stage disease should

rarely be entered into clinical trials as improve-ment cannot be expected in those manifestationsthat are the result of far advanced tissue fibrosiswith severe atrophy. Because spontaneousimprovement in the diffuse disease variant oftenoccurs after several years, untreated controlpatients are necessary for comparison to deter-mine whether a therapeutic regimen beingstudied is superior. Finally, there are limitationsin the availability and application of objectivecriteria for ascertaining improvement (ordeterioration) in the condition, particularly withrespect to visceral changes.One recent review is both comprehensive,

including virtually all publications, and critical,yet at the same time fair, in its interpretation ofresults.2 This concise and informative article ishighly recommended as a valuable reference onthe current status of systemic treatment forsystemic sclerosis.

Patient classificationThe most important task of the managingdoctor is to classify each patient into one of therecognised subsets of systemic sclerosis. This ispossible at the time of the initial visit in twothirds of patients and during follow up in over80% of cases. The two most common variantsare those in which there is either diffuse(widespread) or limited (restricted) skininvolvement.3 4 A great deal is known about thenatural history of each of these subtypes; thisinformation is useful, not only in educating thepatient and family, but also in planning followup visits and monitoring laboratory studies.

It is essential to identify diffuse disease asearly as possible, and long before the appearanceof diagnostic truncal skin thickening. This isthe type and stage of scleroderma in whichintervention has the greatest potential to modifythe disease course. The earliest clues to evolvingdiffuse disease include sclerodermatous skinchanges occurring before the patient's report ofRaynaud's phenomenon, capillary 'dropout' onnailfold microscopy, rapid progression of skinthickening proximal to the digits, palpabletendon friction rubs, polyarthritis with handjoint contractures, and serum antibody to Scl-70.' Subjects with this variant are at considerablyhigher risk for the early development of visceralinvolvement, especially renal crisis, myocardialfailure, interstitial lung disease, and gastro-intestinal complications.

In contrast, limited cutaneous disease ischaracterised by prolonged Raynaud's pheno-menon before any skin thickening, non-progressive or only slowly advancing skin

Department ofMedicine, Division ofRheumatology andClinical ImmunologyvSchool of Medicine,University of PittsburghT A Medsger Jr

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changes, prominence of digital telangiectasiasand subcutaneous calcinosis, and the presenceof serum anticentromere antibody. Subjectswith this subtype rarely if ever developmyocardial or renal disease, but are peculiarlysusceptible to the late (after 10 years or more)development of 'primary' pulmonary arterialhypertension (not secondary to interstitialfibrosis), intestinal malabsorption, biliarycirrhosis, and Sjogren's syndrome withvascuhltis.A third group of patients has coexistent

features of systemic sclerosis and polymyositis.At least three serum autoantibody markers havebeen identified (anti-Jol, anti-PM-Scl, andanti-UlRNP), and the clinical syndromesassociated with them have certain distinctivefeatures.

Disease modifying treatmentNo drug (or combination of drugs) has beenproved to be of value in systemic sclerosis inadequately controlled prospective trials or isgenerally accepted as being useful. Perhaps thisis understandable because most of the currentconcepts ofits pathogenesis have been developedonly within the last decade. The main cellularand extracellular participants in this disorderand possible sites for therapeutic interventionare the vascular endothelium, mononuclearcells, fibroblasts, and collagen.5 Rationaltreatment would be designed to (a) preventendothelial cell cytotoxicity by mononuclearcells; (b) alter communication between mono-nuclear cell subsets; (c) prevent mononuclearcell stimulation of fibroblasts; (d) prevent mastcell degranulation; (e) block fibroblast pro-duction of procollagen; and (t) increasesolubilisation of preformed collagen. The cellsand cell products to which such interventionmay be directed, and the types of treatmentavailable today for the connective tissue diseasesin general have been reviewed.6 Patients withdiffuse disease in whom skin thickening isadvancing are prime candidates for diseasemodifying treatment. In contrast, treatment isoptional in subjects who present for initialevaluation after having passed the peak of skinthickening, and in those seen after spontaneousregression of skin changes no systemic treat-ment is indicated.

