Decreased Nailfold Capillary Density in Limited Scleroderma with Pulmonary Hypertension. and a longer disease duration. 3,4

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1 j : , t j f ASAN PACFC JOURNAL OF ALLERGY AND MMUNOLOGY (1998) 16: Decreased Nalfold Capllary Densty n Lmted Scleroderma wth Pulmonary Hypertenson t r Yang Y. Ong, Tony Nkoloutsopoulos, Coln P. Bond, Malcolm D. Smth, Mchael J. Ahern and Peter J. Roberts-Thomson t t Progressve Systemc Scleross (sclerodenna) s an lulcommon systemc autommune dsorder charactersed by skn scleross, mcrovascular abnormaltes and the presence of certan autoantbodes. 1 There are three clncal varants of sclerodenna. The lmted fonn s charactersed by Raynaud's phenomenon, oesophageal dysmotlty, sclerodactyly and telangectasa, and s frequently assocated wth the presence of ant-centromere antbodes. 2 n contrast the dffuse fonn of sclerodenna nvolves wdespread skn nvolvement of both proxmal and dstal extremtes and frequent vsceral fbross often assocated wth Scl-7 antbodes? Fnally, the thrd group s the overlap varant where patents present wth Raynaud's phenomenon, swollen fngers wth small jont synovts and addtonal features of other connectve tssue dsease (eg. polymyosts, SLE etc).3 Of all three types of scleradenna, the majorty of patents have the lmted fonn wth a later age of onset than those wth dffuse dsease SUMMARY Approxmately 2% of patents wth the lmted form of scleroderma wll develop pulmonary hypertenson whch s generally a late stage fatal complcaton. Why pulmonary hypertenson occurs n ths subset of patents s unknown and t has not been possble to predct whch patents are at rsk. Nalfold capllary dlataton, dstorton and drop occurs unversally n patents wth scleroderma and s generally an early fndng. The present study was conducted to nvestgate whether quanttatve nalfold capllaroscopy could dstngush those lmted scleroderma patents who have establshed pulmonary hypertenson. Quanttatve nalfold capllaroscopy was performed by Vsual mage Analyss n 1 healthy subjects and 2 patents wth lmted scleroderma (18 centromere +ve), of whom 8 had establshed pulmonary hypertenson. t was found that scleroderma patents wth pulmonary hypertenson had a sgnfcant reducton n capllary densty compared wth patents lackng ths complcaton (p <.1). Patents wth scleroderma have sgnfcantly more dlated capllares than controls although no sgnfcant dfferences were observe between the two patent subgroups. The fndng of reduced nalfold capllary densty n scleroderma patents wth establshed pulmonary hypertenson has possble pathogenc sgnfcance and may allow detecton of ths subgroup at an early stage n ther dsease progresson. and a longer dsease duraton. 3,4 Lmted sclerodenna s assocated wth a number of complcatons. These nclude prmary pulmonary hypertenson generally n the absence of ntersttal llulg dsease. Prmary pulmonary hypertenson occurs n approxmately 2% of patents wth lmted sclerodenna and carres a very poor prognoss wth a two-year survval rate of 4%. S Snce there s now effectve treatments for prmary pulmonary hypertenson, there s a need to try and dentfy ths complcaton n the early stages of the dsease for therapeutc nterventons. From the Department of mmunology, Allergy and Arthrts, Flnders Medcal Centre, Adelade, South Australa, 542. Correspondence: Peter J. Roberts-Thomson [