There has been recent interest in the develop-ment of laboratory tests linked to thesepathogenetic events which may reflect diseaseactivity. For example, preliminary studiessuggest that damage to endothelial cells isreflected by plasma levels of factor VIII-vonWillebrand factor antigen7; activation oflymphocytes is associated with increased serumlevels of soluble interleukin 2 receptors8; andprocollagen production by fibroblasts is followedby increased serum procollagen III peptidebreakdown products.9

Anti-inflammatory agentsAnti-inflammatory drugs and corticosteroidshave been disappointing in systemic sclerosis,perhaps because the inflammatory phase of the

disease gives way rapidly to a fibrotic stage, inwhich such agents would not be expected to beof benefit. Because of their potential toxicitycorticosteroids should be restricted to patientswith inflammatory myopathy or symptomaticserositis. On occasion, refractory arthritis andthe 'oedematous' phase of skin involvementrespond favourably to relatively small doses ofcorticosteroids, such as prednisone 5-10 mg/day.Myositis, however, may require higher doses.After the first two years of diffuse diseasecorticosteroids are seldom indicated and usuallycan be discontinued uneventfully. High dosecorticosteroid treatment may precipitate acuterenal failure, especially of the normotensivetype with prominent microangiopathic haemo-lytic anaemia.'°

Immunosuppressive methodsAs noted above, there is mounting evidence thathumoral and cell mediated' immune abnormal-ities play an important part in the pathogenesisof systemic sclerosis. Consequendy, variousforms of immunosuppression have beenproposed. Several potential beneficial effectscan be suggested, including altered interactionsbetween immunocompetent cells and inhibitionof overactive fibroblasts by soluble mediators. "

Azathioprine (150 mg/day, mean 24 months)was considered beneficial in an uncontrolledtrial, although only eight of 21 patients had skinsoftening and ulcer healing and three discon-tinued the drug because offever. 2 Chlorambucilresults have been mixed.'3 14 A recent threeyear, double blind, controlled trial of chloram-bucil versus placebo in 65 patients with systemicsclerosis was negative.'5 At the doses used(increasing to 0-1 mg/kg daily after one year andremaining the same thereafter) there wasevidence of immunosuppression as the grouptreated with chlorambucil developed significantreduction of the mean absolute lymphocytecount compared with the untreated group. Asin rheumatoid arthritis,'6 late developingmalignancy may be a limiting feature of the useof such alkylating agents.

Apheresis has been advocated,'7 but itseffects are not uniformly beneficial'8 and aredifficult to evaluate because of confoundingimmunosuppressive and corticosteroid treat-ment and lack of controls. Lymphoplasma-pheresis seems to have a better rationale thanplasmapheresis, and a preliminary report wasencouraging.'9 In the latter investigation sixpatients treated with lymphoplasmapheresisand five with plasmapheresis were randomlyallocated to receive pheresis for three monthsand were compared with five untreated controls.The lymphoplasmapheresis group had a signi-ficant improvement in disease 'score' comparedwith the other two groups. Both pheresis groupshad better doctor and patient global assessmentscores, but these re'sults might have beeninfluenced by the single blind design andbecause the doctor was aware of the treatmentgroups. Difficulty with vascular access, localhaematomas and infections, and high costs arelimiting features of this procedure.

Cyclosporin A has been used in a limited

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Treatment ofsystemic sclerosis

number of patients," and higher doses havebeen followed by instances of hypertension andrenal insufficiency, both of which could beattributed to either the drug or scleroderma.Lower doses of cyclosporin may be an importantcompromise, but inadequate numbers ofpatients have been studied thus far. An extensionof a previous study2' includes 16 patients,almost all of whom had diffuse disease. Theyreceived 2 5-5 0 mg/kg daily and have beenfollowed up for an average of 16-8 months. Themean skin thickness score decreased over 40%and a weighted organ score improved from 7-4to 5-7 after one year, but the diffusing capacitywas unchanged. Four patients developed renaldisease, three considered to be due to sclero-derma and one to cyclosporin.

Recombinant interferon gamma, which iscapable of inhibiting collagen synthesis byfibroblasts in vitro,22 has been evaluated in apilot study. It was given in a dose of 100 pg/dayintramuscularly for six months, and the authorsreported significant improvement in skinthickness, several musculoskeletal measure-ments, dysphagia, and creatinine clearancewithout serious toxicity.23

Intravenous 5-fluorouracil was used in anopen trial in 12 patients treated for a mean ofover eight months.24 After initial 'induction'with a total of 8 mg every other day and, later,daily doses of 8-12-5 mg/kg, a weekly main-tenance dose of 10-20 mg was given. Theresults of this uncontrolled study wereencouraging.Renewed interest in the use of methotrexate

in rheumatoid arthritis and polymyositis hasraised the possibility that this drug might beeffective in other connective tissue diseases.Improvement in two patients with systemicsclerosis treated with methotrexate has beenreported,25 and three of the four patients wehave treated for 0 8-2 5 years have had reducedskin thickening (Medsger T A, unpublisheddata).

These preliminary observations would appearto justify a larger pilot study.Two reports of patients with cutaneous

sclerosis (probably diffuse fasciitis) and aplasticanaemia have been published, in which the skinimproved after treatment with antithymocyteglobulin.26 27 In contrast, a small controlledstudy of total lymphoid irradiation was negative,with only transient skin improvement andprogression of oesophageal and interstitial lungdisease.28To date, there is no general agreement on the

effectiveness of immunosuppressive therapy insystemic sclerosis. More information on theabnormal mononuclear cell subsets involved isneeded before specific treatment can bedesigned to regulate them. Nevertheless, theuse of immunosuppressive measures is justifiedin patients with rapidly progressive, lifethreatening or disabling disease, provided thereis informed consent and close surveillance foradverse effects.

CoichicineColchicine can inhibit the accumulation of

collagen by blocking the conversion of pro-collagen to collagen, probably throughinterference with microtubule mediatedtransport,29 or perhaps by stimulation ofcollagenase production.30 Although toxicity isnot a serious limiting factor, only one shortterm, double blind study3' and its subsequentlong term open follow up have suggestedimprovement.32 Nineteen patients (15 withdiffuse disease) were treated for 19-57 monthswith a mean of 10 mg colchicine per week.Seventeen of these patients improved in at leastthree categories of end points, most of whichwere subjective in their reporting or measure-ment. Without a control group these datacannot be interpreted and may represent onlythe natural history of late stage diffuse disease.Several other short term trials of 12-18 monthswere negative,33 34 and in some patientsprogression of skin, musculoskeletal, andpulmonary involvement was reported.33 Thelack of long term controlled studies makesdefmitive conclusions impossible, but the dataavailable to date do not support a role forcolchicine in treating the systemic aspects ofscleroderma.

D-PenicillamineD-Penicillamine is a compound capable ofinterfering with the intermolecular cross linkingof collagen35 and also possesses immuno-suppressive activity. Reports on systemicsclerosis from England,36 Denmark,37 and theSoviet Union38 have been optimistic. In a largeretrospective analysis of patients with diffusescleroderma, with disease duration of less thanthree years, 73 treated patients showed signi-ficantly reduced skin thickness and jointcontractures after 18-30 months compared with45 untreated patients with comparable initialdisease duration and severity.39 Patients treatedwith D-penicillamine also had better survival,owing in part to a considerably lower incidenceof subsequent renal disease. In another reportall of 18 patients with diffuse disease hadimprovement of skin thickening while receivingD-penicillamine, with a mean maximum per-centage of skin surface affected declining from65% to 15% after 4-6 years.'The initial D-penicillamine dose of 250

mg/day (on an empty stomach to enhanceabsorption) is increased every two to threemonths to a maximum of 750 to 1500 mg/day.In these studies most patients with early diffusedisease had progression of skin changes duringthe first six to 12 months of treatment. There-after, the pace of skin thickening diminishedand improvement began. The first areas to clearwere the last to have been affected-that is,central areas, including the trunk, upper arms,and thighs. Regression was often dramatic, withonly sclerodactyly remaining after three to fiveyears of treatment. Late recurrences afterdiscontinuation of the drug have been seen,40and thus continuation of a low maintenancedose (250 mg/day) is recommended in patientswho have improved.The use of D-penicillamine may be accom-

panied by a disturbing plethora of potential side

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effects, including haematological abnormalitiesand a variety of autoimmune problems, such aspemphigus, nephrotic syndrome, a lupus-likeor polymyositis-like illness, Goodpasture'ssyndrome, and myasthenia gravis. Up to aquarter of patients are forced to discontinuethe drug permanently, especially during thefirst three to six months.4' Careful monitoringof white blood cell and platelet counts and ofurine protein are required.