2 82 ONG, ET AL. t s known that abnormal- performed on the rng fnger of each tes n nalfold capllares occur un- hand. Ths s because the 4th and versally n all subsets of scleroder- 5th dgts have prevously been rna. These abnormaltes nclude shown to have the longest caplcapllary dlataton, angogeness, lares and the most promnent capbushy formaton as well as capllary llary venous plexus. 9 The capllary destructon and dropout. 6,7 Prevous studes have examned the relatonshp between dsease duraton and capllary loss or enlargement. They found that there was no sgnfcant correlaton between dsease duraton and capllary loss or enlargement but these studes have been qualtatve n nature. 8 Ths present study ams to quanttatvely measure the relatonshp between dsease duraton and capllary loss or enlargement n patents wth lmted scleroderma wth and wthout pulmonary hypertenson usng our recently descrbed technque of vdeo mage analyss. 7 abnormaltes are also most promnent n the dstal capllary row. The capllares were vsualsed by a Mcro-Orent mcroscope wth 6 x magnfcaton. Cold lght was provded by Euromex Fbre Optc lght source. A Sony CCD Colour Camera was attached to the mcroscope and was lnked to a NEC MultSync 3 FG computer. To vsualse the capllares a drop of mcroscope ol was placed on the nalbed to reduce the refractve error. The capllares were then dgtalsed on the Vdeo Pro software. A mnmum of 4 mages were captured of each fnger. MATERALS & METHODS Measurements were calbrated accordng to a bopsy ruler and were Patents and' controls measured n mcrometres. Vdeo Ten healthy subjects were mage Analyss technque was then recruted from the laboratory staff used to analyse the data. of Flnders Medcal Centre as controls. Mean age ofthe subjects was 35 years old. Twenty patents wth scleroderma were recruted from the South Australan Scleroderma Regster. Patents were chosen f they had lmted scleroderma, postve ant-centromere antbody status and lved wthn the vcnty of Flnders Medcal Centre. Of these, eght patents had pulmonary hypertenson as confrmed clncally and wth echocardography and/or catheter studes. Patents were contacted by telephone and were asked to come to Flnders Medcal Centre for nalfold capllaroscopy. N alfold mcroscopy and vdeo mage analyss Nalfold capllaroscopy was Capllary dameter was taken to be the maxmum wdth of the loop. Only well vsualsed capllares were measured. A mnmum of 6 mages were analysed n each subject. Mean capllary dameter was then calculated for each subject. Capllary densty was measured by countng well vsualsed capllares on a mnmum of 6 mages per patent. The capllares were marked and counted. An average number of capllares was calculated for each subject. Data analyss All data are presented as +/- standard devaton. Statstcal analyss was performed usng the Wlcoxon Rank Sum test. Dfferences were consdered sgnfcant when the null hypothess had a probablty less than.. Determnng dsease duraton To determne f there s a correlaton between duraton of dsease and capllaroscopc fndngs, duraton of dsease was plotted aganst capllary sze and densty. Duraton of dsease was taken from the frst onset of Raynaud's phenomenon. Correlaton between the varables was determned by lnear regresson. RESULTS Patent demographc detals are shown n Table 1. There were 2 patents wth lmted scleroderma, 18 females and 2 males, of whch 8 females had establshed pulmonary hypertenson. Of the 2 patents, 18 were centromere antbody postve. Capllary dameter There s a sgnfcant dfference n the capllary dameter between healthy controls and patents wth scleroderma (p <.1). There s about a threefold ncrease n the capllary dameter n patents wth scleroderma. Although capllary enlargement does occur n the majorty of patents, there are patents wth normal capllary dameter. There s however no sgnfcant dfference n the sze of the capllares between the two patent subgroups (Fg. 1). Capllary densty There s a sgnfcant reducton n the number of capllares n patents wth scleroderma as compared wth the control group (p <.1). There s also a sgnfcant de

3 J NALFOLD CAPLLAROSCOPY N SCLERODERMA 83 Table 1 Clncal and demographc detals of study populaton -; Healthy Controls Scleroderma v.fthout pulmonary hypertenson Sclerodenna v.fth pulmonary hypertenson Nwnber of patents Age (years) Female:Male 7:3 1:2 ACA postve o 12 8: 6 Dsease duraton (years) Capllary dameter (lm) ± ± ± 1.84 Capllary count (no,o.5 mm) ± ± ± 1. 8 Fg E 5.=: ff q; E ro 4 (5 c: ~ '6. ro 3 () 2 1 Controls Scleroderma wthout Scleroderma wth n = 1 Pulmonary Hypertenson Pulmonary Hypertenson n =12 n=8 Normal nalfold capllary dameter n healthy controls and patents wth scleroderma. ;

4 84 ONG, ET AL P <.1 8.?: 6 c (j) - > ~ 4 '. <1l - L.. t U Controls Scleroderma wthout Scleroderma wth n =1 Pulmonary Hypertenson Pulmonary Hypertenson n =12 n=8 Fg. 2 Normal nalfold capllary densty n healthy controls and patents wth scleroderma, 8 wthout pulmonary hypertenson wth pulmonary hypertenson E 2 D u; 4 E <1l ~o a ::; Duraton of Raynaud's Phenomenon Fg. 3 Correlaton between capllary dameter and dsease duraton n patents wth scleroderma,