Other drugsN-acetylcysteine may reduce disulphide bonds,thus having an action similar to D-penicillamineon collagen, but a one year randomised, pro-spective double blind study of this agent versusplacebo in 22 patients showed few differences.42Cyclofenil, a weak oestrogenic compound,inhibits sulphate incorporation into proteo-glycan. It has been studied in two placebocontrolled trials of six months' duration withmild but unimpressive improvement in thegroups treated with cyclofenil.43" An opentrial of cyclofenil versus D-penicillamine up totwo years in duration showed no differences.45Hepatotoxicity is a limiting factor.Dimethyl sulphoxide, a commercial solvent,

is a vasodilator, an analgesic drug, and can

alter collagen metabolism. Although a numberof uncontrolled studies and anecdotal reportshave indicated its efficacy, three adequatelycontrolled trials concluded that dimethylsulphoxide is not useful for treatment of skinthickening, digital tip ulcers, or visceraldisease.448p-Aminobenzoic acid has been considered as

a possible therapeutic agent for systemicsclerosis. A large retrospective analysis compared223 patients treated for seven to 26 months withp-aminobenzoic acid and 96 patients treatedwith other drugs."9 Most patients treated withp-aminobenzoic acid showed 'moderate tomarked' skin improvement during follow up,but the time of first observation was biased infavour of p-aminobenzoic acid. On the basis ofthese results, and in the absence of long termcontrolled studies, this drug has not beenproved to be effective.

Vascular protectionCirculating platelet aggregates and plasmaf3 thromboglobulin concentrations are reducedafter treatment with dipyridamole and aspirin,50but a randomised double blind trial of theseagents versus placebo for one to two yearsshowed no significant improvement in thetreatment group.5' Factor XIII may play a partin facilitating collagen clearance by macro-phages as it complexes with fibronectin andcollagen. Two preliminary short term (threeweek) intravenous infusion studies of factorXIII have been performed with encouraging

results for subjective improvement andfunctional capacity."2 5 Rigorously controlledlong term studies should be done.The selective serotonin antagonist ketanserin,

although reported to be effective in thetreatment of Raynaud's phenomenon due to

systemic sclerosis,54 did not alter skin or visceraldisease compared with that of untreatedpatients after a one year trial (unreported). a-Methyldopa with propranolol was likewiseineffective in altering disease during a two yearstudy.55 Because of the dramatic antihyper-tensive effect of captopril in many patients with'renal crisis'56 the angiotensin convertingenzyme inhibitors have been considered as apossible primary treatment for the vascularcomponent of systemic sclerosis. One strategy,as yet untested, would be to treat all patientswith early diffuse disease with one of thesedrugs.Low molecular weight dextran is thought to

decrease red blood cell aggregation and thusreduce blood viscosity. A controlled study ofdextran infusion resulted only in a strongsubjective (placebo) effect on the peripheralcirculation.57 The potent vasodilator prosta-glandins and prostacyclin have been examinedin both uncontrolled and controlled studies.Intravenous infusions of both prostaglandinE258 and carboprostacycin59 appear promisingin reducing the frequency and severity ofRaynaud's phenomenon and in promoting thehealing of ischaemic digital tip ulcers; theirbeneficial effects may be prolonged. Plethysmo-graphic evidence for improvement is lessconvincing. The potent vasoactive substancesreleased when mast cells degranulate arebelieved to be important in fibrosing con-ditions. ' Mast cells have been found in increasednumbers and in a degranulated state in sclero-dermatous skin.6' To this end a mast cellstabilising drug, ketotifen, is being studied in aformal clinical trial.

Supporting measuresAlthough the natural history of systemicsclerosis may be extremely difficult to alter,there are many individual organ system com-plications which can be treated successfully andcan improve the patient's quality of life.

Peripheral vascular systemIn systemic sclerosis Raynaud's phenomenonresults from endothelial cell damage, subintimalthickening, and reduced luminal size with anormal vasoconstrictive response to coldexposure and emotional stress, rather than fromexaggerated vasospasm. Most patients are ableto minimise the frequency and severity ofRaynaud's episodes by avoiding the cold andabstaining from tobacco. Dressing warmly withlayers of clothing on the trunk, using mittens orelectric gloves, and covering the head (a majorsource of heat loss) are important. Biofeedbacktechniques may be helpful in some patients.62

Vasodilating drugs are beneficial only to theextent that severe luminal narrowing of bloodvessels is absent. Thus these agents are moreeffective in Raynaud's disease than in Raynaud'sphenomenon secondary to connective tissuedisorders. As noted above, several promisingnew pharmacological agents have provedhelpful in some patients in double blind studies,including the calcium channel blocker nife-

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dipine, which relaxes vascular smooth muscle63;a selective a, adrenergic receptor antag-onist, prazosinTM; a serotonin antagonistwhich selectively blocks 5-hydroxtryptaminereceptors, ketanserin54; topical nitroglycerine";prostaglandin E2'; and prostaglandin 12 (prosta-cyclin).67 Inhibitors of platelet aggregation maybe added in the hope of preventing the formationor propagation of thromboses, or both.When non-healing digital tip ischaemic ulcers

are present, or there is threatened gangrene, amore aggressive approach is required. Patientsare often admitted to hospital and givenadequate analgesics to control pain. Despite anegative controlled study of intra-arterialreserpine68 we use the available substitute,phentolamine, 1-0 mg into the brachial orfemoral artery once every four to six weeks inthis more pressing circumstance. Intermittentcervical sympathetic blocks with local anaes-thetic, as often as every other day for one to twoweeks, may be a helpful adjunct. Digitalsympathectomy is sometimes recommended,but there are insufficient reports to evaluate thistechnique. Surgical thoracic sympathectomy isnot often recommended in systemic sclerosis asit is typically followed by partial, usuallytransient, improvement in Raynaud's pheno-menon.69 When large vessels are affected-forexample, the radial and ulnar arteries, assuggested by palpation and confirmed byDoppler tests, arteriography should be per-formed because successful microvascularsurgical reconstruction has been reported.70After large digital tip infarctions or gangrenehave occurred, tissue demarcation achieved byautoamputation is preferred. However, if painis severe or bacterial superinfection develops,surgical intervention is indicated.7'

SkinMaintaining adequate skin lubrication isdifficult because thickened collagen 'chokesout' normal sweat and eccrine glands. Patientsare urged to bathe less than daily, to avoiddirect contact with household detergents, and touse lubricating creams (especially those con-taining lanolin). Intense pruritus may lead toexcessive scratching with excoriation. Thissymptom tends to occur early in the course ofdiffuse disease, especially over the forearms,and disappears after months or several years.

Ischaemic digital tip ulcers are protected (asmall plastic 'cage' for the fingertip) andimmobilised. Secondary infection is signalledby abrupt erythema, swelling, and increasedpain, and is almost always due to staphylococcus.Owing to the expected reduced vascularity,intravenous rather than oral administration ofantibiotics is preferred.

Ulcerations over the proximal interphalangealjoints, elbows, and malleoli are most commonlyattributable to both local trauma and ischaemia.Skin over these bony prominences is often thinand atrophic rather than thick. Radiographs areindicated to detect underlying septic arthritis orosteomyelitis, which require a surgical approach.Small ulcers may be managed with half strengthhydrogen peroxide soaks two to three times

daily, followed by gentle local *iebridement.Topical care for larger lesions includes theprotective cover of an occlusive dressing, suchas Duoderm.

CalcinosisAccumulation of calcium deposits in the form ofhydroxyapatite is greatest in sites of excessiveuse or trauma (olecranon, patella) and thoseaffected by Raynaud's phenomenon (fingers,especially palmar surfaces). Calcinosis is parti-cularly common in subjects with limitedcutaneous disease and serum anticentromereantibody, but those with longstanding diffusedisease may also develop extensive calcinosis.72Simple surgical excision can sometimes beperformed, provided the overlying skin is intactand is not infiltrated with calcium, which mayinterfere with wound healing.7' Unfortunately,recurrence is common. When skin breakdownand draining fistulous tracts from deeper levelshave developed, primary wound closure is notpossible. Three deaths in our series wereattributed to septicaemia from infected deepcalcinosis.On occasion there is an intense, sterile,

inflammatory reaction surrounding thesehydroxyapatite deposits, along with con-stitutional symptoms such as low grade fever.This process may be dramatically improved by acourse of oral colchicine 0-5 mg once or twicedaily for seven to 10 days.73 Unfortunately, nodiminution of calcific mass follows this treat-ment.No satisfactory medical approaches to

calcinosis have yet been developed. Chelationand probenecid treatment have failed. Lowdose warfarin anticoagulant (Coumadin 10 to2-0 mg/day) has been advocated in the hope ofinterfering with the y carboxylation of glutamicacid, an amino acid common to the coagulationand calcification pathways.74 7 However, thereis no convincing evidence of the effectiveness ofthis regimen.

Joints and tendonsEarly in disease polyarthralgias, polyarthritis,and tenosynovitis (including carpal tunnelsyndrome) are treated with non-steroidal anti-inflammatory drugs or, occasionally, low dosesof corticosteroids (prednisone 5 07-5 mg/day).Local steroid injections and carpal tunnelrelease procedures are occasionally beneficial.Rarely, inflammatory arthritis dominates thecourse, requiring the addition of a remittiveagent as in rheumatoid disease. In a few unusualcases with diffuse scleroderma, extensive para-articular bony lysis occurs, leaving telescopeddigits and psoriatic arthritis-like 'mutilans'deformities.