5 NALFOLD CAPLLAROSCOPY N SCLERODERMA 85 t f Fg. 4 Correlaton between capllary densty and dsease duraton n patents wth scleroderma. t crease n capllary densty n those patents wth pulmonary hypertenson compared wth those patents wthout pulmonary hypertenson (p <.1) (Fg. 2). CorrdaDon be~een duradon of dsease and capllary dameter There s no sgnfcant correlaton between capllary dameter and duraton of the dsease. Normal capllary dameter occurs both n early and long standng dsease. Capllary dlataton may occur n early dsease, however, marked dlataton tends to occur n long standng dsease (Fg. 3). CorrdaDon be~een duradon of dsease and capllary densty There s no sgnfcant correlaton between dsease duraton and capllary densty. Normal numbers of capllares can be preserved late n the dsease, however t appears that the most severe capllary dropout tends to occur n long standng dsease (Fg. 4). DSCUSSON Past studes have shown that n patents wth scleroderma, there s sgnfcant capllary dlataton and dropout?,7 Ths study confrms the fndngs from prevous studes. There s approxmately a threefold ncrease n the sze of capllares n those wth scleroderma compared wth the normal populaton. From our study, we have shown that capllary enlargement occurs n patents wth lmted scleroderma, wth and wthout pulmonary hypertenson. There was however no correlaton between capllary enlargement and the presence of pulmonary hypertenson. Capllary enlargement also had no sgnfcant relatonshp to dsease duraton, as shown n prevous studes although we noted that marked enlargement seldom occurred n early dsease. Of partcular nterest was the fndng of the sgnfcant reducton n capllary densty whch occurred n those patents wth pulmonary hypertenson compared wth those wthout pulmonary hypertenson. Ths suggests that the same mmunologcal process s responsble for the capllary loss n both the lungs and the nalfold. However, capllary dropout was not lmted to those patents wth pulmonary hypertenson. t was also seen n patents wth long standng dsease (> 1 years) and occurred less severely n early stage dsease. t would be of nterest to follow those patents wth capllary dropout wthout pulmonary hypertenson prospectvely to see f capllary dropout was a predctor of lung pathology. n concluson, we have shown that n the subgroup of patents wth lmted scleroderma wth pulmonary hypertenson, there appears to be sgnfcant reducton n capllary densty, n excess of that seen n patents wthout lung dsease. t s possble that the same mmunologcal mechansms respon- t f

6 86 ONG, ET AL. sble for the nalfold changes are REFERENCES D. Pulmonary vascular aspects of responsble for the damage n the systemc scleross. Aust NZ Med pulmonary vascular bed. Nalfold 1. LeRoy EC, Black CM, Fleschmajer R 1996; 26: et al. Scleroderma (systemc sclero- 6. Carpenter PH, Marcq HR. Mcrovascapllaroscopy may therefore be a ss). Classfcaton, subsets and patho culature n systemc scleross. Rheum useful technque to assess future geness. Rheumatol1988; 15: Ds Cln North Am 199; 16: patents for possble development of 2. Scleroderma. n: Bradley, McClus 7. Chandran G, Smmons L, Cheng G et pulmonary hypertenson. key, eds. Clncal hrummology. Ox- al. The abnormaltes of nalfold caplford: Oxford Unversty Press, lares n scleroderma as assessed by 3. Chandran G, Smth M, Ahem M, vdeo mage analyss and photomcro Roberts-Thomson P. A study of scle scopy. Asan Pacfc Allergy mmu ACKNOWLEDGMENT roderma n South Australa: Preva no11996; 14: lence, subset characterstcs and nal 8. Lovy M, MacCarter D, Stegerwald We would lke to thank fold capllaroscopy. Aust NZ Med C. Relatonshp between nalfold Paul Stoll for provdng help wth 1995; 25: capllary abnormaltes and organ the Vdeo mage Analyss, Mechell 4. Bond C, Ple KD, McNel 1 et al. nvolvement n systemc scleross. South Australan Scleroderma Regs Arth Rheum 1985; 28: Barker for expert secretaral help ter: Analyss ofdeceased patents. Pa 9. Marcq HR, Maze C. Nalfold capland all patents who partcpated n thology (n press). lary abnormaltes. Cln Rheum Ds ths study. 5. Wallrnan LL, Penny R, Wllamson 1982; 8(2):