Joint symptoms often disappear after two tothree years, but some patients, especially thosewith diffuse disease, are left with significantflexion contractures of the digits. Appropriateearly treatment consists of physical therapy withemphasis on active extension and range ofmotion exercises to preserve all finger jointmotions. Dynamic splinting is not effective inretarding the progression of deformities.76

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Later, should there be severe contracturesleading to more than 90 degrees of proximalinterphalangeal joint flexion, fusion of thesejoints in 45 degrees of flexion with shortening isoften recommended.7' The result is a straighter,more cosmetically appealing finger position andreduced disability from traumatic ulcerations,but hand function may not improve. Proximalinterphalangeal joint replacement arthroplastieshave also been performed with improvement inboth hand function and appearance.77 Thesesurgical approaches are usually elective ratherthan urgent, but if septic arthritis with osteo-myelitis develops there is little choice but to use

intravenous antibiotics, to excise infected anddevitalised tissue promptly, and to fuse thejoint.

MuscleMost patients with systemic sclerosis have a

bland myopathy with increased perimysial andepimysial connective tissue deposition butwithout evidence of inflammation. Muscleshortening and contracture may result, but are

usually mild. A daily physical therapy pro-

gramme emphasising full range of motion of all

large joints should be prescribed.Some patients with scleroderma have an

overlap with polymyositis, in which the typicalsigns of muscle inflammation are present. Thesesubjects should be treated with corticosteroids,using prednisone (up to but not exceeding 20mg/day) alone or in combination with metho-trexate, azathioprine, or another immuno-suppressive agent.

Gastrointestinal tractMOUTHMaintaining oral hygiene may be difficultbecause of limited access, hand deformities,loose teeth related to loss of lamina dura, andaccelerated dental caries due to associatedSjogren's syndrome. Regular visits to a dentistfor prophylaxis, a long-handle tooth brush, andmouth stretching exercises are recommended.78For edentulous subjects with microstomia a

flexible prosthesis has been designed toaugment the exercise programme.79 Rarely,surgical resection of perioral fibrotic tissues isindicated. Another recognised cause of limitedoral aperture amenable to surgical repair is bonyerosion of the mandibular condyle at thetemporomandibular joint.80 Patients shouldlearn to chew food thoroughly and to avoidthose foods that are likely to cause substernaldysphagia-for example, meat and bread.

OESOPHAGUSTwo available prokinetic drugs may improveoesophageal motor function-metoclopramide5-10 mg 15 minutes before meals and atbedtime8' and cisapride.82 Both are effectivebut only if oesophageal smooth muscle is notseverely atrophic or replaced by fibrous tissue.Nifedipine causes both vascular and intestinaltract smooth muscle relaxation, and whileimproving Raynaud's phenomenon, it may

simultaneously worsen pre-existing oesophagealhypomotility and symptoms of reflux oeso-phagitis.83 In this circumstance diltiazem maybe a safer vasodilator.84Symptoms of reflux oesophagitis should be

eliminated to minimise acid damage of the distaloesophageal mucosa, a cause of bleeding, and toprevent oesophageal stricture and Barrett'schanges, the latter predisposing to oesophagealcarcinoma. Appropriate antireflux measuresinclude maintaining an upright position duringand after eating, avoiding large meals and foodbefore bedtime, raising the head of the bed onblocks, taking antacids 45 to 60 minutes aftermeals and at bedtime, and using histamine 2(H2) receptor blocking drugs and mucosalcytoprotective agents-for example, sucralfateslurry I10 g before meals and at bedtime. Ifsymptoms cannot be adequately controlled,direct visualisation by upper endoscopy isperformed to detect distal oesophageal ulcera-tion, candidiasis, or other unexpected orunrelated disease. Stricture, should it occur,generally requires periodic dilatation. Althoughthese outpatient procedures are usually welltolerated, they should not be consideredroutine, as oesophageal perforation or excessivebleeding may result. Successful excision ofstrictures and elimination of gastro-oesophagealreflux by a variety of surgical procedures havebeen reported,85 86 but there is a high rate ofrecurrence. Partial oesophagectomy with shortsegment colon interposition may eliminatestricture, but the colon itself is often affected byscleroderma.

SMALL INTESTINEPrimary small bowel involvement with markedatrophy and fibrous replacement ofthe intestinalmusculature leads to gross abdominal disten-sion, diarrhoea, weight loss, and a malabsorptionsyndrome. When such changes are evident fromplain radiographs or clinical information,barium studies should be avoided because theymay cause life threatening impactions, andcalcium channel blockers should be used withgreat caution as they may worsen small bowelmotility. Metoclopramide is of theoretical butlittle practical benefit.87Temporary improvement in steatorrhoea can

be achieved after the administration of anti-biotics, which reduce proximal small intestinalovergrowth of micro-organisms interfering withthe absorption of fats and fat soluble vitamins.Empirically, broad spectrum agents, such asampicillin, tetracycline, co-trimoxazole, andmetronidazole, are given, usually in two to threeweek courses, and then rotated, including atime with no antibiotics. A more accurate choiceof antibacterial agents requires quantitativeaerobic and anaerobic cultures of duodenalcontents obtained by upper endoscopy.Replacement of calcium and fat solublevitamins, iron, vitamin B-12, and use ofmedium chain triglycerides and protein supple-mentation also may be necessary. Ultimately,complete or partial parenteral hyperalimentationwill be required.88 With careful attention tosterile technique, venous access may be main-

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tained for two or more years,89 but the risk ofsepticaemia is high and premature death is therule.Abdominal bloating and episodes of pseudo-

obstruction from adynamic ileus are frequent.Radiographs may suggest a focal, segmentalproblem, and it is often tempting (but dangerous)to consider an exploratory laparotomy. Mani-pulation of the sclerodermatous bowel oftenresults in prolonged ileus, and thus con-servative intraluminal decompression ispreferable. Partial bowel resection is rarelyindicated as the disease is almost alwaysgeneralised and recurrence is the rule. Pneuma-tosis cystoides intestinalis results from dissectionof luminal gas into the bowel wall. Thiscondition is typically benign, but may result in asterile pneumoperitoneum, which should betreated conservatively with bowel decom-pression, supplemental nasal oxygen, andintravenous antibiotics to reduce excessive gasformation by intestinal micro-organisms.

COLONThe most common symptom of large intestinalhypomotility is constipation, which is treatedsuccessfully with stool softeners and increaseddietary bulk to stimulate emptying. Anorectalmuscular incompetence results in rectal seepageand prolapse, which are uncommon but may beincapacitating and uncorrectable. Pessaries havebeen designed but often become dislodged.Several surgical procedures have been proposed,but the tissues involved are atrophic and aredifficult to suture. A perineal approach isfavoured because intra-abdominal surgery oftenresults in ileus.9 Wide mouthed sacculations ofthe colon are asymptomatic, but rarely mayperforate and cause a diverticular abscess orgeneralised acute bacterial peritonitis.

LungAcute, symptomatic pleuritis is treated withnon-steroidal anti-inflammatory agents and,rarely, corticosteroids are required. It is likelythat a chronic inflammatory process (macro-phages, lymphocytes) precedes and influencesthe development of pulmonary interstitialfibrosis. If such inflammation is detected (bygallium scan, bronchoalveolar lavage, or openlung biopsy), and if pulmonary function isdeteriorating, intervention is indicated. Forexample, if high cell counts are found on lavage(>20 million cells per millilitre), especially withan increased proportion of lymphocytes(>10%), concomitant treatment with high dosecorticosteroids (prednisone 60 mg/day) and anyone of several immunosuppressive drugs may bejustified.9 D-Penicillamine has been shown intwo studies to retard progression of lung diseasein treated compared with untreated patients,92 93but the changes noted may be more statisticallythan clinically significant. All patients withinterstitial fibrosis are at increased risk frombacterial pneumonitis; they should be protectedwith influenza and pneumococcal vaccines andtreated promptly and vigorously with antibioticsif bronchitis or pneumonia develops.

Secondary pulmonary arterial hypertensioncan result from longstanding pulmonary fibrosisand is usually low grade and slowly progressive.Far more ominous is the development of'primary' pulmonary hypertension, whichoccurs in a small proportion (5%) of patientswith limited cutaneous changes, is acceleratedin pace, and almost uniformly fatal after two tofour years. Rapidly worsening exertionaldyspnoea (over several months) and severelyreduced diffusing capacity for carbon monoxideare clues to this diagnosis before evidence ofright ventricular dysfunction. Vasodilators areineffective as the problem appears to be non-inflammatory subintimal proliferation ofarteries and arterioles rather than vasospasm.94Care should be taken to exclude multiplepulmonary emboli and association with anti-cardiolipin antibody; both of these underlyingconditions may be stabilised by the use ofanticoagulation. Late in the course of primarypulmonary hypertension there is often hypoxiawith minimal exercise or at rest and anginal-likesubstemal chest pain or sudden death due toventricular arrhythmia. Supplemental oxygen isneeded both at night and during daytimeactivities. Single lung or heart lung trans-plantation is a theoretical option which has notas yet been pursued in patients with systemicsclerosis.

HeartAcute pericarditis is unusual in systemicsclerosis, but is treated with non-steroidal anti-inflammatory drugs or, if necessary, withcorticosteroids in standard doses. Pericardio-centesis is rarely required for impending oractual tamponade.

Myocardial involvement is almost always dueto widespread fibrosis, which leads to leftventricular hypokinesis and congestive heartfailure. There is some speculation that repeatedepisodes of coronary arterial spasm maycontribute to myocardial fibrosis. The clinicalrole of vasodilators, such as calcium channelblockers, is unproved, but it has been shownthat pretreatment with nifedipine can preventthallium perfusion defects after cold chal-lenge.95 Ventricular, nodal, and supraventriculararrhythmias may be extremely difficult tocontrol and can be fatal. As in other cardio-myopathies there is increased sensitivity todigitalis, and greater reliance is placed ondietary sodium restriction and diuretics.Myocarditis is rare in scleroderma, and has beenreported only in association with polymyositisaffecting skeletal muscle; here corticosteroidtreatment is clearly indicated.

Secondary causes of heart disease includc leftheart failure due to 'renal crisis' with malignantsystemic arterial hypertension or right heartfailure due to one of the several pulmonaryproblems discussed above. In these instances,treatment of the primary problem is indicated,if possible.

KidneyNew, potent antihypertensive drugs andimproved dialysis procedures and care have

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dramatically reduced mortality in sclerodermarenal disease.' In particular, the angiotensinconverting enzyme inhibitor captopril is thedrug of first choice. However, even moreimportant than treatment is anticipation. It iscrucial to identify the patient at high risk, whogenerally has rapidly progressive, diffusecutaneous disease of less than three years'duration.97 Although most of these subjectsalready have affected truncal skin, some veryearly in disease have more limited but alsorapidly increasing skin changes and oftenpalpable tendon friction rubs. These patientsmust be followed up closely for the developmentof symptoms (headache, blurred vision) or signs(hypertension, proteinuria, azotaemia, or micro-angiopathic haemolytic anaemia) which heraldrenal disease. Any patient classified as havingdiffuse disease, who has the onset of arterialhypertension during the course of scleroderma,should have stimulated plasma renin levelsobtained and, if these are increased should begiven an angiotensin converting enzymeinhibitor.98 It is rare that blood pressure cannotbe controlled by captopril alone or in com-bination with other agents, such as minoxidil,hydralazine, or propranolol.9 100

Unfortunately, a number of patients haveprogressive renal insufficiency and ultimatelyrequire dialysis despite prompt and completeblood pressure control. Poor vascular access andreduced peritoneal clearance have been claimedto be limitations of haemodialysis and peritonealdialysis, respectively, but in our experiencethese problems are not common. A number ofpatients continuing treatment with captoprilhave been able to discontinue dialysis after fourto 15 months,'0' an occurrence virtuallyunheard of before the availability of angiotensinconverting enzyme inhibitors. If no return ofrenal function occurs after 18-24 months, renaltransplantation should be considered as in manyinstances it has been performed successfully. 102

SummaryProper classification of patients into diffusecutaneous and limited cutaneous subsets andthe anticipation of complications are the keys tothe management of subjects with systemicsclerosis (scleroderma). Patients with earlydiffuse disease and rapidly progressive skinthickening are at highest risk of developingserious disease of the internal organs (intestine,lung, heart, kidney) and should be consideredfor disease modifying treatment. The targets ofthe disease and sites of possible intervention arevascular endothelium (vasoprotective agents),mononuclear cell subsets (immunosuppressiveagents), and fibroblasts (colchicine, D-penicil-lamine). A number of new agents with soundscientific rationale are currently undergoingtherapeutic trials. Much can be done to improvethe lifestyle of those with scleroderma. Themost dramatic recent development is the abilityto reverse kidney disease by the prompt use ofangiotensin converting enzyme inhibitors andmodern methods of renal dialysis and trans-plantation. Scleroderma is not a hopelessdisease.

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